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Bioscience of D-Amino Acid Oxidase from Biochemistry to Pathophysiology

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D-amino acid oxidase (DAO or DAAO, EC 1.4.3.3) is a flavoenzyme catalyzing oxidative deamination of D-amino acids. DAO has been reported in all domains of life, but is most diversely found in eukaryotes. Favorable substrates for DAO are neutral or basic D-amino acids, which are usually produced by bacteria in ...

D-amino acid oxidase (DAO or DAAO, EC 1.4.3.3) is a flavoenzyme catalyzing oxidative deamination of D-amino acids. DAO has been reported in all domains of life, but is most diversely found in eukaryotes. Favorable substrates for DAO are neutral or basic D-amino acids, which are usually produced by bacteria in nature, albeit with some variations among species. Therefore, DAO appears to be employed in eukaryotes to catabolize bacterial D-amino acids.

One evolutional exception for DAO’s substrates is D-serine, which is synthesized de novo in mammalian brain. D-Serine is converted from L-serine in the central nervous system (CNS) and modulates excitatory neurotransmission through binding to N-methyl-D-aspartate (NMDA)-type glutamate receptors. DAO, found at high level in the hindbrain and spinal cord, determines distribution of D-serine, which exists in forebrain-shifted manner. Therefore, DAO in the mammalian CNS has been extensively studied in relation to modulatory function of the NMDA receptors through degrading D-serine. Although regional and cellular distribution of DAO in the human CNS still remains controversial, association of DAO gene with neurologic and psychiatric diseases has raised its neurophysiological and etiological significance in humans. Notably, regulation of human DAO activity has been regarded as a target for drug development in the area. Human DAO shows peculiar properties that distinguish it from other non-primate mammal homologues: it shows a stable homodimeric state, a low activity/kinetic efficiency, low affinity for FAD, and a specific modulation by pLG72 binding.

In contrast to its role in mammalian CNS, role of DAO in peripheral tissues is less understood. DAO activity has been reported in the kidney, liver (rats and humans), neutrophils, and small intestine. Such “peripheral DAO” is thought to be involved not only in intrinsic catabolism of D-serine but also of D-amino acids originated from food or commensal microbiota, as well as in hydrogen sulfide production. Renal DAO is reported in the proximal tubules and its role in renal diseases has recently been highlighted in terms of dysregulation of both D-amino acids and hydrogen sulfide. A further aspect in “peripheral DAO” is a role in innate immunity. Since host-microbe interface involves DAO expressed in neutrophils or intestinal epithelial layer, bactericidal effect of hydrogen peroxide generated through catabolism of D-amino acids from pathogenic or commensal bacteria has provided a distinct aspect of DAO physiology from neurobiology.

This Research Topic focuses on all aspects of eukaryotic (especially mammalian) DAO including structure, enzyme biochemistry, regulation, drug development, and physiology and/or pathology in the CNS or peripheral organs. We welcome the contribution of Original Research and Reviews articles.


Keywords: D-amino acid oxidase, D-serine, NMDA receptor, pLG72, bacterial D-amino acids


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