About this Research Topic
Dietary proteins, whether consumed with vegetarian or non-vegetarian diets, yield a variety of biologically important organic compounds known as amino acids upon hydrolysis. After a first-pass splanchnic extraction, amino acids become available to the whole body for the synthesis of proteins and other biomolecules necessary for cell metabolism and function. Achievement of a metabolic balance of plasma and intracellular amino acid availability requires a coordinated inter-organ metabolism of synthetic and catabolic pathways, naturally established in biological systems.
Among the 20 amino acids found in proteins, L-arginine plays a central role in the activity of the vascular endothelium, since it is the main substrate for endothelial nitric oxide synthase (eNOS). Unfortunately, mechanisms regulating L-arginine synthesis, plasma levels and intracellular availability remain elusive and attempts to enhance L-arginine availability for eNOS activity by oral intake were largely unsuccessful, due to the catabolic process in the hepatic urea cycle.
The discovery of the urea cycle, by Hans Krebs and Kurt Henseleit in 1932 marked a historical milestone in the field of cyclic metabolic pathways in living cells. The complete cycle takes place in periportal hepatocytes for the synthesis of urea, a crucial mechanism for disposal of toxic ammonia, where the enzyme arginase is known to play a central role.
Two arginase isoenzymes, AI (hepatic arginase) and AII (extrahepatic arginase) are present in mammalian tissues. Significant differences exist between the two isoenzymes regarding their subcellular localization, with AI residing in the cytosolic compartment and AII localized in the mitochondrion, as well as differences in isoelectric point, substrate affinity, and immunological cross-reactivity. However, both arginases have high specificity for the binding of and catabolic actions on its substrate, L-arginine.
Since arginase is a powerful competitor of eNOS, inhibition of arginase has emerged as a strategy to treat vascular endothelial dysfunction. However, besides the relevant function of arginase for ammonia disposal in the hepatic urea cycle, the numerous studies pointing toward other important functions of arginase in extrahepatic tissues including brain, kidney and immune cells raises the need for alternative approaches to enhance L-arginine availability. A more efficient approach to improve L-arginine availability for normal physiological cardiovascular and other organ functions could be to provide its precursor L-citrulline.
This Research Topic is intended to include original articles and reviews addressing the importance of amino acid metabolism in health and disease, with special emphasis on the inter-organ L-citrulline/L-arginine axis, and its implications in vascular and non-vascular cells. We will moreover address potential benefits and/or harmful outcomes from supplemental intervention in animal models, with projections toward human therapy.
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