The Multifaceted Roles of Proline in Cell Behavior

Abstract

Herein, we review the multifaceted roles of proline in cell biology. This peculiar cyclic imino acid is: (i) A main precursor of extracellular collagens (the most abundant human proteins), antimicrobial peptides (involved in innate immunity), salivary proteins (astringency, teeth health) and cornifins (skin permeability); (ii) an energy source for pathogenic bacteria, protozoan parasites, and metastatic cancer cells, which engage in extracellular-protein degradation to invade their host; (iii) an antistress molecule (an osmolyte and chemical chaperone) helpful against various potential harms (UV radiation, drought/salinity, heavy metals, reactive oxygen species); (iv) a neural metabotoxin associated with schizophrenia; (v) a modulator of cell signaling pathways such as the amino acid stress response and extracellular signal-related kinase pathway; (vi) an epigenetic modifier able to promote DNA and histone hypermethylation; (vii) an inducer of proliferation of stem and tumor cells; and (viii) a modulator of cell morphology and migration/invasiveness. We highlight how proline metabolism impacts beneficial tissue regeneration, but also contributes to the progression of devastating pathologies such as fibrosis and metastatic cancer.

Introduction

In 1900, Richard M. Willstätter reported the synthesis of (S)-pyrrolidine-2-carboxylic acid, better known as L-Pro. Town (1928) reported the purification of L-Pro from gliadin proteins, and Levine (1959) reported that nitrous acid destroys all amino acids apart from L-Pro in hydrolyzed gelatins, and highlighted its unusual structure. L-Pro is a small (115.13 g/mol), cyclic, non-polar, non-toxic, odorless, sweet-tasting imino acid, with unique physicochemical proprieties and numerous biotechnological applications (Figure 1). For instance, acting as an enantioselective organocatalyst, L-Pro makes possible the synthesis of therapeutically active enantiopure drugs (Table 1). Moreover, acting as a chemical chaperone, L-Pro can prevent protein aggregation/fibrillation, and is therefore used to stabilize monoclonal antibodies, to generate protein crystals (Table 1), and for the cryopreservation of biological specimens, including stem cells and oocytes (Table 1). Due to its peculiar cyclic structure, its metabolism relies on specific enzymes. For instance, in mammalian cells L-Pro is synthesized from L-glutamate in a two-step intramitochondrial process catalyzed by aldehyde dehydrogenase 18 family member A1 (ALDH18A1) and pyrroline-5-carboxylate reductase 1 (PYCR1) enzymes (Figure 1), whereas it is oxidized to L-glutamate in a two-step intramitochondrial process catalyzed by proline dehydrogenase (PRODH) and pyrroline-5-carboxylate dehydrogenase (P5CDH) enzymes (Figure 1).

FIGURE 1

Proline in Extracellular Matrix Production

L-Proline residues constitute nearly 6% of the human proteome, mainly concentrated in L-Pro-rich proteins, with up to 1 × 10⁴L-Pro-rich motifs/stretches occurring in 1.8 × 10⁴ human proteins (Morgan and Rubenstein, 2013; Mandal et al., 2014). In addition to a high L-Pro content (up to 50% of total residues), L-Pro-rich peptides/proteins share extracellular localization (secreted proteins), a dedicated translation factor (EIF5A), and a requirement for timely L-Pro-tRNA loading (Doerfel et al., 2013; Gutierrez et al., 2013; Wu et al., 2020; Faundes et al., 2021). Free L-Pro is derived from dietary sources (animal collagens or vegetable extensins) or from de novo biosynthesis (Figure 1), which relies on mitochondrial generation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) (Tran et al., 2021; Zhu et al., 2021). Why so many extracellular proteins are rich in L-Pro is a fascinating question; L-Pro residues destabilize α-helices and β-sheets protein secondary structures, enables turns and poly-Pro helices, and are major ‘disorder-promoting’ residues in intrinsically disordered proteins (Theillet et al., 2013; Alderson et al., 2018; Mateos et al., 2020).

Matrix Collagens

Collagens constitute ∼30% of total human proteins (Smith and Rennie, 2007), and are secreted by cells of CTs such as bone, cartilage, tendon, ligament, and interconnected fluid-filled CTs (Benias et al., 2018) that support and connects all other tissues (epithelial, muscular, etc.). Collagen synthesis is highly dependent on L-Pro availability (∼170 μM in plasma) (Psychogios et al., 2011), and inherited mutations in ALDH18A1 or PYCR1 (de novoL-Pro biosynthesis) are a cause of abnormal CT development (Table 2). Extrinsic (dietary) L-Pro is essential during adult life to preserve bone density in a mice model of osteoporosis (Nam et al., 2016), collagen deposition in rats, pigs, chickens and fish (Li and Wu, 2018; He et al., 2021), and L-Pro homeostasis in humans (Jaksic et al., 1990; Bertolo and Burrin, 2008).

Antimicrobial Peptides

L-Proline-rich antimicrobial peptides (PrAMPs), involved in innate immunity, are the first line of defense against infections (Graf and Wilson, 2019), and they contain up to 50% L-Pro residues, and are secreted by insects, crustaceans and mammals (Table 3; Mishra et al., 2018). Mechanistically, PrAMPs are channeled by the peptide antibiotic transporter SbmA into the bacterial cytoplasm (Mattiuzzo et al., 2007; Runti et al., 2013), where they bind ribosomal proteins and inhibit protein synthesis (Figure 2 and Table 3; Graf et al., 2017; Graf and Wilson, 2019; Baliga et al., 2021).

FIGURE 2

Salivary Proteins

Unstructured L-Pro-rich salivary proteins (PRPs) contain up to 40% L-Pro residues and account for ∼70% of total proteins in human saliva (Messana et al., 2015; Lorenzo-Pouso et al., 2018). The acinar cells of parotid and submandibular salivary glands synthesize and secrete acidic (aPRP) and basic (bPRP) proteins (Figure 2). While aPRPs bind calcium and protect the tooth surface, bPRPs bind polyphenols/tannins inducing the astringency sensation that influences diet selection (Canon et al., 2021; Dufourc, 2021). Since tannins induce ER stress and ATF4 expression (Nagesh et al., 2018), and since ATF4 in turn induces the transcription of L-Pro biosynthesis genes (ALDH18A1 and PYCR1) (Han et al., 2013; D’Aniello et al., 2015; Gonen et al., 2019), it is tempting to hypothesize that a neutralizing response axis (ER stress→ATF4→L-Pro biosynthesis→PRP synthesis/secretion) can be induced by tannins in salivary glands.

Cornified Cell Envelope

Skin is the largest organ of the human body, and it protects internal tissues/organs from water and heat loss, physicochemical insults (e.g., UV light), and microbial attack. Cornifins (or SPRRs) are cross-bridging L-Pro-rich proteins of the cell envelope (Marvin et al., 1992; Steinert et al., 1998a,b), a 5–15 nm thick layer of proteins deposited in epidermis corneocytes (Figure 2). Cornifins are markers of psoriasis syndrome (Luo et al., 2020) and are induced in some tumors (Deng et al., 2020; Sasahira et al., 2021).

Cell Wall Proteins

The extracellular space in plants and algae contains up to 10% dry weight of hydroxyproline (L-Pro-OH)-rich glycoproteins (HRGPs) such as extensins (Showalter, 1993; Lamport et al., 2011), in which L-Pro-OH constitutes up to 30% of total amino acids (Kieliszewski and Lamport, 1994). Besides being structural pilasters, HRGPs are involved in (i) tissue/organ development (embryo, xylem, pod, root hairs, pollen) (Wu et al., 2001; Velasquez et al., 2011; Ogawa-Ohnishi et al., 2013), (ii) a defense mechanism against environmental stress (heat stress, mechanical wounding and bacterial infection) (Francisco and Tierney, 1990; Zhang et al., 2021b), and (iii) an oxygen barrier in the parenchyma of nitrogen-fixing legume root nodules (nodulins) (Scheres et al., 1990; Sherrier et al., 2005). HRGP synthesis requires free L-Pro, and plants respond to pathogen attack by inducing L-Pro accumulation and HRGP synthesis (Fabro et al., 2004).

Proline in Energy Provision

Cells obtain energy/ATP through oxidation of glucose, fatty acids or L-glutamine. However, some cells obtain energy via oxidation of L-Pro in a three-step process (see Figure 3) that converts L-Pro into α-KG, a Krebs cycle intermediate (Tanner et al., 2018). Up to 30 ATP equivalents per L-Pro molecule can sustain the growth of dissimilar cell types, from bacteria to insect muscle cells and human cancer cells (Servet et al., 2012; Nishida et al., 2016). Of note, human genetic defects in L-Pro oxidation are not associated with any developmental deficiency, suggesting that any normal cell type in the human body is strictly reliant on L-Pro energy.

FIGURE 3

Cancer Cells

Pancreatic and mammary tumor tissues are full of collagens, providing a large reservoir of free L-Pro (Linder et al., 2001; Barcus et al., 2017). Prolyl-specific peptidases are induced in cancer cells and can release L-Pro-rich peptides and free L-Pro in their microenvironment by degrading ECM collagens (Figure 3; Pure and Blomberg, 2018). For instance, free L-Pro is accumulated in esophageal carcinoma tissue, where it reaches significantly higher levels than in neighboring normal tissues (Sun et al., 2019). Free L-Pro is transported inside cancer cells, where it can be used for anabolic and catabolic purposes. Indeed, PDAC cancer cells (Olivares et al., 2017), colorectal cancer cells (Liu et al., 2012a), and transformed mammary epithelial cells (MCF10A H-Ras^V12) growing as 3D spheroids (Elia et al., 2017) use L-Pro to obtain energy/ATP (Figure 3). L-Pro is also used to produce new collagens (L-Pro recycling), and, eventually, to alter the ECM composition/stiffness (D’Aniello et al., 2020).

Insect Vectors and Protozoan Parasites

Protozoan parasites adapt their metabolism to the mutable environments encountered throughout their life cycle, including the hemolymph of their insect vectors (Bringaud et al., 2012). Trypanosoma brucei, the causative agent of sleeping sickness, is transmitted by tsetse flies (Glossina diptera), and both organisms can oxidize L-Pro to accomplish ATP biosynthesis (Figure 3; Michalkova et al., 2014; Mantilla et al., 2017; Smith et al., 2017; Dolezelova et al., 2020; Haindrich et al., 2021; Villafraz et al., 2021). L-Pro sustains Trypanosoma cruzi (the causative agent of Chagas disease) cell invasion and intracellular epimastigote-to-trypomastigote transition (Figure 3; Martins et al., 2009; Mantilla et al., 2015; Barison et al., 2017). Parasites also utilize L-Pro for anabolic purposes. For instance, halofuginone, a selective inhibitor of PRS, blocks the synthesis of L-Pro-rich proteins and the proliferation of Plasmodium falciparum (the causative agent of malaria) (Hewitt et al., 2017).

Insect Flight Muscle

Flight is one of the highest ATP/energy-requiring processes in animals, and the muscle cells involved can make use of different energy sources including carbohydrates (e.g., honeybee Apis mellifera) and fatty acids (e.g., butterflies) (Bursell, 1975; Candy et al., 1997). Some insects, such as Locusta migratoria, Bombus impatiens (bumblebee), Vespula vulgaris and Glossina diptera, oxidize L-Pro to power flight (Figure 3; Teulier et al., 2016). L-Pro supports flight muscle cells of Aedes aegypti mosquitoes that feed on blood and can obtain free L-Pro from the hydrolysis of blood proteins and/or from alanine in the fat body (Goldstrohm et al., 2003; Scaraffia and Wells, 2003; Mazzalupo et al., 2016). Indeed, free L-Pro is abundant in the hemolymph of adult female mosquitoes and other insects such as Diaphorina citri, the vector of Candidatus Liberibacter asiaticus (huanglongbing) (Killiny et al., 2017).

Polyamine and Citrate Precursors

Some cells use the carbon skeleton of L-Pro to synthesize L-ornithine and L-arginine. For instance, in the gut of neonates, L-glutamate to pyrroline-5-carboxylate conversion is negligible, hence dietary L-Pro is the only source of L-arginine (Tomlinson et al., 2011a,b). In motile human spermatozoa, L-Pro is the precursor of polyamines such as putrescine, spermidine and spermine (Figure 3; Wu et al., 2005, 2008), which are deregulated in hyper-proliferative cancer cells (Bachmann and Geerts, 2018), and thus a potential target for therapeutic anticancer intervention (Murray-Stewart et al., 2016). The three-step L-Pro to α-KG conversion is also activated to generate Krebs-derived metabolic intermediates. For instance, cells of mouse retinal pigment epithelium use L-Pro to synthesize and export citrate, which is consumed by the outer retina (Figure 3; Chao et al., 2017; Yam et al., 2019; Du et al., 2021).

Proline in Antistress Response

Living cells are subjected to a fluctuating environment involving transient or continuous changes in physicochemical parameters such as temperature, humidity and UV radiation. For instance, humans renal and corneal cells are exposed to discontinuous but substantial variations in osmolality/salinity. To prevent the detrimental effects of such harmful environmental imbalances, cells utilize adaptive mechanisms, including accumulation of highly soluble non-toxic osmolytes and chemical chaperones (protein stabilizers) such as L-Pro. Of course, living cells can tolerate extensive accumulation of L-Pro (up to a 100-fold increase) without suffering of the ionic imbalances induced by accumulation of inorganic osmolytes (e.g., Na⁺, K⁺, Mg⁺² or Ca⁺² salts).

Osmoprotection

Hypertonic shocks induce water outflow, which reduces the cell volume and lowers macromolecule stability (Burg et al., 2007; Hoffmann et al., 2009; Stadmiller et al., 2017). Cells respond by accumulating L-Pro, which generates an opposite force of water retention (Figure 4). In bacteria, L-Pro accumulation occurs by uptake of extracellular free L-Pro after the induction (up to 700-fold) of a low-affinity L-Pro transporter (Csonka and Hanson, 1991), through degradation of extracellular L-Pro-rich proteins (Zaprasis et al., 2013) and/or de novoL-Pro biosynthesis (Patel et al., 2018). The ability to accumulate L-Pro is vital to organisms inhabiting mutable (fresh/brackish water, intertidal) habitats, such as gastropod mollusks (Wiesenthal et al., 2019). Plants respond to drought, salinity and freezing temperatures by accumulating L-Pro (Yoshiba et al., 1997; Szabados and Savoure, 2010; Hnilickova et al., 2021; Papu et al., 2021), and in tomato cells concentrations can reach 60 mM (500-fold higher than normal levels) (Handa et al., 1983). L-Pro accumulation protects human cells from hyperosmotic stress (Thiemicke and Neuert, 2021). Indeed, L-Pro uptake facilitates the recovery a viable cell volume after hypertonic stress (Law, 1991; Bevilacqua et al., 2005; Krokowski et al., 2017), and the PP1 phosphatase subunit protein PPP1R15A/GADD34 promotes cis-to-trans Golgi trafficking, and the plasma membrane localization of SLC38A2 L-Pro transporter (Figure 4; Krokowski et al., 2017).

FIGURE 4

Antifreeze Activity

In yeast, L-Pro accumulation confers ethanol and freezing tolerance (Takagi, 2008). In overwintering insects, L-Pro contributes to water retention and freezing tolerance (Figure 4), and levels increase to ∼80% of the total pool of free amino acids (Kostal et al., 2011, 2016; Rozsypal et al., 2018; Stetina et al., 2018). Of note, hyperprolinemic larvae of the fly Chymomyza costata can survive immersion in liquid nitrogen (−196°C) (Kostal et al., 2011). In Drosophila larvae, an L-Pro-rich diet increases the whole-body L-Pro concentration (up to 60 mM) and freezing tolerance (Kostal et al., 2012).

Radical Scavenging

L-Proline protects various human cells such as HEK293, HeLa, HepG2, Jurkat, BJAB, WM35, skin keratinocytes and fibroblasts against ROS-mediated oxidative stress (Figure 4; Wondrak et al., 2005; Krishnan et al., 2008; Natarajan et al., 2012). Of note, the five-membered ring of L-Pro molecule, known as pyrrolidine or tetrahydropyrrole, quenches hydroxyl radicals (^⋅OH) (Signorelli, 2016). In plants L-Pro accumulates in response to oxidative compounds (Yang et al., 2009; Ben Rejeb et al., 2015), and contributes to protect plants from photo-oxidative stress (i.e., light-dependent generation of ROS) (Liang et al., 2013). Recently, it emerged that salivary L-Pro-rich proteins can neutralize ROS, and specifically hydroxyl radicals (Komatsu et al., 2020).

Heavy Metal Detoxification

In plants, L-Pro is accumulated after exposure to heavy metals such as cadmium, chromium, and zinc (Sharma et al., 1998; Verbruggen and Hermans, 2008; Hayat et al., 2012; Dubey et al., 2018; Dong et al., 2021; Pejam et al., 2021; Zdunek-Zastocka et al., 2021), and this mitigates the detrimental effects of cadmium in young olive plants (Zouari et al., 2016) and cultured tobacco cells (Islam et al., 2009). Heavy metal toxicity is usually associated with ROS accumulation (Figure 4). Indeed, cadmium induces p53 (Aimola et al., 2012), a transcriptional inducer of PRODH expression (Polyak et al., 1997), which catalyzes L-Pro oxidation in mitochondria, leading to abnormal ROS production and apoptosis (Liu et al., 2006, 2008, 2009; Oscilowska et al., 2021). Thus, a p53→PRODH→ROS→apoptosis axis may be activated as a response to toxic metals such as cadmium.

ER Stress Relief

At a molecular level, various stressful conditions (e.g., suboptimal temperature, high salinity and oxidative agents) can destabilize the structure and conformation of cellular proteins and other macromolecules. Thus, the accumulation of L-Pro (chemical chaperone) represents a convergent response of cells aimed at inhibiting the formation of unfolded/misfolded protein aggregates. In this context, induction of ATF4 expression (Figure 4), and subsequent enhancement of the transcription of genes involved in L-Pro uptake (SLC38A2) and biosynthesis (ALDH18A2, PYCR1) can contribute to intracellular L-Pro accumulation (D’Aniello et al., 2015). By stabilizing protein folding and/or promoting protein refolding, L-Pro can avoid and/or relieve ER stress.

