title: Structure-function relationships in human D-amino acid oxidase.
abstract: Since D-amino acids were identified in mammals, D-serine has been one of the most extensively studied "unnatural amino acids". This brain-enriched transmitter-like molecule plays a pivotal role in the human central nervous system by modulating the activity of NMDA receptors. Physiological levels of D-serine are required for normal brain development and function; thus, any alterations in neuromodulator concentrations might result in NMDA receptor dysfunction, which is known to be involved in several pathological conditions, including neurodegeneration(s), epilepsy, schizophrenia, and bipolar disorder. In the brain, the concentration of D-serine stored in cells is defined by the activity of two enzymes: serine racemase (responsible for both the synthesis and degradation) and D-amino acid oxidase (which catalyzes D-serine degradation). Both enzymes emerged recently as new potential therapeutic targets for NMDA receptor-related diseases. In this review we have focused on human D-amino acid oxidase and provide an extensive overview of the biochemical and structural properties of this flavoprotein and their functional significance. Furthermore, we discuss the mechanisms involved in modulating enzyme activity and stability with the aim to substantiate the pivotal role of D-amino acid oxidase in brain D-serine metabolism in physiological and pathological conditions and to highlight its great significance for novel drug design/development.
authors.affiliation: Dipartimento di Biotecnologie e Scienze della Vita, Università degli studi dell'Insubria, via J.H. Dunant 3, 21100 Varese, Italy. silvia.sacchi@uninsubria.it
authors.forename: Silvia
authors.initials: S
authors.lastname: Sacchi
authors.forename: Laura
authors.initials: L
authors.lastname: Caldinelli
authors.forename: Pamela
authors.initials: P
authors.lastname: Cappelletti
authors.forename: Loredano
authors.initials: L
authors.lastname: Pollegioni
authors.forename: Gianluca
authors.initials: G
authors.lastname: Molla
mesh_terms: D001921:Brain / Q000201:enzymology* / Q000503:physiopathology; D003605:D-Amino-Acid Oxidase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004795:Enzyme Stability; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000503:physiopathology; D018377:Neurotransmitter Agents / Q000737:chemistry / Q000378:metabolism*; D019998:Racemases and Epimerases / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012694:Serine / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission; D000099300:Serine Racemase
chemical_list: D003605:D-Amino-Acid Oxidase; D018377:Neurotransmitter Agents; D019998:Racemases and Epimerases; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D000099300:Serine Racemase; C417983:DAO protein, human