AUTHOR=Pollegioni Loredano , Molla Gianluca , Sacchi Silvia , Murtas Giulia 

TITLE=Human D-aspartate Oxidase: A Key Player in D-aspartate Metabolism

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=8

YEAR=2021

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2021.689719

DOI=10.3389/fmolb.2021.689719

ISSN=2296-889X

ABSTRACT=<p>In recent years, the D-enantiomers of amino acids have been recognized as natural molecules present in all kingdoms, playing a variety of biological roles. In humans, <sc>d</sc>-serine and <sc>d</sc>-aspartate attracted attention for their presence in the central nervous system. Here, we focus on <sc>d</sc>-aspartate, which is involved in glutamatergic neurotransmission and the synthesis of various hormones. The biosynthesis of <sc>d</sc>-aspartate is still obscure, while its degradation is due to the peroxisomal flavin adenine dinucleotide (FAD)-containing enzyme <sc>d</sc>-aspartate oxidase. <sc>d</sc>-Aspartate emergence is strictly controlled: levels decrease in brain within the first days of life while increasing in endocrine glands postnatally and through adulthood. The human <sc>d</sc>-aspartate oxidase (hDASPO) belongs to the <sc>d</sc>-amino acid oxidase-like family: its tertiary structure closely resembles that of human <sc>d</sc>-amino acid oxidase (hDAAO), the enzyme that degrades neutral and basic <sc>d</sc>-amino acids. The structure-function relationships of the physiological isoform of hDASPO (named hDASPO_341) and the regulation of gene expression and distribution and properties of the longer isoform hDASPO_369 have all been recently elucidated. Beyond the substrate preference, hDASPO and hDAAO also differ in kinetic efficiency, FAD-binding affinity, pH profile, and oligomeric state. Such differences suggest that evolution diverged to create two different ways to modulate <sc>d</sc>-aspartate and <sc>d</sc>-serine levels in the human brain. Current knowledge about hDASPO is shedding light on the molecular mechanisms underlying the modulation of <sc>d</sc>-aspartate levels in human tissues and is pushing novel, targeted therapeutic strategies. Now, it has been proposed that dysfunction in NMDA receptor-mediated neurotransmission is caused by disrupted <sc>d</sc>-aspartate metabolism in the nervous system during the onset of various disorders (such as schizophrenia): the design of suitable hDASPO inhibitors aimed at increasing <sc>d</sc>-aspartate levels thus represents a novel and useful form of therapy.</p>