Proline is a Neural Metabotoxin

Schafer et al. (1962) reported a link between hyperprolinemia (HP), characterized by high levels of plasmatic L-Pro, and neuronal dysfunction in human patients. It later emerged that different forms of hereditary human HP (type I or II) are associated with defects in L-Pro oxidation/degradation (Geraghty et al., 1998; Jacquet et al., 2002). Indeed, ectopic expression of PRODH in glioblastoma cells reduces the level of L-Pro (Cappelletti et al., 2018). Free L-Pro can interfere with excitatory presynaptic transmission, and therefore normal neuronal activity in the central nervous system (CNS) (Shafqat et al., 1995; Velaz-Faircloth et al., 1995; Wyse and Netto, 2011). Of note, the psychostimulant methamphetamine induces L-Pro synthesis in human neuroblastoma cells (Jones et al., 2021).

Schizophrenia Induction and Neurotoxicity

Hyperprolinemia is an etiopathogenetic factor of schizophrenia, a heterogeneous disorder that affects about 21 million people worldwide (Disease et al., 2017). HPI Drosophila models (PRODH mutants) exhibit a depressed ‘sluggish’ behavior (Hayward et al., 1993), while HPII models (defects in P5C to L-glutamate conversion due to a P5CDH mutation) display larval and pupal lethality (He and DiMario, 2011). Conversely, PRODH-overexpressing flies exhibit an opposite ‘aggressive’ behavior (Zwarts et al., 2017). HPI mouse models also exhibit sluggish movements (Blake and Russell, 1972; Kanwar et al., 1975) and schizophrenia-related phenotypes (learning, memory and sensorimotor gating) (Gogos et al., 1999; Paterlini et al., 2005). Human patients with genetic defects in PRODH (HPI, L-Pro levels up to 10-fold higher than normal) or in P5CDH (ALDH4A1; HPII, L-Pro levels up to 15-fold higher and P5C excretion) suffer schizoaffective disorders and schizophrenia (Table 2; Liu et al., 2002; Bender et al., 2005; Raux et al., 2007; Clelland et al., 2011; Nagaoka et al., 2020). At high levels, L-Pro can be oxidized/converted into the neurotransmitter L-glutamate, which is associated with schizophrenia (Figure 5). Excess L-glutamate disturbs synaptic transmission and can destroy neurons, a process known as excitotoxicity (Nadler et al., 1988; Cohen and Nadler, 1997). Moreover, acting as a GABA mimetic inhibitor of the GAD enzyme, L-Pro can reduce the synthesis the GABA neurotransmitter, thereby provoking synaptic dysfunction (Figure 5; Crabtree et al., 2016). Of note, L-Pro antagonizes GABA signaling in plants (Haudecoeur et al., 2009).

FIGURE 5

Neural Transporters

In neural tissues, two transporters of L-Pro are expressed; solute carrier family 6 member 7 (SLC6A7, PROT), a member of GABA family, and solute carrier family 6 member 19 (SLC6A19, B°AT1) (Figure 5; Roigaard-Petersen and Sheikh, 1984; Malandro and Kilberg, 1996; Thwaites and Anderson, 2007, 2011; Verrey et al., 2009). Genetic and/or pharmacological inhibition of SLC6A7 reduces locomotor activity and improves mouse learning and memory (Zipp et al., 2014; Schulz et al., 2018). SLC6A7 is induced in fibroblasts of patients suffering of Friedreich’s ataxia, characterized by a lack of control in muscle activity/movements (Napierala et al., 2017). Mutations of SLC6A19 are associated with Hartnup disease, a complex syndrome involving cerebellar ataxia and psychosis (Seow et al., 2004). SLC6A20 (IMINO) is expressed in human neurons and regulates L-Pro and glycine homeostasis (Bae et al., 2021).

Neural Bioactive Peptides

Collagen-derived peptides such as Pro-Pro-OH induce the expression of crucial neural growth factors in the hippocampus of mice, increasing both dopamine concentration in the prefrontal cortex and proliferation of neural progenitor cells, and, eventually, reducing depression-like behavior (Mizushige et al., 2019; Nogimura et al., 2020). L-Pro-containing peptides (Gly-Pro-Glu and cyclo-Gly-Pro) inhibit inflammation and induce vascular remodeling, thereby protecting brain tissues from ischemic injury (Guan and Gluckman, 2009). Moreover, a phosphine analog of Pro-Gly-Pro tripeptide displays neuroprotective properties (Alexey et al., 2021).

Leukodystrophy/Cerebral Hypomyelination

Genetic defects in PYCR2, a PYCR1 paralog, are associated with leukodystrophy-hypomyelinating 10 (HLD10; Table 2), a syndrome characterized by microcephaly and psychomotor disability (Nakayama et al., 2015; Zaki et al., 2016). PYCR2-deficient fibroblasts derived from HLD10 patients are highly susceptible to oxidative stress-induced apoptosis, and this may contribute to this complex phenotype (Reversade et al., 2009; Nakayama et al., 2015).

Proline Modulates Signaling Pathways

The availability of some amino acids influences the activity of cell signaling pathways. For instance, the level of L-glutamine, L-leucine, and L-arginine impacts the mechanistic target of rapamycin (mTOR) pathway (Curi et al., 2007; Xie and Klionsky, 2007; Ryter et al., 2013; Bar-Peled and Sabatini, 2014; Lahiri et al., 2019). L-tyrosine and L-phenylalanine modulate the G protein-coupled receptor 142 (GPR142)-mediated pathway (Lin et al., 2016). It emerged that mESCs, isolated from mouse blastocysts, suffer from a finely regulated partial shortage of L-Pro, and that an increase in free L-Pro availability modulates the activity of the amino acid stress response (AAR), fibroblast growth factor/extracellular signal-related kinase (FGF/ERK), TGFβ, wingless and int-1 (WNT), and redox signaling pathways. As expected, specific signaling modulators such as halofuginone (AAR inducer), SB431542 (TGFβ inhibitor), CHIR99021 (WNT agonist) and PD0325901 (MEK/ERK inhibitor) fully counteract L-Pro supplementation effects (Comes et al., 2013; D’Aniello et al., 2015). Moreover, L-Pro impacts mTOR pathway in porcine trophectoderm cells (Liu et al., 2021).

Amino Acid Starvation Response

In cultured ESCs, exogenously available L-Pro, at a physiological concentration range (50–250 μM), disables the AAR pathway by improving L-Pro-tRNA loading, inactivating (dephosphorylation) eukaryotic translation initiation factor alpha (EIF2α), and eventually, preventing translation of ATF4 mRNA (Figure 6; D’Aniello et al., 2015). In the absence of ATF4, the genes involved in L-Pro biosynthesis (ALDH18A1 and PYCR1), and L-Pro uptake (SLC38A2 and GADD34) are silenced (Gaccioli et al., 2006; D’Aniello et al., 2015). L-Pro-ATF4 interplay also impacts cardiac fibroblast metabolism (Qin et al., 2017). Human kidney and breast cancer cells suffer from a similar intrinsic and partial shortage of L-Pro (Loayza-Puch et al., 2016; Sahu et al., 2016).

FIGURE 6

Extracellular Signal-Regulated Kinase

In stem and cancer cells, a high L-Pro regimen induces phosphorylation of ERK1 and enhances the transcription of ERK-related genes (Figure 6; Liu et al., 2006; D’Aniello et al., 2016). Supplemental L-Pro induces the expression of growth factors (FGF5, FGF8, and FGF13) and the synthesis of collagen, and this can contribute to the induction of the ILK/ERK super-pathway, as revealed by transcriptome analysis (Comes et al., 2013; D’Aniello et al., 2016, 2019b). Indeed, collagen mimics consisting of repeated units (5 or 10) of the Pro-Pro-Gly tripeptide activate phosphoinositide 3-kinase (PI3K)-dependent p38 mitogen-activated protein kinase (MAPK) phosphorylation (Weinberger et al., 2005).

Transforming Growth Factor

In ESCs, supplemental L-Pro induces expression of left-right determination factors (LEFTY1 and LEFTY2) and phosphorylation (activation) of small mother against decapentaplegic (SMAD2), which are extracellular inhibitors and intracellular effector of TGFβ-signaling, respectively (Figure 6; D’Aniello et al., 2015, 2016). In VSMCs of injured arteries (Majesky et al., 1991; Ensenat et al., 2001), and in meniscal fibrochondrocytes (Pangborn and Athanasiou, 2005), supplemental TGFβ induces L-Pro uptake and collagen deposition. A L-Pro→TGFβ→L-Pro regulatory loop should allow the induction of collagen synthesis only when free L-Pro is sufficient to warrant timely tRNA loading, thus avoiding ribosome stalling (ER stress).

Wingless and Int-1

Pluripotent stem cells tend to proliferate as tightly packed cell aggregates, a trend that is inverted by a high L-Pro regimen (Comes et al., 2013). This phenotypic effect of L-Pro is fully counteracted by CHIR99021, a WNT signaling agonist. Moreover, L-Pro abundance delocalizes E-cadherin from the plasma membrane, where it is involved in cell-cell adherent junctions, to the Golgi. This subcellular redistribution of E-cadherin relies on the protein kinase domain containing, cytoplasmic (PKDCC), also known as vertebrate lonesome kinase (VLK) (Figure 6; Comes et al., 2013). L-Pro supplementation induces the expression of insulin-related genes such as IGF2, IGFR1, IGFBP3, IRS1 and IRS2 (D’Aniello et al., 2016), which are modulators of glycogen synthase kinase 3 (GSK3) activity (Desbois-Mouthon et al., 2001), and enhanced translation of collagen XVIII, which contains a frizzled-like domain (Heljasvaara et al., 2017), and can contribute to WNT modulation.

Autophagy

In mouse ESCs, L-Pro supplementation enhances L-Pro-tRNA loading and inhibits autophagy. Accordingly, halofuginone inhibits L-Pro-tRNA loading and activates autophagy (D’Aniello et al., 2015). In human and murine ECSLC, knockdown of Tap73 tumor protein reduces L-Pro biosynthesis and induces autophagy (Sharif et al., 2019). Protracted exposure to free L-Pro induces stem cell motility, invasiveness, and macro-autophagy (D’Aniello et al., 2015). In cancer cells overexpressing PRODH and exposed to a high exogenous L-Pro regimen, autophagy is induced (Liu et al., 2012b).

Reactive Oxygen Species and Hypoxia-Inducible Factors

Electrons released during mitochondrial L-Pro oxidation reduce flavin adenine dinucleotide (FAD) to generate FADH2 and/or O₂ during the production of ROS (Figure 6; Donald et al., 2001). In Arabidopsis thaliana, PRODH-mediated production of sub-lethal levels of ROS induces disease resistance (Cecchini et al., 2011), and in Caenorhabditis elegans this prolongs the nematodes life span (Zarse et al., 2012). In C. elegans, defects in L-Pro catabolism results in premature reproductive senescence and male infertility (Yen and Curran, 2021). In cancer cells, the L-Pro->PRODH->ROS axis can activate either pro-tumorigenic (cell survival) or anti-tumorigenic (cell death) signaling (Moloney and Cotter, 2018; Oscilowska et al., 2021). In rats’ blood cells, hyperprolinemia increases oxidative damage of proteins, lipids and DNA (Ferreira et al., 2014). The effect of L-Pro on intracellular redox balance can be amplified by an NADPH-consuming futile cycle of L-Pro/P5C inter-conversion (Phang, 2019). Besides ROS, oxidative deamination of L-Pro generates α-KG, an essential substrate for hydroxylating dioxygenase enzymes, including PHD1-3 enzymes that catalyze the post-translational hydroxylation of specific proline residues of hypoxia-inducible factors (HIFs) resulting in destabilization of the protein. Indeed, the induction of PRODH activity in cancer cells destabilizes HIF1α and down-regulates the transcription of HIF1α target genes (Liu et al., 2009).

Proline is an Epigenetic Modifier

Several metabolites may influence, directly or indirectly, the activity of chromatin-modifying enzymes, and thus the epigenetic landscape of the cells (Reid et al., 2017; D’Aniello et al., 2019b; Surguchov et al., 2021). L-Pro is not a substrate, product, cofactor, or allosteric regulator of any epigenetic enzyme, but in ESCs its availability influences the activity of ten-eleven translocation (TET; DNA) and Jumonji (JMJ, histone) demethylase enzymes, which are strictly dependent on the availability of O₂, α-KG, and ascorbic acid (vitamin C, VitC) to be active (Figure 7; Comes et al., 2013; D’Aniello et al., 2016, 2019b).

FIGURE 7

DNA Methylation

L-Proline supplementation increases DNA 5-methylcytosine (5mC) and reduces 5-hydroxy-methylcytosine (5hmC) levels, inducing ∼1 × 10³ DMRs distributed throughout all chromosomes of ESCs, with ∼50% of DMRs located in gene promoter regions (mostly H) and ∼20% in gene enhancers (D’Aniello et al., 2016). Importantly, ∼95% of genome sites hypermethylated after L-Pro supplementation are hypomethylated following VitC (50–150 μM) supplementation, indicating that L-Pro and VitC induce opposite epigenetic alterations in the same DNA regions. VitC is needed for the activity of TET demethylases (Blaschke et al., 2013), and ∼90% of genomic regions hypermethylated in by a high L-Pro regimen are hypermethylated also in cells lacking TET-mediated DNA demethylase activity (Lu et al., 2014; D’Aniello et al., 2019a).

Histone Methylation

L-Proline supplementation also triggers a genome-wide reprogramming of H3K9 methylation status, altering more than 1.6 × 10⁴ genome sites located mainly in non-coding intergenic regions (Comes et al., 2013). Demethylation is catalyzed by members of the JMJ dioxygenase enzyme family, and upon silencing of Jmjd1a (H3K9 demethylase), ESCs adopt a molecular (upregulation of Fgf5 and Brachyury genes) and phenotypic (irregular flat-shaped colonies, sensitivity to trypsin digestion) state of pluripotency, similar to that induced by a high L-Pro regimen (Loh et al., 2007). Differences in the expression level and/or in the kinetic parameters (substrate affinity) of different JMJs can explain how L-Pro abundance alters the methylation level of some specific lysine residues (K9, K36) of histone H3.

Metabolic Imbalance

It recently emerged that a sudden and substantial increase in L-Pro stimulates collagen synthesis in the ER of ESCs (D’Aniello et al., 2019a), and that a significant fraction of L-Pro residues of nascent collagens are hydroxylated by prolyl 4-hydroxylase (P4H) dioxygenases, in particular by P4HA1 and P4HA2 enzymes, with depletion of α-KG and VitC. Under such conditions, nuclear dioxygenases such as TETs and JMJs lose activity, and consequently, DNA and histone methylation levels increase (Figure 7). Genetic and pharmacological evidence supports the idea that an abrupt induction of collagen synthesis leads to a similar metabolic imbalance and epigenome alterations also in cancer cells (D’Aniello et al., 2019a).

Proline Induces Proliferation of Stem and Tumor Cells

Pluripotent stem cells shape the ICM in blastocysts of mammals and the apical meristems of plant organs (shoots and roots), and can self-renew and undergo differentiation into various somatic lineages. Cancer cells often display a stem cell-like growth behavior. Of note, L-Pro is a growth limiting metabolite (intrinsic starvation) for embryonic stem cells (D’Aniello et al., 2015), and for many different human cancer cells (D’Aniello et al., 2020). Similarly, L-Pro metabolism also influences the proliferation of meristematic and plant tumor cells (Trovato et al., 2001; Biancucci et al., 2015).

Stem Cells

Supplemental L-Pro (50–250 μM) improves proliferation of ESCs (Figure 8; Washington et al., 2010; Casalino et al., 2011), development of pre-implantation embryos (Morris et al., 2020) and fetus survival (Liu et al., 2019). L-Pro is internalized into stem cell cytoplasm through the SLC38A2 (SNAT2) transporter (Tan et al., 2011), and halofuginone (prolyl-tRNA synthetase inhibitor) fully counteracts L-Pro induction of cell proliferation (D’Aniello et al., 2015). Moreover, halofuginone and L-Pro modify the ESC transcriptome in opposite directions (D’Aniello et al., 2015), showing that mouse ESCs are partially starved of L-Pro, even after incubation in complete rich medium. Of note, during in vitro fertilization of mouse oocytes, L-Pro supplementation improves stem cells (ICM) proliferation and embryo development (Treleaven et al., 2021).

FIGURE 8

Cancer Cells

L-Proline shortage is a major cause of partial ribosome stalling (diricore analysis) suffered by kidney and breast cancer cells (Loayza-Puch et al., 2016). Likewise, up-regulation of L-Pro biosynthesis genes (ALDH18A1 and PYCR1) also reveals L-Pro starvation in tumor cells (D’Aniello et al., 2020). Moreover, ALDH18A1 knock-down activates AAR stress signaling, and reduces melanoma tumor growth both in vitro and in vivo (Kardos et al., 2015), whereas PYCR1 induction improves proliferation and invasiveness of breast, esophagus, lung, melanoma, pancreas, and prostate cancer cells (Nilsson et al., 2014; Ding et al., 2017; Zeng et al., 2017; Cai et al., 2018; Ye et al., 2018; Kardos et al., 2020; Forlani et al., 2021). Of note, kindlerin 2 (KINDLING-2) protein stabilizes the mitochondrial PYCR1 enzyme, increasing L-Pro synthesis and lung adenocarcinoma cell proliferation (Guo et al., 2019). Importantly, translocation of KINDLING-2 into mitochondria is regulated by ECM stiffness (Guo et al., 2019) and PINCH-1 (particularly interesting new Cys-His protein 1) protein (Guo et al., 2020; Ding et al., 2021), and PYCR1 activity is modulated by the mitochondrial deacetylase sirtuin (SIRT3) (Chen et al., 2019). PYCR1 stabilization by KINDLING-2 induces L-Pro synthesis in human lung fibroblasts and contributes to pulmonary fibrosis progression (Zhang et al., 2021a).

Meristematic Cells

Post-embryonic organogenesis in adult plants relies on apical meristems, and a fine-tuned balance between self-renewal and differentiation fates adapts organ morphogenesis to a fluctuating environment (Figure 8; Mattioli et al., 2009; Lehmann et al., 2010; Szabados and Savoure, 2010). In Arabidopsis, L-Pro availability controls root meristem activity (Biancucci et al., 2015) by modifying the expression of L-Pro-rich proteins, and regulating a compartmentalized (mitochondria/cytoplasm) cycle of L-Pro synthesis and degradation that modifies the NADP⁺/NADPH ratio (Verslues and Sharma, 2010). Therefore, it is tempting to hypothesize that the induction of L-Pro accumulation during osmotic shock (see Figure 4), by altering the behavior/fate of stem cells, can contribute to couple a harmful environment (soil wetness) with the induction of organogenesis (root elongation).

Neoplastic Hairy Roots

L-Proline metabolism and plant tumor development are linked by the rolD gene of Agrobacterium rhizogenes, which encodes OCD that catalyzes L-Orn to L-Pro conversion, and is essential for the induction of neoplastic hairy roots (Figure 8; White et al., 1985; Costantino et al., 1994; Trovato et al., 2001). L-Pro accumulates in root tumor-like galls induced by the nematode Meloidogyne javanica or by Agrobacterium tumefaciens (Wachter et al., 2003; Trovato et al., 2018). Importantly, bacteria-induced tumorigenesis is attenuated in transgenic plants with low L-Pro levels (Haudecoeur et al., 2009).

Proline Controls Cell Plasticity

Some metabolites modulate relevant phenotypic transformations such as stem cell differentiation, somatic cell reprogramming, and EMT. For instance, butyric acid drives the differentiation of MSCs into adipocytes (Tugnoli et al., 2019), and, conversely, enhances the reprogramming efficiency of fetal fibroblasts into pluripotent cells (Liang et al., 2010; Mali et al., 2010). Likewise, VitC improves cell differentiation (Cao et al., 2012) and reprogramming (Esteban et al., 2010). Similarly, L-Pro governs the morphology, migratory behavior and pluripotency state of stem cells (Washington et al., 2010; Casalino et al., 2011).

Cytoskeletal Rearrangements

Embryonic stem cells seeded at a low density (50–250 cells/cm²) in a high L-Pro regimen develop flat-shaped cell colonies formed by a core of adherent cells surrounded by a crown of detached cells showing mesenchymal features such as long actin stress fibers and mature focal adhesion complexes (Figure 9; Casalino et al., 2011; Comes et al., 2013). These L-Pro-induced cells are in a ‘metastable’ equilibrium, spread out from the colony core and rapidly moving back to re-establish adherent cell-cell contacts, a fully reversible phenotypic transition known as embryonic stem cell-to-mesenchymal transition (esMT) (Comes et al., 2013). Of note, in detached cells, E-cadherin is delocalized from the plasma membrane to the Golgi (see Figure 6) and unlike canonical EMT, during esMT the CDH1 gene is not down-regulated (Comes et al., 2013).

FIGURE 9

Invasion/Metastasis

After exposure to a high L-Pro regimen, ESCs acquire the ability to migrate through matrigel-coated porous membranes in response to serum gradients, or toward chemo-attractants such as EGF and stromal cell-derived factor 1 (Comes et al., 2013). These cells are able to reach the lung tissues after intravenous injection, and to generate tumors with a histological complexity of teratomas (Comes et al., 2013). Thus, a high L-Pro regimen converts adherent stem cells into spindle-shaped, motile and metastatic stem cells (Figure 9).

Metabolic Reprogramming

The morphological changes induced by L-Pro supplementation are associated with a metabolic switch from a bivalent to a more glycolytic metabolism. Indeed, metabolome profile analysis revealed higher lactate levels and increased susceptibility to 2-DG, a specific inhibitor of the glycolytic pathway (D’Aniello et al., 2016). Moreover, a high L-Pro regimen reduces the mitochondrial membrane potential, which relies on oxidative phosphorylation rates (D’Aniello et al., 2017), thus supporting glycolytic energy metabolism.

Pluripotency

L-Proline supplementation remodels the transcriptome of naïve ESCs by altering the expression of ∼1.5 × 10³ protein-coding genes mainly related to cell adhesion, cell junction, and cell motility functions (Comes et al., 2013; D’Aniello et al., 2017). Cells treated with L-Pro are leukemia inhibitory factor (LIF)-dependent, express pluripotency markers as Nanog homeobox, can differentiate into cardiomyocytes and neurons in vitro, and are able to colonize mouse blastocysts (chimeric embryos; Figure 9; Casalino et al., 2011). Recently, Cermola et al. (2021) reported that L-Pro-treated ESCs can differentiate into primordial germ cell like cells (PGCLCs), and are competent to develop elongated gastruloids, suggesting that L-Pro abundance drives ESCs into an early primed state of pluripotency.

Proline Antagonists

L-Proline-induced esMT is inhibited by well-known chemical modulators of key signaling pathways such as CHIR99021 (WNT agonist) and PD0325901 (TGFβ antagonist) (D’Aniello et al., 2016). Moreover, D’Aniello et al. (2019a) made use of the cell colony morphology to develop a high-throughput screening method, and identified 14 FDA-approved drugs (from 1200 assayed) able to inhibit esMT without preventing L-Pro-induced cell proliferation. Spiramycin (macrolide), Propafenone (flavonoid) and Budesonide (steroid) inhibit esMT and have very different chemical structures, implying molecular complexity in L-Pro-mediated control of stem cell plasticity. Importantly, VitC, but not other antioxidants such as NAC, is a full inhibitor of esMT (D’Aniello et al., 2016).

Conclusion and Perspectives

The control of L-Pro metabolism in human cells is relatively poorly understood, even though it might have a great impact on human health (Figure 10). For instance, PrAMPs displaying potent antimicrobial activity and low toxicity for human cells could be efficient tools to fight multidrug-resistant pathogens, a serious public health concern (Charon et al., 2019). Salivary proline-rich peptides able to neutralize microbe attacks could contribute to avoiding the development of dental caries, an infectious disease that affects billions of people (Werneck et al., 2010; Stromberg et al., 2017). Moreover, salivary proteins could contribute to food choices, and so to nutrition status and health (Melis et al., 2021). Translational suppression of proline-rich proteins by pharmacological targeting of the PRS is emerging as an attractive therapeutic approach for the treatment of different diseases. Of note, halofuginone, a specific inhibitor of the PRS, is already in clinical trials for the treatment of fibrotic diseases (Pines and Spector, 2015), and has been recently shown to inhibit SARS-CoV-2 infection, suppressing the translation of proline-rich host attachment factors (Sandoval et al., 2021).

FIGURE 10

Exploitation of L-Pro as a source of carbon and/or energy appears to be an adaptive response of cells to high-L-Pro microenvironments, which can be generated by pathological tissue damage (bacterial invasion, cancer progression, trauma). Although never measured, it is possible to speculate that in an extremely confined extracellular space, free L-Pro can reach exceptionally high concentrations. L-Pro supports invasiveness of bacteria, parasites and cancer cells, all processes that engage tissue degradation/remodeling (Christgen and Becker, 2019; D’Aniello et al., 2020), and D-Pro-derived peptidomimetic inhibitors of human gelatinases/metalloproteinases involved in tissue remodeling are potential anti-metastatic agents (Lenci et al., 2021). Moreover, enzymes involved in L-Pro metabolism are potential targets of antiparasitic drugs (Saye et al., 2017; Ugwu et al., 2018).

Various stressful conditions, including suboptimal temperature, high salinity and oxidative agents, can alter the conformations of proteins and other macromolecules. Since L-Pro is a potent and non-toxic chemical chaperone, its intracellular accumulation could be an evolutionarily conserved response aimed at inhibiting the formation of unfolded/misfolded protein aggregates. Indeed, hemocompatible gold nanoparticles coated with L-Pro inhibit both collagen fibril formation (Anand et al., 2017) and insulin aggregation (Prajapati et al., 2021), and could provide a basis for creating antifibrotic and antiamyloid formulations.

Numerous studies conclude that at high levels, free L-Pro is a neurotoxin. Lactic acid inhibits PRODH activity, and lactic acidosis syndrome (blood lactic acid >5 mM) is frequently associated with hyperprolinemia, supporting the idea that in adult humans L-Pro homeostasis is strictly dependent on L-Pro oxidation. Of note, L-Pro at high levels is harmful for brain/neural activity, but acting as a chemical chaperone it can prevent protein unfolding/misfolding (Liang et al., 2014). Thus, regulation of L-Pro metabolism is studied in the context of neurodegenerative diseases associated with the formation of protein aggregates, as exemplified by Huntington’s, Parkinson’s, and Alzheimer’s (Powers et al., 2009; Khan et al., 2010).

Beyond some cancer cells, whether and which normal human cells oxidize L-Pro, and whether this contributes to maintain prolinemia, remains unknown. The concomitant activation of L-Pro oxidation (for ATP production in mitochondria) and tRNA loading (for collagen synthesis in the ER) remains uncharacterized at the single-cell level. By generating sublethal amounts of ROS, L-Pro oxidation can induce redox signaling, and eventually a compensatory stress response, through the induction of ROS consuming/neutralizing enzymes. Importantly, in bacteria (Zhang et al., 2015), fungi (Chen and Dickman, 2005) and nematodes (Zarse et al., 2012), L-Pro oxidation increases cell resilience to stressful conditions. However, the induction of stress tolerance by L-Pro oxidation in human cells remains an open question.

Aging is usually associated with a significant reduction (quantitative and qualitative) in CTs (tendon, bone, cartilage), for which L-Pro is essential. Of note, older people and patients suffering hereditary defects L-Pro biosynthesis share a similar aged appearance (e.g., osteopenia, cataracts, wrinkled skin, cutis laxa). Furthermore, sedentary life-induced sarcopenia is associated with hyperprolinemia, but its impact on neural disorders suffered by the elderly is unknown.

How L-Pro availability modulates stem and cancer cell proliferation is an interesting question that is getting increasingly attention. Free L-Pro can improve the translation of L-Pro-rich proteins (Sabi and Tuller, 2015; Chyzynska et al., 2021) or simple protein stretches, as demonstrated for HOXB4 involved in leukemia (Cusan et al., 2017). Recently, cell-based drug screening identified 137 drugs (out of 1200 assayed) able to inhibit stem cell proliferation, of which 80% also inhibited cancer cells (D’Aniello et al., 2019a), suggesting a similar chemosensitivity spectrum. Thus, the development of therapeutic strategies to target L-Pro metabolism may provide new options to eradicate cancer cells. Importantly, L-Pro abundance induces invasiveness in stem cells, a peculiar trait of migrating cancer cells. Certainly, the ability of L-Pro to control morphogenesis is not limited to stem cells. For instance, L-Pro availability influences plant shoot and root development (see Biancucci et al., 2015, for a review), hyphal morphology in the pathogenic fungus Colletotrichum trifolii (Memmott et al., 2002), and filamentation (yeast-to-hyphal transition) in the pathogenic yeast Candida albicans (Dabrowa et al., 1976; Silao et al., 2019).

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

• 1

  AgamiC. P. N.PuchotC.SevestreH. (1987). The role of proline in the asymmetric step of the woodward synthesis of erythromycin.Tetrahedron43:8.

  • Google Scholar

• 2

  AgerberthB.LeeJ. Y.BergmanT.CarlquistM.BomanH. G.MuttV.et al (1991). Amino acid sequence of PR-39. Isolation from pig intestine of a new member of the family of proline-arginine-rich antibacterial peptides.Eur. J. Biochem.202849–854. 10.1111/j.1432-1033.1991.tb16442.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 3

  AimolaP.CarmignaniM.VolpeA. R.Di BenedettoA.ClaudioL.WaalkesM. P.et al (2012). Cadmium induces p53-dependent apoptosis in human prostate epithelial cells.PLoS One7:e33647. 10.1371/journal.pone.0033647

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 4

  AldersonT. R.LeeJ. H.CharlierC.YingJ.BaxA. (2018). Propensity for cis-Proline formation in unfolded proteins.Chembiochem1937–42. 10.1002/cbic.201700548

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 5

  AlexeyV. V.MaximD. E.LyudmilaA. A.AlexeyU. A.ValeryS. P.KristinaS. N.et al (2021). Phosphine modification of proline-glycine-proline tripeptide and study of its neuroprotective properties.Biochem. Biophys. Res. Commun.53915–19. 10.1016/j.bbrc.2020.12.087

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 6

  AnandB. G.DubeyK.ShekhawatD. S.PrajapatiK. P.KarK. (2017). Strategically designed antifibrotic gold nanoparticles to prevent collagen fibril formation.Langmuir3313252–13261. 10.1021/acs.langmuir.7b01504

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 7

  BachmannA. S.GeertsD. (2018). Polyamine synthesis as a target of MYC oncogenes.J. Biol. Chem.29318757–18769. 10.1074/jbc.tm118.003336

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 8

  BaeM.RohJ. D.KimY.KimS. S.HanH. M.YangE.et al (2021). SLC6A20 transporter: a novel regulator of brain glycine homeostasis and NMDAR function.EMBO Mol. Med.13:e12632.

  • Google Scholar

• 9

  BaligaC.BrownT. J.FlorinT.ColonS.ShahV.SkowronK. J.et al (2021). Charting the sequence-activity landscape of peptide inhibitors of translation termination.Proc. Natl. Acad. Sci. U S A.118:e2026465118. 10.1073/pnas.2026465118

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 10

  BarcusC. E.O’learyK. A.BrockmanJ. L.RugowskiD. E.LiuY.GarciaN.et al (2017). Elevated collagen-I augments tumor progressive signals, intravasation and metastasis of prolactin-induced estrogen receptor alpha positive mammary tumor cells.Breast Cancer Res.19:9.

  • Google Scholar

• 11

  BarisonM. J.RapadoL. N.MerinoE. F.Furusho PralE. M.MantillaB. S.MarcheseL.et al (2017). Metabolomic profiling reveals a finely tuned, starvation-induced metabolic switch in Trypanosoma cruzi epimastigotes.J. Biol. Chem.2928964–8977. 10.1074/jbc.m117.778522

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 12

  Bar-PeledL.SabatiniD. M. (2014). Regulation of mTORC1 by amino acids.Trends Cell Biol.24400–406.

  • Google Scholar

• 13

  BaumgartnerM. R.HuC. A.AlmashanuS.SteelG.ObieC.AralB.et al (2000). Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase.Hum. Mol. Genet.92853–2858. 10.1093/hmg/9.19.2853

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 14

  Ben RejebK.Lefebvre-De VosD.Le DisquetI.LeprinceA. S.BordenaveM.MaldineyR.et al (2015). Hydrogen peroxide produced by NADPH oxidases increases proline accumulation during salt or mannitol stress in Arabidopsis thaliana.New Phytol.2081138–1148. 10.1111/nph.13550

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 15

  BenderH. U.AlmashanuS.SteelG.HuC. A.LinW. W.WillisA.et al (2005). Functional consequences of PRODH missense mutations.Am. J. Hum. Genet.76409–420. 10.1086/428142

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 16

  BeniasP. C.WellsR. G.Sackey-AboagyeB.KlavanH.ReidyJ.BuonocoreD.et al (2018). Structure and distribution of an unrecognized interstitium in human tissues.Sci. Rep.8:4947.

  • Google Scholar

• 17

  BenincasaM.PelilloC.ZorzetS.GarrovoC.BiffiS.GennaroR.et al (2010). The proline-rich peptide Bac7(1-35) reduces mortality from Salmonella typhimurium in a mouse model of infection.BMC Microbiol.10:178. 10.1186/1471-2180-10-178

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 18

  BertoloR. F.BurrinD. G. (2008). Comparative aspects of tissue glutamine and proline metabolism.J. Nutr.1382032S–2039S.

  • Google Scholar

• 19

  BevilacquaE.BussolatiO.Dall’astaV.GaccioliF.SalaR.GazzolaG. C.et al (2005). SNAT2 silencing prevents the osmotic induction of transport system A and hinders cell recovery from hypertonic stress.FEBS Lett.5793376–3380. 10.1016/j.febslet.2005.05.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 20

  BholaP. T.HartleyT.BarekeE.Care4Rare Canada Consortium, BoycottK. M.NikkelS. M.et al (2017). Autosomal dominant cutis laxa with progeroid features due to a novel, de novo mutation in ALDH18A1.J. Hum. Genet.62661–663. 10.1038/jhg.2017.18

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 21

  BiancucciM.MattioliR.MoubayidinL.SabatiniS.CostantinoP.TrovatoM. (2015). Proline affects the size of the root meristematic zone in Arabidopsis.BMC Plant Biol.15:263. 10.1186/s12870-015-0637-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 22

  BicknellL. S.PittJ.AftimosS.RamadasR.MawM. A.RobertsonS. P. (2008). A missense mutation in ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), causes an autosomal recessive neurocutaneous syndrome.Eur. J. Hum. Genet.161176–1186. 10.1038/ejhg.2008.91

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 23

  BlakeR. L.RussellE. S. (1972). Hyperprolinemia and prolinuria in a new inbred strain of mice. PRO-Re.Science176809–811. 10.1126/science.176.4036.809

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 24

  BlaschkeK.EbataK. T.KarimiM. M.Zepeda-MartinezJ. A.GoyalP.MahapatraS.et al (2013). Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells.Nature500222–226. 10.1038/nature12362

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 25

  BringaudF.BarrettM. P.ZilbersteinD. (2012). Multiple roles of proline transport and metabolism in trypanosomatids.Front. Biosci. (Landmark Ed)17:349–374. 10.2741/3931

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 26

  BroerS.BaileyC. G.KowalczukS.NgC.VanslambrouckJ. M.RodgersH.et al (2008). Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters.J. Clin. Invest.1183881–3892. 10.1172/jci36625

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 27

  BuletP.DimarcqJ. L.HetruC.LagueuxM.CharletM.HegyG.et al (1993). A novel inducible antibacterial peptide of Drosophila carries an O-glycosylated substitution.J. Biol. Chem.26814893–14897. 10.1016/s0021-9258(18)82417-6

  • CrossRef
  • Google Scholar

• 28

  BurgM. B.FerrarisJ. D.DmitrievaN. I. (2007). Cellular response to hyperosmotic stresses.Physiol. Rev.871441–1474. 10.1152/physrev.00056.2006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 29

  BursellE. (1975). Substrates of oxidative metabolism in dipteran flight muscle.Comp. Biochem. Physiol. B52235–238. 10.1016/0305-0491(75)90057-7

  • CrossRef
  • Google Scholar

• 30

  CaiF.MiaoY.LiuC.WuT.ShenS.SuX.et al (2018). Pyrroline-5-carboxylate reductase 1 promotes proliferation and inhibits apoptosis in non-small cell lung cancer.Oncol. Lett.15731–740.

  • Google Scholar

• 31

  CampbellH. D.WebbG. C.YoungI. G. (1997). A human homologue of the Drosophila melanogaster sluggish-A (proline oxidase) gene maps to 22q11.2, and is a candidate gene for type-I hyperprolinaemia.Hum. Genet.10169–74. 10.1007/s004390050589

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 32

  CandyD. J.BeckerA.WegenerG. (1997). Coordination and integration of metabolism in insect flight.Comp. Biochem. Physiol. Part B: Biochem. Mol. Biol.117:15.

  • Google Scholar

• 33

  CanonF.BelloirC.BourillotE.BrignotH.BriandL.FeronG.et al (2021). Perspectives on astringency sensation: an alternative hypothesis on the molecular origin of astringency.J. Agric. Food Chem.693822–3826. 10.1021/acs.jafc.0c07474

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 34

  CaoH.KeT.LiuR.YuJ.DongC.ChengM.et al (2015). Identification of a novel proline-rich antimicrobial peptide from Brassica napus.PLoS One10:e0137414. 10.1371/journal.pone.0137414

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 35

  CaoN.LiuZ.ChenZ.WangJ.ChenT.ZhaoX.et al (2012). Ascorbic acid enhances the cardiac differentiation of induced pluripotent stem cells through promoting the proliferation of cardiac progenitor cells.Cell Res.22219–236. 10.1038/cr.2011.195

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 36

  CappellettiP.TallaritaE.RabattoniV.CampomenosiP.SacchiS.PollegioniL. (2018). Proline oxidase controls proline, glutamate, and glutamine cellular concentrations in a U87 glioblastoma cell line.PLoS One13:e0196283. 10.1371/journal.pone.0196283

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 37

  CasalinoL.ComesS.LambazziG.De StefanoB.FilosaS.De FalcoS.et al (2011). Control of embryonic stem cell metastability by L-proline catabolism.J. Mol. Cell Biol.3108–122. 10.1093/jmcb/mjr001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 38

  CasteelsP.AmpeC.JacobsF.VaeckM.TempstP. (1989). Apidaecins: antibacterial peptides from honeybees.EMBO J.82387–2391. 10.1002/j.1460-2075.1989.tb08368.x

  • CrossRef
  • Google Scholar

• 39

  CecchiniN. M.MonteolivaM. I.AlvarezM. E. (2011). Proline dehydrogenase contributes to pathogen defense in Arabidopsis.Plant Physiol.1551947–1959. 10.1104/pp.110.167163

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 40

  CermolaF.D’anielloC.TateR.De CesareD.Martinez-AriasA.MinchiottiG.et al (2021). Gastruloid development competence discriminates different states of pluripotency.Stem Cell Rep.16354–369. 10.1016/j.stemcr.2020.12.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 41

  ChaoJ. R.KnightK.EngelA. L.JankowskiC.WangY.MansonM. A.et al (2017). Human retinal pigment epithelial cells prefer proline as a nutrient and transport metabolic intermediates to the retinal side.J. Biol. Chem.29212895–12905. 10.1074/jbc.m117.788422

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 42

  CharonJ.MantecaA.InnisC. A. (2019). Using the bacterial ribosome as a discovery platform for peptide-based antibiotics.Biochemistry5875–84. 10.1021/acs.biochem.8b00927

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 43

  ChenC.DickmanM. B. (2005). Proline suppresses apoptosis in the fungal pathogen Colletotrichum trifolii.Proc. Natl. Acad. Sci. U S A.1023459–3464. 10.1073/pnas.0407960102

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 44

  ChenS.YangX.YuM.WangZ.LiuB.LiuM.et al (2019). SIRT3 regulates cancer cell proliferation through deacetylation of PYCR1 in proline metabolism.Neoplasia21665–675. 10.1016/j.neo.2019.04.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 45

  ChenX.LiJ.SunH.LiS.ChenT.LiuG.et al (2017). High-level heterologous production and functional secretion by recombinant Pichia pastoris of the shortest proline-rich antibacterial honeybee peptide Apidaecin.Sci. Rep.7:14543.

  • Google Scholar

• 46

  ChoudharyS.KishoreN.HosurR. V. (2015). Inhibition of insulin fibrillation by osmolytes: mechanistic insights.Sci. Rep.5:17599.

  • Google Scholar

• 47

  ChoudharyS.SaveS. N.KishoreN.HosurR. V. (2016). Synergistic inhibition of protein fibrillation by proline and sorbitol: biophysical investigations.PLoS One11:e0166487. 10.1371/journal.pone.0166487

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 48

  ChowdhuryT.MandalS. M.DuttaS.GhoshA. K. (2021). Identification of a novel proline-rich antimicrobial protein from the hemolymph of Antheraea mylitta.Arch. Insect. Biochem. Physiol.106:e21771.

  • Google Scholar

• 49

  ChristgenS. L.BeckerD. F. (2019). Role of proline in pathogen and host interactions.Antioxid. Redox. Signal.30683–709. 10.1089/ars.2017.7335

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 50

  ChyzynskaK.LabunK.JonesC.GrellscheidS. N.ValenE. (2021). Deep conservation of ribosome stall sites across RNA processing genes.NAR Genom Bioinform.3:lqab038.

  • Google Scholar

• 51

  ClellandC. L.ReadL. L.BaraldiA. N.BartC. P.PappasC. A.PanekL. J.et al (2011). Evidence for association of hyperprolinemia with schizophrenia and a measure of clinical outcome.Schizophr. Res.131139–145. 10.1016/j.schres.2011.05.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 52

  CociancichS.DupontA.HegyG.LanotR.HolderF.HetruC.et al (1994). Novel inducible antibacterial peptides from a hemipteran insect, the sap-sucking bug Pyrrhocoris apterus.Biochem. J.300(Pt 2), 567–575. 10.1042/bj3000567

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 53

  CohenS. M.NadlerJ. V. (1997). Proline-induced potentiation of glutamate transmission.Brain Res.761271–282. 10.1016/s0006-8993(97)00352-1

  • CrossRef
  • Google Scholar

• 54

  ComesS.GagliardiM.LapranoN.FicoA.CimminoA.PalamidessiA.et al (2013). L-Proline induces a mesenchymal-like invasive program in embryonic stem cells by remodeling H3K9 and H3K36 methylation.Stem Cell Rep.1307–321. 10.1016/j.stemcr.2013.09.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 55

  CostantinoP.CaponeI.CardarelliM.De PaolisA.MauroM. L.TrovatoM. (1994). Bacterial plant oncogenes: the rol genes’ saga.Genetica94203–211. 10.1007/bf01443434

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 56

  CoulthardG.ErbW.AggarwalV. K. (2012). Stereocontrolled organocatalytic synthesis of prostaglandin PGF2alpha in seven steps.Nature489278–281. 10.1038/nature11411

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 57

  CoutelierM.GoizetC.DurrA.HabarouF.MoraisS.Dionne-LaporteA.et al (2015). Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia.Brain1382191–2205.

  • Google Scholar

• 58

  CrabtreeG. W.ParkA. J.GordonJ. A.GogosJ. A. (2016). Cytosolic accumulation of L-Proline disrupts GABA-Ergic transmission through GAD blockade.Cell Rep.17570–582. 10.1016/j.celrep.2016.09.029

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 59

  CsonkaL. N.HansonA. D. (1991). Prokaryotic osmoregulation: genetics and physiology.Annu. Rev. Microbiol.45569–606. 10.1146/annurev.mi.45.100191.003033

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 60

  CuriR.NewsholmeP.ProcopioJ.LagranhaC.GorjaoR.Pithon-CuriT. C. (2007). Glutamine, gene expression, and cell function.Front. Biosci.12:344–357. 10.2741/2068

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 61

  CusanM.VegiN. M.MulawM. A.BamezaiS.KaiserL. M.DeshpandeA. J.et al (2017). Controlled stem cell amplification by HOXB4 depends on its unique proline-rich region near the N terminus.Blood129319–323. 10.1182/blood-2016-04-706978

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62

  DabrowaN.TaxerS. S.HowardD. H. (1976). Germination of Candida albicans induced by proline.Infect. Immun.13830–835. 10.1128/iai.13.3.830-835.1976

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 63

  D’AnielloC.CermolaF.PalamidessiA.WanderlinghL. G.GagliardiM.MigliaccioA.et al (2019a). Collagen Prolyl hydroxylation-dependent metabolic perturbation governs epigenetic remodeling and mesenchymal transition in pluripotent and Cancer cells.Cancer Res.793235–3250. 10.1158/0008-5472.can-18-2070

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 64

  D’AnielloC.CermolaF.PatriarcaE. J.MinchiottiG. (2019b). Metabolic–Epigenetic axis in pluripotent state transitions.Epigenomes3:13. 10.3390/epigenomes3030013

  • CrossRef
  • Google Scholar

• 65

  D’AnielloC.CermolaF.PatriarcaE. J.MinchiottiG. (2017). Vitamin C in stem cell biology: impact on extracellular matrix homeostasis and epigenetics.Stem Cells Int.2017:8936156.

  • Google Scholar

• 66

  D’AnielloC.FicoA.CasalinoL.GuardiolaO.Di NapoliG.CermolaF.et al (2015). A novel autoregulatory loop between the Gcn2-Atf4 pathway and (L)-Proline [corrected] metabolism controls stem cell identity.Cell Death Differ.221094–1105. 10.1038/cdd.2015.24

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 67

  D’AnielloC.HabibiE.CermolaF.ParisD.RussoF.FiorenzanoA.et al (2016). Vitamin C and l-Proline antagonistic effects capture alternative states in the pluripotency continuum.Stem Cell Rep.81–10. 10.1016/j.stemcr.2016.11.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 68

  D’AnielloC.PatriarcaE. J.PhangJ. M.MinchiottiG. (2020). Proline metabolism in tumor growth and metastatic progression.Front. Oncol.10:776. 10.3389/fonc.2020.00776

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 69

  de BarsyA. M.MoensE.DierckxL. (1968). Dwarfism, oligophrenia and degeneration of the elastic tissue in skin and cornea. a new syndrome?.Helv. Paediatr. Acta23305–313.

  • Google Scholar

• 70

  DengY.ZhengX.ZhangY.XuM.YeC.LinM.et al (2020). High SPRR1A expression is associated with poor survival in patients with colon cancer.Oncol. Lett.193417–3424.

  • Google Scholar

• 71

  Desbois-MouthonC.CadoretA.Blivet-Van EggelpoelM. J.BertrandF.CherquiG.PerretC.et al (2001). Insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades involving GSK-3beta inhibition and Ras activation.Oncogene20252–259. 10.1038/sj.onc.1204064

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 72

  DingJ.KuoM. L.SuL.XueL.LuhF.ZhangH.et al (2017). Human mitochondrial pyrroline-5-carboxylate reductase 1 promotes invasiveness and impacts survival in breast cancers.Carcinogenesis38519–531. 10.1093/carcin/bgx022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73

  DingZ.EricksenR. E.LeeQ. Y.HanW. (2021). Reprogramming of mitochondrial proline metabolism promotes liver tumorigenesis.Amino Acids. Online ahead of print.

  • Google Scholar

• 74

  DiseaseG. B. D.InjuryI.PrevalenceC. (2017). Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.Lancet3901211–1259.

  • Google Scholar

• 75

  DoerfelL. K.WohlgemuthI.KotheC.PeskeF.UrlaubH.RodninaM. V. (2013). EF-P is essential for rapid synthesis of proteins containing consecutive proline residues.Science33985–88. 10.1126/science.1229017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 76

  DolashkaP.MoshtanskaV.BorisovaV.DolashkiA.StevanovicS.DimanovT.et al (2011). Antimicrobial proline-rich peptides from the hemolymph of marine snail Rapana venosa.Peptides321477–1483. 10.1016/j.peptides.2011.05.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 77

  DolezelovaE.KunzovaM.DejungM.LevinM.PanicucciB.RegnaultC.et al (2020). Cell-based and multi-omics profiling reveals dynamic metabolic repurposing of mitochondria to drive developmental progression of Trypanosoma brucei.PLoS Biol.18:e3000741. 10.1371/journal.pbio.3000741

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 78

  DonaldS. P.SunX. Y.HuC. A.YuJ.MeiJ. M.ValleD.et al (2001). Proline oxidase, encoded by p53-induced gene-6, catalyzes the generation of proline-dependent reactive oxygen species.Cancer Res.611810–1815.

  • Google Scholar

• 79

  DongX.ChangY.ZhengR.WangX.YanX.MaX. F. (2021). Phytoremediation of cadmium contaminated soil: impacts on morphological traits. proline content and stomata parameters of sweet sorghum seedlings.Bull. Environ. Contam. Toxicol.106528–535. 10.1007/s00128-021-03125-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 80

  DuJ.ZhuS.LimR. R.ChaoJ. R. (2021). Proline metabolism and transport in retinal health and disease.Amino Acids. Online ahead of print.

  • Google Scholar

• 81

  DubeyS.GuptaA.KhareA.JainG.BoseS.RaniV. (2018). Long- and short-term protective responses of rice seedling to combat Cr(VI) toxicity.Environ. Sci. Pollut. Res. Int.2536163–36172. 10.1007/s11356-018-3422-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 82

  DufourcE. J. (2021). Wine tannins, saliva proteins and membrane lipids.Biochim. Biophys. Acta Biomembr.1863:183670. 10.1016/j.bbamem.2021.183670

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 83

  EliaI.BroekaertD.ChristenS.BoonR.RadaelliE.OrthM. F.et al (2017). Proline metabolism supports metastasis formation and could be inhibited to selectively target metastasizing cancer cells.Nat. Commun.8:15267.

  • Google Scholar

• 84

  ElnagdiN. M.Al-HokbanyN. S. (2012). Organocatalysis in synthesis: L-proline as an enantioselective catalyst in the synthesis of pyrans and thiopyrans.Molecules174300–4312. 10.3390/molecules17044300

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 85

  EnsenatD.HassanS.ReynaS. V.SchaferA. I.DuranteW. (2001). Transforming growth factor-beta 1 stimulates vascular smooth muscle cell L-proline transport by inducing system a amino acid transporter 2 (SAT2) gene expression.Biochem. J.360507–512. 10.1042/bj3600507

  • CrossRef
  • Google Scholar

• 86

  EstebanM. A.WangT.QinB.YangJ.QinD.CaiJ.et al (2010). Vitamin C enhances the generation of mouse and human induced pluripotent stem cells.Cell Stem Cell671–79.

  • Google Scholar

• 87

  FabroG.KovacsI.PavetV.SzabadosL.AlvarezM. E. (2004). Proline accumulation and AtP5CS2 gene activation are induced by plant-pathogen incompatible interactions in Arabidopsis.Mol. Plant Microbe Interact.17343–350. 10.1094/mpmi.2004.17.4.343

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 88

  FaundesV.JenningsM. D.CrillyS.LegraieS.WithersS. E.CuvertinoS.et al (2021). Impaired eIF5A function causes a mendelian disorder that is partially rescued in model systems by spermidine.Nat. Commun.12:833.

  • Google Scholar

• 89

  FerreiraA. G.SchererE. B.Da CunhaA. A.ManfrediniV.BianciniG. B.VanzinC. S.et al (2014). Hyperprolinemia induces DNA, protein and lipid damage in blood of rats: antioxidant protection.Int. J. Biochem. Cell Biol.5420–25. 10.1016/j.biocel.2014.05.027

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 90

  FischerB.CallewaertB.SchroterP.CouckeP. J.SchlackC.OttC. E.et al (2014). Severe congenital cutis laxa with cardiovascular manifestations due to homozygous deletions in ALDH18A1.Mol. Genet. Metab.112310–316. 10.1016/j.ymgme.2014.05.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 91

  Fischer-ZirnsakB.Escande-BeillardN.GaneshJ.TanY. X.Al BughailiM.LinA. E.et al (2015). Recurrent de novo mutations affecting residue Arg138 of Pyrroline-5-Carboxylate synthase cause a progeroid form of autosomal-dominant cutis laxa.Am. J. Hum. Genet.97483–492. 10.1016/j.ajhg.2015.08.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92

  FlorinT.MaracciC.GrafM.KarkiP.KlepackiD.BerninghausenO.et al (2017). An antimicrobial peptide that inhibits translation by trapping release factors on the ribosome.Nat. Struct. Mol. Biol.24752–757. 10.1038/nsmb.3439

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 93

  ForlaniG.SabbioniG.RagnoD.PetrollinoD.BorgattiM. (2021). Phenyl-substituted aminomethylene-bisphosphonates inhibit human P5C reductase and show antiproliferative activity against proline-hyperproducing tumour cells.J. Enzyme. Inhib. Med. Chem.361248–1257. 10.1080/14756366.2021.1919890

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 94

  FranciscoS. M.TierneyM. L. (1990). Isolation and characterization of a proline-rich cell wall protein from soybean seedlings.Plant Physiol.941897–1902. 10.1104/pp.94.4.1897

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 95

  FreimarkD.SehlC.WeberC.HudelK.CzermakP.HofmannN.et al (2011). Systematic parameter optimization of a Me(2)SO- and serum-free cryopreservation protocol for human mesenchymal stem cells.Cryobiology6367–75. 10.1016/j.cryobiol.2011.05.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 96

  FremeauR. T.Jr.CaronM. G.BlakelyR. D. (1992). Molecular cloning and expression of a high affinity L-proline transporter expressed in putative glutamatergic pathways of rat brain.Neuron8915–926. 10.1016/0896-6273(92)90206-s

  • CrossRef
  • Google Scholar

• 97

  GaccioliF.HuangC. C.WangC.BevilacquaE.Franchi-GazzolaR.GazzolaG. C.et al (2006). Amino acid starvation induces the SNAT2 neutral amino acid transporter by a mechanism that involves eukaryotic initiation factor 2alpha phosphorylation and cap-independent translation.J. Biol. Chem.28117929–17940. 10.1074/jbc.m600341200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 98

  GagnonM. G.RoyR. N.LomakinI. B.FlorinT.MankinA. S.SteitzT. A. (2016). Structures of proline-rich peptides bound to the ribosome reveal a common mechanism of protein synthesis inhibition.Nucleic Acids Res.442439–2450. 10.1093/nar/gkw018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 99

  GennaroR.SkerlavajB.RomeoD. (1989). Purification, composition, and activity of two bactenecins, antibacterial peptides of bovine neutrophils.Infect. Immun.573142–3146. 10.1128/iai.57.10.3142-3146.1989

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 100

  GennaroR.ZanettiM.BenincasaM.PoddaE.MianiM. (2002). Pro-rich antimicrobial peptides from animals: structure, biological functions and mechanism of action.Curr. Pharm. Des.8763–778. 10.2174/1381612023395394

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 101

  GeraghtyM. T.VaughnD.NicholsonA. J.LinW. W.Jimenez-SanchezG.ObieC.et al (1998). Mutations in the Delta1-pyrroline 5-carboxylate dehydrogenase gene cause type II hyperprolinemia.Hum. Mol. Genet.71411–1415. 10.1093/hmg/7.9.1411

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 102

  GogosJ. A.SanthaM.TakacsZ.BeckK. D.LuineV.LucasL. R.et al (1999). The gene encoding proline dehydrogenase modulates sensorimotor gating in mice.Nat. Genet.21434–439. 10.1038/7777

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 103

  GoldstrohmD. A.PenningtonJ. E.WellsM. A. (2003). The role of hemolymph proline as a nitrogen sink during blood meal digestion by the mosquito Aedes aegypti.J. Insect Physiol.49115–121. 10.1016/s0022-1910(02)00267-6

  • CrossRef
  • Google Scholar

• 104

  GonenN.MellerA.SabathN.ShalgiR. (2019). Amino acid biosynthesis regulation during endoplasmic reticulum stress is coupled to protein expression demands.iScience19204–213. 10.1016/j.isci.2019.07.022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 105

  GrafM.HuterP.MaracciC.PeterekM.RodninaM. V.WilsonD. N. (2018). Visualization of translation termination intermediates trapped by the Apidaecin 137 peptide during RF3-mediated recycling of RF1.Nat. Commun.9:3053.

  • Google Scholar

• 106

  GrafM.MardirossianM.NguyenF.SeefeldtA. C.GuichardG.ScocchiM.et al (2017). Proline-rich antimicrobial peptides targeting protein synthesis.Nat. Prod. Rep.34702–711. 10.1039/c7np00020k

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 107

  GrafM.WilsonD. N. (2019). Intracellular antimicrobial peptides targeting the protein synthesis machinery.Adv. Exp. Med. Biol.111773–89. 10.1007/978-981-13-3588-4_6

  • CrossRef
  • Google Scholar

• 108

  GreeneM. L.LietmanP. S.RosenbergL. E.SeegmillerJ. E. (1973). Familial hyperglycinuria. New defect in renal tubular transport of glycine and imino acids.Am. J. Med.54265–271.

  • Google Scholar

• 109

  GuanJ.GluckmanP. D. (2009). IGF-1 derived small neuropeptides and analogues: a novel strategy for the development of pharmaceuticals for neurological conditions.Br. J. Pharmacol.157881–891. 10.1111/j.1476-5381.2009.00256.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 110

  GueguenY.BernardR.JulieF.PaulinaS.DelphineD. G.FranckV.et al (2009). Oyster hemocytes express a proline-rich peptide displaying synergistic antimicrobial activity with a defensin.Mol. Immunol.46516–522. 10.1016/j.molimm.2008.07.021

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 111

  GuernseyD. L.JiangH.EvansS. C.FergusonM.MatsuokaM.NightingaleM.et al (2009). Mutation in pyrroline-5-carboxylate reductase 1 gene in families with cutis laxa type 2.Am. J. Hum. Genet.85120–129. 10.1016/j.ajhg.2009.06.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112

  GuoL.CuiC.WangJ.YuanJ.YangQ.ZhangP.et al (2020). PINCH-1 regulates mitochondrial dynamics to promote proline synthesis and tumor growth.Nat. Commun.11:4913.

  • Google Scholar

• 113

  GuoL.CuiC.ZhangK.WangJ.WangY.LuY.et al (2019). Kindlin-2 links mechano-environment to proline synthesis and tumor growth.Nat. Commun.10:845.

  • Google Scholar

• 114

  GutierrezE.ShinB. S.WoolstenhulmeC. J.KimJ. R.SainiP.BuskirkA. R.et al (2013). eIF5A promotes translation of polyproline motifs.Mol. Cell5135–45. 10.1016/j.molcel.2013.04.021

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 115

  HaindrichA. C.ErnstV.NaguleswaranA.OliveresQ. F.RoditiI.RentschD. (2021). Nutrient availability regulates proline/alanine transporters in Trypanosoma brucei.J. Biol. Chem.296:100566. 10.1016/j.jbc.2021.100566

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 116

  HanJ.BackS. H.HurJ.LinY. H.GildersleeveR.ShanJ.et al (2013). ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death.Nat. Cell Biol.15481–490. 10.1038/ncb2738

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 117

  HandaS.BressanR. A.HandaA. K.CarpitaN. C.HasegawaP. M. (1983). Solutes contributing to osmotic adjustment in cultured plant cells adapted to water stress.Plant Physiol.73834–843. 10.1104/pp.73.3.834

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 118

  HaudecoeurE.PlanamenteS.CirouA.TannieresM.ShelpB. J.MoreraS.et al (2009). Proline antagonizes GABA-induced quenching of quorum-sensing in Agrobacterium tumefaciens.Proc. Natl. Acad. Sci. U S A.10614587–14592. 10.1073/pnas.0808005106

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 119

  HayatS.HayatQ.AlyemeniM. N.WaniA. S.PichtelJ.AhmadA. (2012). Role of proline under changing environments: a review.Plant Signal. Behav.71456–1466. 10.4161/psb.21949

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 120

  HaywardD. C.DelaneyS. J.CampbellH. D.GhysenA.BenzerS.KasprzakA. B.et al (1993). The sluggish-A gene of Drosophila melanogaster is expressed in the nervous system and encodes proline oxidase, a mitochondrial enzyme involved in glutamate biosynthesis.Proc. Natl. Acad. Sci. U S A.902979–2983. 10.1073/pnas.90.7.2979

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 121

  HeF.DiMarioP. J. (2011). Drosophila delta-1-pyrroline-5-carboxylate dehydrogenase (P5CDh) is required for proline breakdown and mitochondrial integrity-Establishing a fly model for human type II hyperprolinemia.Mitochondrion11397–404. 10.1016/j.mito.2010.12.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 122

  HeW.LiP.WuG. (2021). Amino acid nutrition and metabolism in chickens.Adv. Exp. Med. Biol.1285109–131. 10.1007/978-3-030-54462-1_7

  • CrossRef
  • Google Scholar

• 123

  HeljasvaaraR.AikioM.RuotsalainenH.PihlajaniemiT. (2017). Collagen XVIII in tissue homeostasis and dysregulation - lessons learned from model organisms and human patients.Matrix Biol.57-5855–75. 10.1016/j.matbio.2016.10.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 124

  HewittS. N.DranowD. M.HorstB. G.AbendrothJ. A.ForteB.HallyburtonI.et al (2017). Biochemical and structural characterization of selective allosteric inhibitors of the plasmodium falciparum drug target, Prolyl-tRNA-synthetase.ACS Infect. Dis.334–44.

  • Google Scholar

• 125

  HnilickovaH.KrausK.VachovaP.HnilickaF. (2021). Salinity stress affects photosynthesis, malondialdehyde formation, and proline content in Portulaca oleracea L.Plants (Basel)10:845. 10.3390/plants10050845

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 126

  HoffmannE. K.LambertI. H.PedersenS. F. (2009). Physiology of cell volume regulation in vertebrates.Physiol. Rev.89193–277. 10.1152/physrev.00037.2007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 127

  HungJ. J.DearB. J.DininA. K.BorwankarA. U.MehtaS. K.TruskettT. T.et al (2018). Improving viscosity and stability of a highly concentrated monoclonal antibody solution with concentrated proline.Pharm. Res.35:133.

  • Google Scholar

• 128

  IgnatovaZ.GieraschL. M. (2006). Inhibition of protein aggregation in vitro and in vivo by a natural osmoprotectant.Proc. Natl. Acad. Sci. U S A.10313357–13361. 10.1073/pnas.0603772103

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 129

  IslamM. M.HoqueM. A.OkumaE.BanuM. N.ShimoishiY.NakamuraY.et al (2009). Exogenous proline and glycinebetaine increase antioxidant enzyme activities and confer tolerance to cadmium stress in cultured tobacco cells.J. Plant Physiol.1661587–1597. 10.1016/j.jplph.2009.04.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 130

  JacquetH.BerthelotJ.BonnemainsC.SimardG.Saugier-VeberP.RauxG.et al (2003). The severe form of type I hyperprolinaemia results from homozygous inactivation of the PRODH gene.J. Med. Genet.40:e7.

  • Google Scholar

• 131

  JacquetH.DemilyC.HouyE.HecketsweilerB.BouJ.RauxG.et al (2005). Hyperprolinemia is a risk factor for schizoaffective disorder.Mol. Psychiatry10479–485. 10.1038/sj.mp.4001597

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 132

  JacquetH.RauxG.ThibautF.HecketsweilerB.HouyE.DemillyC.et al (2002). PRODH mutations and hyperprolinemia in a subset of schizophrenic patients.Hum. Mol. Genet.112243–2249. 10.1093/hmg/11.19.2243

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 133

  JaksicT.WagnerD. A.YoungV. R. (1990). Plasma proline kinetics and concentrations in young men in response to dietary proline deprivation.Am. J. Clin. Nutr.52307–312. 10.1093/ajcn/52.2.307

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 134

  JonesB.BalasubramaniamM.LebowitzJ. J.TaylorA.VillaltaF.KhoshboueiH.et al (2021). Activation of proline biosynthesis is critical to maintain glutamate homeostasis during acute methamphetamine exposure.Sci. Rep.11:1422.

  • Google Scholar

• 135

  JukkolaA.KauppilaS.RisteliL.VuopalaK.RisteliJ.LeistiJ.et al (1998). New lethal disease involving type I and III collagen defect resembling geroderma osteodysplastica, De Barsy syndrome, and Ehlers-Danlos syndrome IV.J. Med. Genet.35513–518. 10.1136/jmg.35.6.513

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 136

  KanwarY. S.KrakowerC. A.ManaligodJ. R.JusticeP.WongP. W. (1975). Biochemical, morphological and hybrid studies in hyperprolinemic mice.Biomedicine22209–216.

  • Google Scholar

• 137

  KarayiorgouM.MorrisM. A.MorrowB.ShprintzenR. J.GoldbergR.BorrowJ.et al (1995). Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11.Proc. Natl. Acad. Sci. U S A.927612–7616. 10.1073/pnas.92.17.7612

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 138

  KardosG. R.GowdaR.DinavahiS. S.KimballS.RobertsonG. P. (2020). Salubrinal in combination with 4E1RCat synergistically impairs melanoma development by disrupting the protein synthetic machinery.Front. Oncol.10:834. 10.3389/fonc.2020.00834

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 139

  KardosG. R.WastykH. C.RobertsonG. P. (2015). Disruption of proline synthesis in melanoma inhibits protein production mediated by the GCN2 pathway.Mol. Cancer Res.131408–1420. 10.1158/1541-7786.mcr-15-0048

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 140

  KaurR.PariaP.SainiA. G.SutharR.BhatiaV.AttriS. V. (2021). Metabolic epilepsy in hyperprolinemia type II due to a novel nonsense ALDH4A1 gene variant.Metab. Brain Dis.361413–1417. 10.1007/s11011-021-00757-w

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 141

  KhanS. H.AhmadN.AhmadF.KumarR. (2010). Naturally occurring organic osmolytes: from cell physiology to disease prevention.IUBMB Life62891–895. 10.1002/iub.406

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 142

  KieliszewskiM. J.LamportD. T. (1994). Extensin: repetitive motifs, functional sites, post-translational codes, and phylogeny.Plant J.5157–172. 10.1046/j.1365-313x.1994.05020157.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 143

  KillinyN.HijazF.El-SheshenyI.AlfaressS.JonesS. E.RogersM. E. (2017). Metabolomic analyses of the haemolymph of the Asian citrus psyllid Diaphorina citri, the vector of huanglongbing.Physiol. Entomol.42134–145. 10.1111/phen.12183

  • CrossRef
  • Google Scholar

• 144

  KletaR.RomeoE.RisticZ.OhuraT.StuartC.Arcos-BurgosM.et al (2004). Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder.Nat. Genet.36999–1002. 10.1038/ng1405

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 145

  KnappeD.PiantavignaS.HansenA.MechlerA.BinasA.NolteO.et al (2010). Oncocin (VDKPPYLPRPRPPRRIYNR-NH2): a novel antibacterial peptide optimized against gram-negative human pathogens.J. Med. Chem.535240–5247. 10.1021/jm100378b

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 146

  KomatsuT.KobayashiK.MorimotoY.HelmerhorstE.OppenheimF.Chang-Il LeeM. (2020). Direct evaluation of the antioxidant properties of salivary proline-rich proteins.J. Clin. Biochem. Nutr.67131–136. 10.3164/jcbn.19-75

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 147

  KostalV.KorbelovaJ.PoupardinR.MoosM.SimekP. (2016). Arginine and proline applied as food additives stimulate high freeze tolerance in larvae of Drosophila melanogaster.J. Exp. Biol.2192358–2367. 10.1242/jeb.142158

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 148

  KostalV.SimekP.ZahradnickovaH.CimlovaJ.StetinaT. (2012). Conversion of the chill susceptible fruit fly larva (Drosophila melanogaster) to a freeze tolerant organism.Proc. Natl. Acad. Sci. U S A.1093270–3274. 10.1073/pnas.1119986109

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 149

  KostalV.ZahradnickovaH.SimekP. (2011). Hyperprolinemic larvae of the drosophilid fly, Chymomyza costata, survive cryopreservation in liquid nitrogen.Proc. Natl. Acad. Sci. U S A.10813041–13046. 10.1073/pnas.1107060108

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 150

  KragolG.HoffmannR.ChattergoonM. A.LovasS.CudicM.BuletP.et al (2002). Identification of crucial residues for the antibacterial activity of the proline-rich peptide, pyrrhocoricin.Eur. J. Biochem.2694226–4237. 10.1046/j.1432-1033.2002.03119.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 151

  KretzR.BozorgmehrB.KariminejadM. H.RohrbachM.HausserI.BaumerA.et al (2011). Defect in proline synthesis: pyrroline-5-carboxylate reductase 1 deficiency leads to a complex clinical phenotype with collagen and elastin abnormalities.J. Inherit. Metab. Dis.34731–739. 10.1007/s10545-011-9319-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 152

  KrishnanN.DickmanM. B.BeckerD. F. (2008). Proline modulates the intracellular redox environment and protects mammalian cells against oxidative stress.Free Radic. Biol. Med.44671–681. 10.1016/j.freeradbiomed.2007.10.054

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 153

  KrizsanA.PrahlC.GoldbachT.KnappeD.HoffmannR. (2015). Short Proline-Rich antimicrobial peptides inhibit either the bacterial 70S ribosome or the assembly of its large 50S subunit.Chembiochem162304–2308. 10.1002/cbic.201500375

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 154

  KrokowskiD.GuanB. J.WuJ.ZhengY.PattabiramanP. P.JobavaR.et al (2017). GADD34 function in protein trafficking promotes adaptation to hyperosmotic stress in human corneal cells.Cell Rep.212895–2910. 10.1016/j.celrep.2017.11.027

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 155

  LahiriV.HawkinsW. D.KlionskyD. J. (2019). Watch what you (Self-) eat: autophagic mechanisms that modulate metabolism.Cell Metab.29803–826. 10.1016/j.cmet.2019.03.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 156

  LamportD. T.KieliszewskiM. J.ChenY.CannonM. C. (2011). Role of the extensin superfamily in primary cell wall architecture.Plant Physiol.15611–19. 10.1104/pp.110.169011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 157

  LawR. O. (1991). Amino acids as volume-regulatory osmolytes in mammalian cells.Comp. Biochem. Physiol. A Comp. Physiol.99263–277. 10.1016/0300-9629(91)90001-s

  • CrossRef
  • Google Scholar

• 158

  LehmannS.FunckD.SzabadosL.RentschD. (2010). Proline metabolism and transport in plant development.Amino Acids39949–962. 10.1007/s00726-010-0525-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 159

  LenciE.AngeliA.CalugiL.InnocentiR.CartaF.SupuranC. T.et al (2021). Multitargeting application of proline-derived peptidomimetics addressing cancer-related human matrix metalloproteinase 9 and carbonic anhydrase II.Eur. J. Med. Chem.214:113260. 10.1016/j.ejmech.2021.113260

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 160

  LevashinaE. A.OhresserS.BuletP.ReichhartJ. M.HetruC.HoffmannJ. A. (1995). Metchnikowin, a novel immune-inducible proline-rich peptide from Drosophila with antibacterial and antifungal properties.Eur. J. Biochem.233694–700. 10.1111/j.1432-1033.1995.694_2.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 161

  LevineM. (1959). A new method for isolation of hydroxy-L-proline and L-proline from gelatin.J. Biol. Chem.2341731–1732. 10.1016/s0021-9258(18)69916-8

  • CrossRef
  • Google Scholar

• 162

  LiN.YuJ.YangF.ShaoY.WuS.LiuB.et al (2021). L-Proline: an effective agent for frozen and post-thawed donkey semen storage.J. Equine Vet. Sci.101:103393. 10.1016/j.jevs.2021.103393

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 163

  LiP.WuG. (2018). Roles of dietary glycine, proline, and hydroxyproline in collagen synthesis and animal growth.Amino Acids5029–38. 10.1007/s00726-017-2490-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 164

  LiW. F.MaG. X.ZhouX. X. (2006). Apidaecin-type peptides: biodiversity, structure-function relationships and mode of action.Peptides272350–2359. 10.1016/j.peptides.2006.03.016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 165

  LiangG.TaranovaO.XiaK.ZhangY. (2010). Butyrate promotes induced pluripotent stem cell generation.J. Biol. Chem.28525516–25521. 10.1074/jbc.m110.142059

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 166

  LiangX.DickmanM. B.BeckerD. F. (2014). Proline biosynthesis is required for endoplasmic reticulum stress tolerance in Saccharomyces cerevisiae.J. Biol. Chem.28927794–27806. 10.1074/jbc.m114.562827

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 167

  LiangX.ZhangL.NatarajanS. K.BeckerD. F. (2013). Proline mechanisms of stress survival.Antioxid. Redox. Signal.19998–1011. 10.1089/ars.2012.5074

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 168

  LinD. S.ChangJ. H.LiuH. L.WeiC. H.YeungC. Y.HoC. S.et al (2011). Compound heterozygous mutations in PYCR1 further expand the phenotypic spectrum of De Barsy syndrome.Am. J. Med. Genet. A155A3095–3099. 10.1002/ajmg.a.34326

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 169

  LinH. V.EfanovA. M.FangX.BeaversL. S.WangX.WangJ.et al (2016). GPR142 controls tryptophan-induced insulin and incretin hormone secretion to improve glucose metabolism.PLoS One11:e0157298. 10.1371/journal.pone.0157298

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 170

  LindeC. M.HoffnerS. E.RefaiE.AnderssonM. (2001). . In vitro activity of PR-39, a proline-arginine-rich peptide, against susceptible and multi-drug-resistant Mycobacterium tuberculosis.J. Antimicrob. Chemother47575–580. 10.1093/jac/47.5.575

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 171

  LinderS.Castanos-VelezE.Von RosenA.BiberfeldP. (2001). Immunohistochemical expression of extracellular matrix proteins and adhesion molecules in pancreatic carcinoma.Hepatogastroenterology481321–1327.

  • Google Scholar

• 172

  ListB.CastelloC. (2001). A novel proline-catalyzed three-component reaction of ketones, aldehydes, and Meldrum’s acid.Synlett1687–1689. 10.1055/s-2001-18095

  • CrossRef
  • Google Scholar

• 173

  ListB.HoangL.MartinH. J. (2004). New mechanistic studies on the proline-catalyzed aldol reaction.Proc. Natl. Acad. Sci. U S A.1015839–5842. 10.1073/pnas.0307979101

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 174

  LiuH.HeathS. C.SobinC.RoosJ. L.GalkeB. L.BlundellM. L.et al (2002). Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia.Proc. Natl. Acad. Sci. U S A.993717–3722. 10.1073/pnas.042700699

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 175

  LiuN.DaiZ.ZhangY.ChenJ.YangY.WuG.et al (2019). Maternal L-proline supplementation enhances fetal survival, placental development, and nutrient transport in micedagger.Biol. Reprod.1001073–1081. 10.1093/biolre/ioy240

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 176

  LiuN.YangY.SiX.JiaH.ZhangY.JiangD.et al (2021). L-Proline activates mammalian target of rapamycin complex 1 and modulates redox environment in porcine trophectoderm cells.Biomolecules11:742. 10.3390/biom11050742

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 177

  LiuW.GlundeK.BhujwallaZ. M.RamanV.SharmaA.PhangJ. M. (2012a). Proline oxidase promotes tumor cell survival in hypoxic tumor microenvironments.Cancer Res.723677–3686. 10.1158/0008-5472.can-12-0080

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 178

  LiuW.LeA.HancockC.LaneA. N.DangC. V.FanT. W.et al (2012b). Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC.Proc. Natl. Acad. Sci. U S A.1098983–8988. 10.1073/pnas.1203244109

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 179

  LiuY.BorchertG. L.DonaldS. P.DiwanB. A.AnverM.PhangJ. M. (2009). Proline oxidase functions as a mitochondrial tumor suppressor in human cancers.Cancer Res.696414–6422. 10.1158/0008-5472.can-09-1223

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 180

  LiuY.BorchertG. L.SurazynskiA.HuC. A.PhangJ. M. (2006). Proline oxidase activates both intrinsic and extrinsic pathways for apoptosis: the role of ROS/superoxides, NFAT and MEK/ERK signaling.Oncogene255640–5647. 10.1038/sj.onc.1209564

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 181

  LiuY.BorchertG. L.SurazynskiA.PhangJ. M. (2008). Proline oxidase, a p53-induced gene, targets COX-2/PGE2 signaling to induce apoptosis and inhibit tumor growth in colorectal cancers.Oncogene276729–6737. 10.1038/onc.2008.322

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 182

  Loayza-PuchF.RooijersK.BuilL. C.ZijlstraJ.Oude VrielinkJ. F.LopesR.et al (2016). Tumour-specific proline vulnerability uncovered by differential ribosome codon reading.Nature530490–494. 10.1038/nature16982

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 183

  LohY. H.ZhangW.ChenX.GeorgeJ.NgH. H. (2007). Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells.Genes Dev.212545–2557. 10.1101/gad.1588207

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 184

  Lorenzo-PousoA. I.Perez-SayansM.BravoS. B.Lopez-JornetP.Garcia-VenceM.Alonso-SampedroM.et al (2018). Protein-Based salivary profiles as novel biomarkers for oral diseases.Dis. Markers2018:6141845.

  • Google Scholar

• 185

  LuF.LiuY.JiangL.YamaguchiS.ZhangY. (2014). Role of tet proteins in enhancer activity and telomere elongation.Genes Dev.282103–2119. 10.1101/gad.248005.114

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 186

  LuoY.LuoY.ChangJ.XiaoZ.ZhouB. (2020). Identification of candidate biomarkers and pathways associated with psoriasis using bioinformatics analysis.Hereditas157:30.

  • Google Scholar

• 187

  MackintoshJ. A.VealD. A.BeattieA. J.GooleyA. A. (1998). Isolation from an ant Myrmecia gulosa of two inducible O-glycosylated proline-rich antibacterial peptides.J. Biol. Chem.2736139–6143. 10.1074/jbc.273.11.6139

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 188

  MaginiP.Marco-MarinC.Escamilla-HonrubiaJ. M.MartinelliD.Dionisi-ViciC.FaravelliF.et al (2019). P5CS expression study in a new family with ALDH18A1-associated hereditary spastic paraplegia SPG9.Ann. Clin. Transl. Neurol.61533–1540.

  • Google Scholar

• 189

  MajeskyM. W.LindnerV.TwardzikD. R.SchwartzS. M.ReidyM. A. (1991). Production of transforming growth factor beta 1 during repair of arterial injury.J. Clin. Invest.88904–910. 10.1172/jci115393

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 190

  MalandroM. S.KilbergM. S. (1996). Molecular biology of mammalian amino acid transporters.Annu. Rev. Biochem.65305–336. 10.1146/annurev.bi.65.070196.001513

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 191

  MaliP.ChouB. K.YenJ.YeZ.ZouJ.DoweyS.et al (2010). Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigenetic remodeling and the expression of pluripotency-associated genes.Stem Cells28713–720. 10.1002/stem.402

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 192

  MandalA.MandalS.ParkM. H. (2014). Genome-wide analyses and functional classification of proline repeat-rich proteins: potential role of eIF5A in eukaryotic evolution.PLoS One9:e111800. 10.1371/journal.pone.0111800

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 193

  MantillaB. S.MarcheseL.Casas-SanchezA.DyerN. A.EjehN.BiranM.et al (2017). Proline metabolism is essential for trypanosoma Brucei brucei survival in the tsetse vector.PLoS Pathog13:e1006158. 10.1371/journal.ppat.1006158

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 194

  MantillaB. S.PaesL. S.PralE. M.MartilD. E.ThiemannO. H.Fernandez-SilvaP.et al (2015). Role of Delta1-pyrroline-5-carboxylate dehydrogenase supports mitochondrial metabolism and host-cell invasion of Trypanosoma cruzi.J. Biol. Chem.2907767–7790. 10.1074/jbc.m114.574525

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 195

  MardirossianM.BarriereQ.TimchenkoT.MullerC.PacorS.MergaertP.et al (2018a). Fragments of the non-lytic proline-rich antimicrobial peptide Bac5 kill E. coli cells by inhibiting protein synthesis.Antimicrob Agents Chemother.62:e00534-18.

  • Google Scholar

• 196

  MardirossianM.PerebaskineN.BenincasaM.GambatoS.HofmannS.HuterP.et al (2018b). The dolphin proline-rich antimicrobial peptide Tur1A inhibits protein synthesis by targeting the bacterial ribosome.Cell Chem. Biol.25530–539.e7.

  • Google Scholar

• 197

  MardirossianM.GrzelaR.GiglioneC.MeinnelT.GennaroR.MergaertP.et al (2014). The host antimicrobial peptide Bac71-35 binds to bacterial ribosomal proteins and inhibits protein synthesis.Chem. Biol.211639–1647. 10.1016/j.chembiol.2014.10.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 198

  MartinsR. M.CovarrubiasC.RojasR. G.SilberA. M.YoshidaN. (2009). Use of L-proline and ATP production by Trypanosoma cruzi metacyclic forms as requirements for host cell invasion.Infect. Immun.773023–3032. 10.1128/iai.00138-09

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 199

  MarvinK. W.GeorgeM. D.FujimotoW.SaundersN. A.BernackiS. H.JettenA. M. (1992). Cornifin, a cross-linked envelope precursor in keratinocytes that is down-regulated by retinoids.Proc. Natl. Acad. Sci. U S A.8911026–11030. 10.1073/pnas.89.22.11026

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 200

  MateosB.Conrad-BillrothC.SchiavinaM.BeierA.KontaxisG.KonratR.et al (2020). The ambivalent role of proline residues in an intrinsically disordered protein: from disorder promoters to compaction facilitators.J. Mol. Biol.4323093–3111. 10.1016/j.jmb.2019.11.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 201

  MatsumotoK.YamazakiK.KawakamiS.MiyoshiD.OoiT.HashimotoS.et al (2017). In vivo target exploration of apidaecin based on acquired resistance induced by gene overexpression (ARGO assay).Sci. Rep.7:12136.

  • Google Scholar

• 202

  MattioliR.CostantinoP.TrovatoM. (2009). Proline accumulation in plants: not only stress.Plant Signal. Behav.41016–1018. 10.4161/psb.4.11.9797

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 203

  MattiuzzoM.BandieraA.GennaroR.BenincasaM.PacorS.AntchevaN.et al (2007). Role of the Escherichia coli SbmA in the antimicrobial activity of proline-rich peptides.Mol. Microbiol.66151–163. 10.1111/j.1365-2958.2007.05903.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 204

  MazzalupoS.IsoeJ.BelloniV.ScaraffiaP. Y. (2016). Effective disposal of nitrogen waste in blood-fed Aedes aegypti mosquitoes requires alanine aminotransferase.FASEB J.30111–120. 10.1096/fj.15-277087

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 205

  MelisM.MastinuM.PintusS.CabrasT.CrnjarR.Tomassini BarbarossaI. (2021). Differences in salivary proteins as a function of PROP taster status and gender in normal weight and obese subjects.Molecules26:2244. 10.3390/molecules26082244

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 206

  MemmottS. D.HaY. S.DickmanM. B. (2002). Proline reverses the abnormal phenotypes of Colletotrichum trifolii associated with expression of endogenous constitutively active Ras.Appl. Environ. Microbiol.681647–1651. 10.1128/aem.68.4.1647-1651.2002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 207

  MessanaI.CabrasT.IavaroneF.ManconiB.HuangL.MartelliC.et al (2015). Chrono-proteomics of human saliva: variations of the salivary proteome during human development.J. Proteome Res.141666–1677. 10.1021/pr501270x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 208

  MichalkovaV.BenoitJ. B.WeissB. L.AttardoG. M.AksoyS. (2014). Vitamin B6 generated by obligate symbionts is critical for maintaining proline homeostasis and fecundity in tsetse flies.Appl. Environ. Microbiol.805844–5853. 10.1128/aem.01150-14

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 209

  MishraA. K.ChoiJ.MoonE.BaekK. H. (2018). Tryptophan-Rich and proline-rich antimicrobial peptides.Molecules23:815. 10.3390/molecules23040815

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 210

  MizushigeT.NogimuraD.NagaiA.MitsuhashiH.TagaY.KusubataM.et al (2019). Ginger-Degraded Collagen hydrolysate exhibits antidepressant activity in mice.J. Nutr. Sci. Vitaminol. (Tokyo)65251–257. 10.3177/jnsv.65.251

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 211

  MoloneyJ. N.CotterT. G. (2018). ROS signalling in the biology of cancer.Semin. Cell Dev. Biol.8050–64. 10.1016/j.semcdb.2017.05.023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 212

  MorganA. A.RubensteinE. (2013). Proline: the distribution, frequency, positioning, and common functional roles of proline and polyproline sequences in the human proteome.PLoS One8:e53785. 10.1371/journal.pone.0053785

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 213

  MorrisM. B.OzsoyS.ZadaM.ZadaM.ZamfirescuR. C.TodorovaM. G.et al (2020). Selected amino acids promote mouse pre-implantation embryo development in a growth factor-like manner.Front. Physiol.11:140. 10.3389/fphys.2020.00140

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 214

  Murray-StewartT. R.WosterP. M.CaseroR. A.Jr. (2016). Targeting polyamine metabolism for cancer therapy and prevention.Biochem. J.4732937–2953. 10.1042/bcj20160383

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 215

  NadlerJ. V.WangA.HakimA. (1988). Toxicity of L-proline toward rat hippocampal neurons.Brain Res.456168–172. 10.1016/0006-8993(88)90358-7

  • CrossRef
  • Google Scholar

• 216

  NagaokaA.KuniiY.HinoM.IzumiR.NagashimaC.TakeshimaA.et al (2020). ALDH4A1 expression levels are elevated in postmortem brains of patients with schizophrenia and are associated with genetic variants in enzymes related to proline metabolism.J. Psychiatr. Res.123119–127. 10.1016/j.jpsychires.2020.02.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 217

  NageshP. K. B.HatamiE.ChowdhuryP.KashyapV. K.KhanS.HafeezB. B.et al (2018). Tannic acid induces endoplasmic reticulum stress-mediated apoptosis in Prostate cancer.Cancers (Basel)10:68. 10.3390/cancers10030068

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 218

  NakayamaT.Al-MaawaliA.El-QuessnyM.RajabA.KhalilS.StolerJ. M.et al (2015). Mutations in PYCR2, encoding Pyrroline-5-Carboxylate reductase 2, cause microcephaly and hypomyelination.Am. J. Hum. Genet.96709–719. 10.1016/j.ajhg.2015.03.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 219

  NamS. Y.YoouM. S.KimH. M.JeongH. J. (2016). Efficacy of proline in the treatment of menopause.Exp. Biol. Med. (Maywood)241611–619. 10.1177/1535370216629011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 220

  NapieralaJ. S.LiY.LuY.LinK.HauserL. A.LynchD. R.et al (2017). Comprehensive analysis of gene expression patterns in Friedreich’s ataxia fibroblasts by RNA sequencing reveals altered levels of protein synthesis factors and solute carriers.Dis. Model Mech.101353–1369. 10.1242/dmm.030536

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 221

  NatarajanS. K.ZhuW.LiangX.ZhangL.DemersA. J.ZimmermanM. C.et al (2012). Proline dehydrogenase is essential for proline protection against hydrogen peroxide-induced cell death.Free Radic. Biol. Med.531181–1191. 10.1016/j.freeradbiomed.2012.07.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 222

  NilssonR.JainM.MadhusudhanN.SheppardN. G.StrittmatterL.KampfC.et al (2014). Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer.Nat. Commun.5:3128.

  • Google Scholar

• 223

  NishidaI.WatanabeD.TakagiH. (2016). Putative mitochondrial alpha-ketoglutarate-dependent dioxygenase Fmp12 controls utilization of proline as an energy source in Saccharomyces cerevisiae.Microb Cell3522–528. 10.15698/mic2016.10.535

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 224

  NogimuraD.MizushigeT.TagaY.NagaiA.ShojiS.AzumaN.et al (2020). Prolyl-hydroxyproline, a collagen-derived dipeptide, enhances hippocampal cell proliferation, which leads to antidepressant-like effects in mice.FASEB J.345715–5723. 10.1096/fj.201902871r

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 225

  Ogawa-OhnishiM.MatsushitaW.MatsubayashiY. (2013). Identification of three hydroxyproline O-arabinosyltransferases in Arabidopsis thaliana.Nat. Chem. Biol.9726–730. 10.1038/nchembio.1351

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 226

  OlivaresO.MayersJ. R.GouirandV.TorrenceM. E.GicquelT.BorgeL.et al (2017). Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions.Nat. Commun.8:16031.

  • Google Scholar

• 227

  OscilowskaI.HuynhT. Y. L.BaszanowskaW.ProkopI.SurazynskiA.GalliM.et al (2021). Proline oxidase silencing inhibits p53-dependent apoptosis in MCF-7 breast cancer cells.Amino Acids. Online ahead of print.

  • Google Scholar

• 228

  PangbornC. A.AthanasiouK. A. (2005). Effects of growth factors on meniscal fibrochondrocytes.Tissue Eng.111141–1148. 10.1089/ten.2005.11.1141

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 229

  PanzaE.Escamilla-HonrubiaJ. M.Marco-MarinC.GougeardN.De MicheleG.MorraV. B. (2016). ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism.Brain139:e3. 10.1093/brain/awv247

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 230

  PapuS.BerliF.PiccoliP.PatonD.Ortega RodriguezD. R.RoigF. A. (2021). Physiological, biochemical, and anatomical responses of Araucaria araucana seedlings to controlled water restriction.Plant Physiol. Biochem.16547–56. 10.1016/j.plaphy.2021.05.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 231

  PatelS. M.SeravalliJ.LiangX.TannerJ. J.BeckerD. F. (2021). Disease variants of human Delta(1)-pyrroline-5-carboxylate reductase 2 (PYCR2).Arch. Biochem. Biophys.703:108852. 10.1016/j.abb.2021.108852

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 232

  PatelV. K.SrivastavaR.SharmaA.SrivastavaA. K.SinghS.SrivastavaA. K.et al (2018). Halotolerant Exiguobacterium profundum PHM11 tolerate salinity by accumulating L-Proline and fine-tuning gene expression profiles of related metabolic pathways.Front. Microbiol.9:423. 10.3389/fmicb.2018.00423

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 233

  PaterliniM.ZakharenkoS. S.LaiW. S.QinJ.ZhangH.MukaiJ.et al (2005). Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice.Nat. Neurosci.81586–1594. 10.1038/nn1562

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 234

  PejamF.ArdebiliZ. O.Ladan-MoghadamA.DanaeeE. (2021). Zinc oxide nanoparticles mediated substantial physiological and molecular changes in tomato.PLoS One16:e0248778. 10.1371/journal.pone.0248778

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 235

  PelssA.GandhamsettyN.SmithJ. R.MailholD.SilviM.WatsonA.et al (2018). Re-optimization of the organocatalyzed double aldol domino process to a key enal intermediate and its application to the total synthesis of Delta(1)(2)-Prostaglandin J(3).Chemistry249542–9545. 10.1002/chem.201802498

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 236

  PembertonT. A.StillB. R.ChristensenE. M.SinghH.SrivastavaD.TannerJ. J. (2012). Proline: mother Nature’s cryoprotectant applied to protein crystallography.Acta Crystallogr. D. Biol. Crystallogr.681010–1018. 10.1107/s0907444912019580

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 237

  PhangJ. M. (2019). Proline metabolism in cell regulation and cancer biology: recent advances and hypotheses.Antioxid. Redox. Signal.30635–649. 10.1089/ars.2017.7350

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 238

  PinesM.SpectorI. (2015). Halofuginone - the multifaceted molecule.Molecules20573–594. 10.3390/molecules20010573

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 239

  PolyakK.XiaY.ZweierJ. L.KinzlerK. W.VogelsteinB. (1997). A model for p53-induced apoptosis.Nature389300–305.

  • Google Scholar

• 240

  PowersE. T.MorimotoR. I.DillinA.KellyJ. W.BalchW. E. (2009). Biological and chemical approaches to diseases of proteostasis deficiency.Annu. Rev. Biochem.78959–991. 10.1146/annurev.biochem.052308.114844

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 241

  PrajapatiK. P.PanigrahiA.PurohitS.AnsariM.DubeyK.BeheraR. K.et al (2021). Osmoprotectant coated thermostable gold nanoparticles efficiently restrict temperature-induced amyloid aggregation of insulin.J. Phys. Chem. Lett.121803–1813. 10.1021/acs.jpclett.0c03492

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 242

  PsychogiosN.HauD. D.PengJ.GuoA. C.MandalR.BouatraS.et al (2011). The human serum metabolome.PLoS One6:e16957. 10.1371/journal.pone.0016957

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 243

  PureE.BlombergR. (2018). Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics.Oncogene374343–4357. 10.1038/s41388-018-0275-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 244

  QiaoY.CaiH. L.YangX.ZangY. Y.ChenZ. G. (2018). Effects of natural deep eutectic solvents on lactic acid bacteria viability during cryopreservation.Appl. Microbiol. Biotechnol.1025695–5705. 10.1007/s00253-018-8996-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 245

  QinP.ArabacilarP.BernardR. E.BaoW.OlzinskiA. R.GuoY.et al (2017). Activation of the amino acid response pathway blunts the effects of cardiac stress.J. Am. Heart Assoc.6:e004453.

  • Google Scholar

• 246

  QinQ.ZhaoL.LiuZ.LiuT.QuJ.ZhangX.et al (2020). Bioinspired l-Proline oligomers for the cryopreservation of oocytes via controlling ice growth.ACS Appl. Mater. Interfaces1218352–18362. 10.1021/acsami.0c02719

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 247

  RanceG. A.KhlobystovA. N. (2014). The effects of interactions between proline and carbon nanostructures on organocatalysis in the Hajos-Parrish-Eder-Sauer-Wiechert reaction.Nanoscale611141–11146. 10.1039/c4nr04009k

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 248

  RauxG.BumselE.HecketsweilerB.Van AmelsvoortT.ZinkstokJ.Manouvrier-HanuS.et al (2007). Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome.Hum. Mol. Genet.1683–91. 10.1093/hmg/ddl443

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 249

  ReidM. A.DaiZ.LocasaleJ. W. (2017). The impact of cellular metabolism on chromatin dynamics and epigenetics.Nat. Cell Biol.191298–1306. 10.1038/ncb3629

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 250

  ReversadeB.Escande-BeillardN.DimopoulouA.FischerB.ChngS. C.LiY.et al (2009). Mutations in PYCR1 cause cutis laxa with progeroid features.Nat. Genet.411016–1021.

  • Google Scholar

• 251

  Roigaard-PetersenH.SheikhM. I. (1984). Renal transport of neutral amino acids. Demonstration of Na+-independent and Na+-dependent electrogenic uptake of L-proline, hydroxy-L-proline and 5-oxo-L-proline by luminal-membrane vesicles.Biochem. J.22025–33. 10.1042/bj2200025

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 252

  RoncevicT.Cikes-CulicV.MaravicA.CapanniF.GerdolM.PacorS.et al (2020). Identification and functional characterization of the astacidin family of proline-rich host defence peptides (PcAst) from the red swamp crayfish (Procambarus clarkii, Girard 1852).Dev. Comp. Immunol.105:103574. 10.1016/j.dci.2019.103574

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 253

  RoyR. N.LomakinI. B.GagnonM. G.SteitzT. A. (2015). The mechanism of inhibition of protein synthesis by the proline-rich peptide oncocin.Nat. Struct. Mol. Biol.22466–469. 10.1038/nsmb.3031

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 254

  RozsypalJ.MoosM.SimekP.KostalV. (2018). Thermal analysis of ice and glass transitions in insects that do and do not survive freezing.J. Exp. Biol.221:jeb170464.

  • Google Scholar

• 255

  RudolphA. S.CroweJ. H. (1985). Membrane stabilization during freezing: the role of two natural cryoprotectants, trehalose and proline.Cryobiology22367–377. 10.1016/0011-2240(85)90184-1

  • CrossRef
  • Google Scholar

• 256

  RuntiG.Lopez Ruiz, MdelC.StoilovaT.HussainR.JennionsM.et al (2013). Functional characterization of SbmA, a bacterial inner membrane transporter required for importing the antimicrobial peptide Bac7(1-35).J. Bacteriol.1955343–5351. 10.1128/jb.00818-13

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 257

  RyterS. W.CloonanS. M.ChoiA. M. (2013). Autophagy: a critical regulator of cellular metabolism and homeostasis.Mol. Cells367–16. 10.1007/s10059-013-0140-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 258

  SabiR.TullerT. (2015). A comparative genomics study on the effect of individual amino acids on ribosome stalling.BMC Genomics16(Suppl. 10):S5. 10.1186/1471-2164-16-S10-S5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 259

  SahuN.Dela CruzD.GaoM.SandovalW.HavertyP. M.LiuJ.et al (2016). Proline starvation induces unresolved ER stress and hinders mTORC1-Dependent tumorigenesis.Cell Metab.24753–761. 10.1016/j.cmet.2016.08.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 260

  SamuelD.KumarT. K.GaneshG.JayaramanG.YangP. W.ChangM. M.et al (2000). Proline inhibits aggregation during protein refolding.Protein Sci.9344–352. 10.1110/ps.9.2.344

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 261

  SamuelD.KumarT. K.JayaramanG.YangP. W.YuC. (1997). Proline is a protein solubilizing solute.Biochem. Mol. Biol. Int.41235–242. 10.1080/15216549700201241

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 262

  Sanchez-PartidaL. G.SetchellB. P.MaxwellW. M. (1998). Effect of compatible solutes and diluent composition on the post-thaw motility of ram sperm.Reprod. Fertil. Dev.10347–357. 10.1071/r98053

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 263

  SandovalD. R.ClausenT. M.NoraC.CribbsA. P.DenardoA.ClarkA. E.et al (2021). The Prolyl-tRNA synthetase inhibitor halofuginone inhibits SARS-CoV-2 infection.bioRxiv [preprint]10.1101/2021.03.22.436522

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 264

  SasahiraT.Kurihara-ShimomuraM.ShimomuraH.BosserhoffA. K.KiritaT. (2021). Identification of oral squamous cell carcinoma markers MUC2 and SPRR1B downstream of TANGO.J. Cancer Res. Clin. Oncol.1471659–1672. 10.1007/s00432-021-03568-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 265

  SayeM.FargnoliL.ReigadaC.LabadieG. R.PereiraC. A. (2017). Evaluation of proline analogs as trypanocidal agents through the inhibition of a proline transporter.Biochim. Biophys. Acta18612913–2921. 10.1016/j.bbagen.2017.08.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 266

  ScaraffiaP. Y.WellsM. A. (2003). Proline can be utilized as an energy substrate during flight of Aedes aegypti females.J. Insect Physiol.49591–601. 10.1016/s0022-1910(03)00031-3

  • CrossRef
  • Google Scholar

• 267

  SchaferI. A.ScriverC. R.EfronM. L. (1962). Familial hyperprolinemia, cerebral dysfunction and renal anomalies occurring in a family with hereditary nephropathy and deafness.N. Engl. J. Med.26751–60. 10.1056/nejm196207122670201

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 268

  ScheresB.Van De WielC.ZalenskyA.HorvathB.SpainkH.Van EckH.et al (1990). The ENOD12 gene product is involved in the infection process during the pea-Rhizobium interaction.Cell60281–294. 10.1016/0092-8674(90)90743-x

  • CrossRef
  • Google Scholar

• 269

  SchulzD.MorschelJ.SchusterS.EulenburgV.GomezaJ. (2018). Inactivation of the mouse L-Proline transporter PROT alters glutamatergic synapse biochemistry and perturbs behaviors required to respond to environmental changes.Front. Mol. Neurosci.11:279. 10.3389/fnmol.2018.00279

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 270

  ScriverC. R. (1968). Renal tubular transport of proline, hydroxyproline, and glycine. 3. genetic basis for more than one mode of transport in human kidney.J. Clin. Invest.47823–835. 10.1172/jci105776

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 271

  SeefeldtA. C.GrafM.PerebaskineN.NguyenF.ArenzS.MardirossianM.et al (2016). Structure of the mammalian antimicrobial peptide Bac7(1-16) bound within the exit tunnel of a bacterial ribosome.Nucleic Acids Res.442429–2438. 10.1093/nar/gkv1545

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 272

  SeefeldtA. C.NguyenF.AntunesS.PerebaskineN.GrafM.ArenzS.et al (2015). The proline-rich antimicrobial peptide Onc112 inhibits translation by blocking and destabilizing the initiation complex.Nat. Struct. Mol. Biol.22470–475. 10.1038/nsmb.3034

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 273

  SeowH. F.BroerS.BroerA.BaileyC. G.PotterS. J.CavanaughJ. A.et al (2004). Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19.Nat. Genet.361003–1007. 10.1038/ng1406

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 274

  SeriM.CusanoR.ForaboscoP.CintiR.CaroliF.PiccoP.et al (1999). Genetic mapping to 10q23.3-q24.2, in a large Italian pedigree, of a new syndrome showing bilateral cataracts, gastroesophageal reflux, and spastic paraparesis with amyotrophy.Am. J. Hum. Genet.64586–593. 10.1086/302241

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 275

  ServetC.GhelisT.RichardL.ZilbersteinA.SavoureA. (2012). Proline dehydrogenase: a key enzyme in controlling cellular homeostasis.Front. Biosci. (Landmark Ed)17:607–620. 10.2741/3947

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 276

  ShafqatS.Velaz-FairclothM.HenziV. A.WhitneyK. D.Yang-FengT. L.SeldinM. F. (1995). Human brain-specific L-proline transporter: molecular cloning, functional expression, and chromosomal localization of the gene in human and mouse genomes.Mol. Pharmacol.48219–229.

  • Google Scholar

• 277

  ShamovaO.BrogdenK. A.ZhaoC.NguyenT.KokryakovV. N.LehrerR. I. (1999). Purification and properties of proline-rich antimicrobial peptides from sheep and goat leukocytes.Infect. Immun.674106–4111. 10.1128/iai.67.8.4106-4111.1999

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 278

  SharifT.DaiC.MartellE.Ghassemi-RadM. S.HanesM. R.MurphyP. J.et al (2019). TAp73 modifies metabolism and positively regulates growth of cancer stem-like cells in a redox-sensitive manner.Clin. Cancer Res.252001–2017. 10.1158/1078-0432.ccr-17-3177

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 279

  SharmaS. S.SchatH.VooijsR. (1998). In vitro alleviation of heavy metal-induced enzyme inhibition by proline.Phytochemistry491531–1535. 10.1016/s0031-9422(98)00282-9

  • CrossRef
  • Google Scholar

• 280

  SherrierD. J.TaylorG. S.SilversteinK. A.GonzalesM. B.VandenboschK. A. (2005). Accumulation of extracellular proteins bearing unique proline-rich motifs in intercellular spaces of the legume nodule parenchyma.Protoplasma22543–55. 10.1007/s00709-005-0090-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 281

  ShiX. Z.ZhaoX. F.WangJ. X. (2014). A new type antimicrobial peptide astacidin functions in antibacterial immune response in red swamp crayfish Procambarus clarkii.Dev. Comp. Immunol.43121–128. 10.1016/j.dci.2013.11.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 282

  ShowalterA. M. (1993). Structure and function of plant cell wall proteins.Plant Cell59–23. 10.2307/3869424

  • CrossRef
  • Google Scholar

• 283

  SignorelliS. (2016). The fermentation analogy: a point of view for understanding the intriguing role of proline accumulation in stressed plants.Front. Plant Sci.7:1339. 10.3389/fpls.2016.01339

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 284

  SilaoF. G. S.WardM.RymanK.WallstromA.BrindefalkB.UdekwuK.et al (2019). Mitochondrial proline catabolism activates Ras1/cAMP/PKA-induced filamentation in Candida albicans.PLoS Genet.15:e1007976. 10.1371/journal.pgen.1007976

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 285

  SkidmoreD. L.ChitayatD.MorganT.HinekA.FischerB.DimopoulouA.et al (2011). Further expansion of the phenotypic spectrum associated with mutations in ALDH18A1, encoding Delta(1)-pyrroline-5-carboxylate synthase (P5CS).Am. J. Med. Genet. A155A1848–1856. 10.1002/ajmg.a.34057

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 286

  SlavotinekA. M.PikeM.MillsK.HurstJ. A. (1996). Cataracts, motor system disorder, short stature, learning difficulties, and skeletal abnormalities: a new syndrome?Am. J. Med. Genet.6242–47. 10.1002/(sici)1096-8628(19960301)62:1<42::aid-ajmg9>3.0.co;2-y

  • CrossRef
  • Google Scholar

• 287

  SmithK.RennieM. J. (2007). New approaches and recent results concerning human-tissue collagen synthesis.Curr. Opin. Clin. Nutr. Metab. Care10582–590. 10.1097/mco.0b013e328285d858

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 288

  SmithT. K.BringaudF.NolanD. P.FigueiredoL. M. (2017). Metabolic reprogramming during the Trypanosoma brucei life cycle.F1000Res6:F1000FacultyRev-683.

  • Google Scholar

• 289

  StadmillerS. S.Gorensek-BenitezA. H.GusemanA. J.PielakG. J. (2017). Osmotic shock induced protein destabilization in living cells and its reversal by glycine betaine.J. Mol. Biol.4291155–1161. 10.1016/j.jmb.2017.03.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 290

  SteinertP. M.CandiE.KartasovaT.MarekovL. (1998a). Small proline-rich proteins are cross-bridging proteins in the cornified cell envelopes of stratified squamous epithelia.J. Struct. Biol.12276–85. 10.1006/jsbi.1998.3957

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 291

  SteinertP. M.KartasovaT.MarekovL. N. (1998b). Biochemical evidence that small proline-rich proteins and trichohyalin function in epithelia by modulation of the biomechanical properties of their cornified cell envelopes.J. Biol. Chem.27311758–11769. 10.1074/jbc.273.19.11758

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 292

  StensvagK.HaugT.SperstadS. V.RekdalO.IndrevollB.StyrvoldO. B. (2008). Arasin 1, a proline-arginine-rich antimicrobial peptide isolated from the spider crab, Hyas araneus.Dev. Comp. Immunol.32275–285. 10.1016/j.dci.2007.06.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 293

  StetinaT.HulaP.MoosM.SimekP.SmilauerP.KostalV. (2018). Recovery from supercooling, freezing, and cryopreservation stress in larvae of the drosophilid fly. Chymomyza costata.Sci. Rep.8:4414.

  • Google Scholar

• 294

  StrombergN.EsbergA.ShengN.MarellL.Lofgren-BurstromA.DanielssonK.et al (2017). Genetic- and lifestyle-dependent dental caries defined by the acidic proline-rich protein genes PRH1 and PRH2.EBioMedicine2638–46. 10.1016/j.ebiom.2017.11.019

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 295

  SunC.LiT.SongX.HuangL.ZangQ.XuJ.et al (2019). Spatially resolved metabolomics to discover tumor-associated metabolic alterations.Proc. Natl. Acad. Sci. U S A.11652–57. 10.1073/pnas.1808950116

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 296

  SunH.GlasmacherB.HofmannN. (2012). Compatible solutes improve cryopreservation of human endothelial cells.Cryo. Lett.33485–493.

  • Google Scholar

• 297

  SurguchovA.BernalL.SurguchevA. A. (2021). Phytochemicals as regulators of genes involved in synucleinopathies.Biomolecules11:624. 10.3390/biom11050624

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 298

  SzabadosL.SavoureA. (2010). Proline: a multifunctional amino acid.Trends Plant Sci.1589–97. 10.1016/j.tplants.2009.11.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 299

  TakagiH. (2008). Proline as a stress protectant in yeast: physiological functions, metabolic regulations, and biotechnological applications.Appl. Microbiol. Biotechnol.81211–223. 10.1007/s00253-008-1698-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 300

  TanB. S.LonicA.MorrisM. B.RathjenP. D.RathjenJ. (2011). The amino acid transporter SNAT2 mediates L-proline-induced differentiation of ES cells.Am. J. Physiol. Cell Physiol.300C1270–C1279.

  • Google Scholar

• 301

  TancrediF.GuazziG.AuricchioS. (1970). Renal iminoglycinuria without intestinal malabsorption of glycine and imino acids.J. Pediatr.76386–392. 10.1016/s0022-3476(70)80477-2

  • CrossRef
  • Google Scholar

• 302

  TaniguchiM.OchiaiA.KondoH.FukudaS.IshiyamaY.SaitohE.et al (2016). Pyrrhocoricin, a proline-rich antimicrobial peptide derived from insect, inhibits the translation process in the cell-free Escherichia coli protein synthesis system.J. Biosci. Bioeng.121591–598. 10.1016/j.jbiosc.2015.09.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 303

  TannerJ. J.FendtS. M.BeckerD. F. (2018). The proline cycle as a potential cancer therapy target.Biochemistry573433–3444. 10.1021/acs.biochem.8b00215

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 304

  TeulierL.WeberJ. M.CrevierJ.DarveauC. A. (2016). Proline as a fuel for insect flight: enhancing carbohydrate oxidation in hymenopterans.Proc. Biol. Sci.283:20160333. 10.1098/rspb.2016.0333

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 305

  TheilletF. X.KalmarL.TompaP.HanK. H.SelenkoP.DunkerA. K.et al (2013). The alphabet of intrinsic disorder: I. act like a Pro: on the abundance and roles of proline residues in intrinsically disordered proteins.Intrinsically Disord Proteins1:e24360. 10.4161/idp.24360

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 306

  ThiemickeA.NeuertG. (2021). Kinetics of osmotic stress regulate a cell fate switch of cell survival.Sci. Adv.7:eabe1122. 10.1126/sciadv.abe1122

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 307

  ThwaitesD. T.AndersonC. M. (2007). Deciphering the mechanisms of intestinal imino (and amino) acid transport: the redemption of SLC36A1.Biochim. Biophys. Acta1768179–197. 10.1016/j.bbamem.2006.10.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 308

  ThwaitesD. T.AndersonC. M. (2011). The SLC36 family of proton-coupled amino acid transporters and their potential role in drug transport.Br. J. Pharmacol.1641802–1816. 10.1111/j.1476-5381.2011.01438.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 309

  TomlinsonC.RafiiM.BallR. O.PencharzP. B. (2011a). Arginine can be synthesized from enteral proline in healthy adult humans.J. Nutr.1411432–1436. 10.3945/jn.110.137224

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 310

  TomlinsonC.RafiiM.SgroM.BallR. O.PencharzP. (2011b). Arginine is synthesized from proline, not glutamate, in enterally fed human preterm neonates.Pediatr. Res.6946–50. 10.1203/pdr.0b013e3181fc6ab7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 311

  TownB. W. (1928). The isolation of pure l-proline.Biochem. J.221083–1086. 10.1042/bj0221083

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 312

  TranD. H.KesavanR.RionH.SoflaeeM. H.SolmonsonA.BezwadaD.et al (2021). Mitochondrial NADP(+) is essential for proline biosynthesis during cell growth.Nat. Metab.3571–585. 10.1038/s42255-021-00374-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 313

  TreleavenT.HardyM. L. M.Guttman-JonesM.MorrisM. B.DayM. L. (2021). In vitro fertilisation of mouse oocytes in L-Proline and L-Pipecolic acid improves subsequent development.Cells10:1352. 10.3390/cells10061352

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 314

  TrovatoM.MarasB.LinharesF.CostantinoP. (2001). The plant oncogene rolD encodes a functional ornithine cyclodeaminase.Proc. Natl. Acad. Sci. U S A.9813449–13453. 10.1073/pnas.231320398

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 315

  TrovatoM.MattioliR.CostantinoP. (2018). From A. rhizogenes RolD to plant P5CS: exploiting proline to control plant development.Plants (Basel)7:108. 10.3390/plants7040108

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 316

  TugnoliB.BernardiniC.ForniM.PivaA.StahlC. H.GrilliE. (2019). Butyric acid induces spontaneous adipocytic differentiation of porcine bone marrow-derived mesenchymal stem cells.Vitro Cell Dev. Biol. Anim.5517–24. 10.1007/s11626-018-0307-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 317

  UgwuD. I.OkoroU. C.MishraN. K. (2018). Synthesis of proline derived benzenesulfonamides: a potent anti-Trypanosoma brucei gambiense agent.Eur. J. Med. Chem.154110–116. 10.1016/j.ejmech.2018.05.017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 318

  ValleD.GoodmanS. I.ApplegarthD. A.ShihV. E.PhangJ. M. (1976). Type II hyperprolinemia. Delta1-pyrroline-5-carboxylic acid dehydrogenase deficiency in cultured skin fibroblasts and circulating lymphocytes.J. Clin. Invest.58598–603. 10.1172/jci108506

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 319

  ValleD. L.PhangJ. M.GoodmanS. I. (1974). Type 2 hyperprolinemia: absence of delta1-pyrroline-5-carboxylic acid dehydrogenase activity.Science1851053–1054. 10.1126/science.185.4156.1053

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 320

  VelasquezS. M.RicardiM. M.DoroszJ. G.FernandezP. V.NadraA. D.Pol-FachinL.et al (2011). O-glycosylated cell wall proteins are essential in root hair growth.Science3321401–1403. 10.1126/science.1206657

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 321

  Velaz-FairclothM.Guadano-FerrazA.HenziV. A.FremeauR. T.Jr. (1995). Mammalian brain-specific L-proline transporter. neuronal localization of mRNA and enrichment of transporter protein in synaptic plasma membranes.J. Biol. Chem.27015755–15761. 10.1074/jbc.270.26.15755

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 322

  VerbruggenN.HermansC. (2008). Proline accumulation in plants: a review.Amino Acids35753–759. 10.1007/s00726-008-0061-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 323

  VerreyF.SingerD.RamadanT.Vuille-Dit-BilleR. N.MariottaL.CamargoS. M. (2009). Kidney amino acid transport.Pflugers. Arch.45853–60.

  • Google Scholar

• 324

  VersluesP. E.SharmaS. (2010). Proline metabolism and its implications for plant-environment interaction.Arabidopsis Book8:e0140. 10.1199/tab.0140

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 325

  VillafrazO.BiranM.PinedaE.PlazollesN.CahoreauE.Ornitz Oliveiraet al (2021). Procyclic trypanosomes recycle glucose catabolites and TCA cycle intermediates to stimulate growth in the presence of physiological amounts of proline.PLoS Pathog17:e1009204. 10.1371/journal.ppat.1009204

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 326

  WachterR.LanghansM.AloniR.GotzS.WeilmunsterA.KoopsA.et al (2003). Vascularization, high-volume solution flow, and localized roles for enzymes of sucrose metabolism during tumorigenesis by Agrobacterium tumefaciens.Plant Physiol.1331024–1037. 10.1104/pp.103.028142

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 327

  WangA.BolenD. W. (1996). Effect of proline on lactate dehydrogenase activity: testing the generality and scope of the compatibility paradigm.Biophys. J.712117–2122. 10.1016/s0006-3495(96)79410-9

  • CrossRef
  • Google Scholar

• 328

  WashingtonJ. M.RathjenJ.FelquerF.LonicA.BettessM. D.HamraN.et al (2010). L-Proline induces differentiation of ES cells: a novel role for an amino acid in the regulation of pluripotent cells in culture.Am. J. Physiol. Cell Physiol.298C982–C992.

  • Google Scholar

• 329

  WeinbergerB.HannaN.LaskinJ. D.HeckD. E.GardnerC. R.GereckeD. R.et al (2005). Mechanisms mediating the biologic activity of synthetic proline, glycine, and hydroxyproline polypeptides in human neutrophils.Mediators Inflamm.200531–38. 10.1155/mi.2005.31

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 330

  WerneckR. I.MiraM. T.TrevilattoP. C. (2010). A critical review: an overview of genetic influence on dental caries.Oral. Dis.16613–623. 10.1111/j.1601-0825.2010.01675.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 331

  WhiteF. F.TaylorB. H.HuffmanG. A.GordonM. P.NesterE. W. (1985). Molecular and genetic analysis of the transferred DNA regions of the root-inducing plasmid of Agrobacterium rhizogenes.J. Bacteriol.16433–44. 10.1128/jb.164.1.33-44.1985

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 332

  WiesenthalA. A.MullerC.HarderK.HildebrandtJ. P. (2019). Alanine, proline and urea are major organic osmolytes in the snail Theodoxus fluviatilis under hyperosmotic stress.J. Exp. Biol.222(Pt 3):jeb193557.

  • Google Scholar

• 333

  WondrakG. T.JacobsonM. K.JacobsonE. L. (2005). Identification of quenchers of photoexcited States as novel agents for skin photoprotection.J. Pharmacol. Exp. Ther.312482–491. 10.1124/jpet.104.075101

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 334

  WuG.BazerF. W.DattaS.JohnsonG. A.LiP.SatterfieldM. C.et al (2008). Proline metabolism in the conceptus: implications for fetal growth and development.Amino Acids35691–702. 10.1007/s00726-008-0052-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 335

  WuG.BazerF. W.HuJ.JohnsonG. A.SpencerT. E. (2005). Polyamine synthesis from proline in the developing porcine placenta.Biol. Reprod.72842–850. 10.1095/biolreprod.104.036293

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 336

  WuH.De GraafB.MarianiC.CheungA. Y. (2001). Hydroxyproline-rich glycoproteins in plant reproductive tissues: structure, functions and regulation.Cell Mol. Life. Sci.581418–1429. 10.1007/pl00000785

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 337

  WuJ.SubbaiahK. C. V.XieL. H.JiangF.KhorE. S.MickelsenD.et al (2020). Glutamyl-Prolyl-tRNA synthetase regulates proline-rich pro-fibrotic protein synthesis during cardiac fibrosis.Circ. Res.127827–846. 10.1161/circresaha.119.315999

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 338

  WyseA. T.NettoC. A. (2011). Behavioral and neurochemical effects of proline.Metab. Brain Dis.26159–172. 10.1007/s11011-011-9246-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 339

  XieZ.KlionskyD. J. (2007). Autophagosome formation: core machinery and adaptations.Nat. Cell Biol.91102–1109. 10.1038/ncb1007-1102

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 340

  YamM.EngelA. L.WangY.ZhuS.HauerA.ZhangR.et al (2019). Proline mediates metabolic communication between retinal pigment epithelial cells and the retina.J. Biol. Chem.29410278–10289. 10.1074/jbc.ra119.007983

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 341

  YamaguchiM.ShiraishiT.HiramaM. (1996). Asymmetric michael addition of malonate anions to prochiral acceptors catalyzed by L-proline rubidium salt.J. Org. Chem.613520–3530. 10.1021/jo960216c

  • CrossRef
  • Google Scholar

• 342

  YangS. L.LanS. S.GongM. (2009). Hydrogen peroxide-induced proline and metabolic pathway of its accumulation in maize seedlings.J. Plant Physiol.1661694–1699. 10.1016/j.jplph.2009.04.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 343

  YeY.WuY.WangJ. (2018). Pyrroline-5-carboxylate reductase 1 promotes cell proliferation via inhibiting apoptosis in human malignant melanoma.Cancer Manag. Res.106399–6407. 10.2147/cmar.s166711

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 344

  YenC. A.CurranS. P. (2021). Incomplete proline catabolism drives premature sperm aging.Aging Cell20:e13308.

  • Google Scholar

• 345

  YoonS. C.JangY. L.KimJ. W.ChoE. Y.ParkD. Y.HongK. S.et al (2016). Linkage and association analyses of schizophrenia with genetic variations on chromosome 22q11 in Koreans.Psychiatry Investig.13630–636. 10.4306/pi.2016.13.6.630

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 346

  YoshibaY.KiyosueT.NakashimaK.Yamaguchi-ShinozakiK.ShinozakiK. (1997). Regulation of levels of proline as an osmolyte in plants under water stress.Plant Cell Physiol.381095–1102. 10.1093/oxfordjournals.pcp.a029093

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 347

  ZakiM. S.BhatG.SultanT.IssaM.JungH. J.DikogluE.et al (2016). PYCR2 mutations cause a lethal syndrome of microcephaly and failure to thrive.Ann. Neurol.8059–70. 10.1002/ana.24678

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 348

  ZaprasisA.BrillJ.ThuringM.WunscheG.HeunM.BarzantnyH.et al (2013). Osmoprotection of Bacillus subtilis through import and proteolysis of proline-containing peptides.Appl. Environ. Microbiol.79576–587. 10.1128/aem.01934-12

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 349

  ZarseK.SchmeisserS.GrothM.PriebeS.BeusterG.KuhlowD.et al (2012). Impaired insulin/IGF1 signaling extends life span by promoting mitochondrial L-proline catabolism to induce a transient ROS signal.Cell Metab.15451–465. 10.1016/j.cmet.2012.02.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 350

  Zdunek-ZastockaE.GrabowskaA.MichniewskaB.OrzechowskiS. (2021). Proline concentration and its metabolism are regulated in a leaf age dependent manner but not by abscisic acid in pea plants exposed to cadmium stress.Cells10:946. 10.3390/cells10040946

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 351

  ZengT.ZhuL.LiaoM.ZhuoW.YangS.WuW.et al (2017). Knockdown of PYCR1 inhibits cell proliferation and colony formation via cell cycle arrest and apoptosis in prostate cancer.Med. Oncol.34:27.

  • Google Scholar

• 352

  ZhangL.AlfanoJ. R.BeckerD. F. (2015). Proline metabolism increases katG expression and oxidative stress resistance in Escherichia coli.J. Bacteriol.197431–440. 10.1128/jb.02282-14

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 353

  ZhangL.XueX.YanJ.YanL. Y.JinX. H.ZhuX. H.et al (2016a). Cryobiological characteristics of L-proline in mammalian oocyte cryopreservation.Chin. Med. J. (Engl)1291963–1968. 10.4103/0366-6999.187846

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 354

  ZhangL.XueX.YanJ.YanL. Y.JinX. H.ZhuX. H.et al (2016b). L-proline: a highly effective cryoprotectant for mouse oocyte vitrification.Sci. Rep.6:26326.

  • Google Scholar

• 355

  ZhangP.WangJ.LuoW.YuanJ.CuiC.GuoL.et al (2021a). Kindlin-2 acts as a key mediator of lung fibroblast activation and pulmonary fibrosis progression.Am. J. Respir. Cell Mol. Biol.6554–69. 10.1165/rcmb.2020-0320oc

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 356

  ZhangX.GongX.LiD.YueH.QinY.LiuZ.et al (2021b). Genome-Wide identification of PRP genes in apple genome and the role of MdPRP6 in response to heat stress.Int. J. Mol. Sci.22:5942. 10.3390/ijms22115942

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 357

  ZhuJ.SchworerS.BerisaM.KyungY. J.RyuK. W.YiJ.et al (2021). Mitochondrial NADP(H) generation is essential for proline biosynthesis.Science372968–972. 10.1126/science.abd5491

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 358

  ZippG. G.BarbosaJ.GreenM. A.TerranovaK. M.FinkC.YuX. C.et al (2014). Novel inhibitors of the high-affinity L-proline transporter as potential therapeutic agents for the treatment of cognitive disorders.Bioorg. Med. Chem. Lett.243886–3890. 10.1016/j.bmcl.2014.06.049

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 359

  ZouariM.Ben AhmedC.ElloumiN.BellassouedK.DelmailD.LabrousseP.et al (2016). Impact of proline application on cadmium accumulation, mineral nutrition and enzymatic antioxidant defense system of Olea europaea L. cv Chemlali exposed to cadmium stress.Ecotoxicol. Environ. Saf.128195–205. 10.1016/j.ecoenv.2016.02.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 360

  ZwartsL.VulstekeV.BuhlE.HodgeJ. J. L.CallaertsP. (2017). SlgA, encoded by the homolog of the human schizophrenia-associated gene PRODH, acts in clock neurons to regulate Drosophila aggression.Dis. Model. Mech.10705–716.

  • Google Scholar