Human D-Amino Acid Oxidase: Structure, Function, and Regulation
TLDR
The known properties of human DAAO suggest that its activity must be finely tuned to fulfill a main physiological function such as the control of D-serine levels in the brain as well as the role of post-translational modifications on its main biochemical properties at the cellular level.Abstract:
D-Amino acid oxidase (DAAO) is an FAD-containing flavoenzyme that catalyzes with absolute stereoselectivity the oxidative deamination of all natural D-amino acids, the only exception being the acidic ones. This flavoenzyme plays different roles during evolution and in different tissues in humans. Its three-dimensional structure is well conserved during evolution: minute changes are responsible for the functional differences between enzymes from microorganism sources and those from humans. In recent years several investigations focused on human DAAO, mainly because of its role in degrading the neuromodulator D-serine in the central nervous system. D-Serine is the main coagonist of N-methyl D-aspartate receptors, i.e., excitatory amino acid receptors critically involved in main brain functions and pathologic conditions. Human DAAO possesses a weak interaction with the FAD cofactor; thus, in vivo it should be largely present in the inactive, apoprotein form. Binding of active-site ligands and the substrate stabilizes flavin binding, thus pushing the acquisition of catalytic competence. Interestingly, the kinetic efficiency of the enzyme on D-serine is very low. Human DAAO interacts with various proteins, in this way modulating its activity, targeting, and cell stability. The known properties of human DAAO suggest that its activity must be finely tuned to fulfill a main physiological function such as the control of D-serine levels in the brain. At present, studies are focusing on the epigenetic modulation of human DAAO expression and the role of post-translational modifications on its main biochemical properties at the cellular level.read more
Citations
More filters
Journal ArticleDOI
L-serine synthesis via the phosphorylated pathway in humans
TL;DR: It is believed that an in-depth investigation of these enzymes is crucial to identify the molecular mechanisms involved in modulating concentrations of the serine enantiomers and for studying the interplay between glial and neuronal cells and also to determine the most suitable therapeutic approach for various diseases.
Journal ArticleDOI
D-cysteine is an endogenous regulator of neural progenitor cell dynamics in the mammalian brain.
Evan R. Semenza,Maged M. Harraz,Efrat Abramson,Adarsha P. Malla,Chirag Vasavda,Moataz M. Gadalla,Michael D. Kornberg,Solomon H. Snyder,Robin Roychaudhuri +8 more
TL;DR: Using chiral high-performance liquid chromatography and a stereospecific luciferase assay, this paper identified endogenous d-cysteine in the mammalian brain and implicate it as a physiologic regulator of NPC homeostasis in the developing brain.
Journal ArticleDOI
The Role of D-Amino Acids in Alzheimer's Disease.
TL;DR: In this paper, the experimental findings linking D-serine and D-aspartate, through NMDA receptor modulation, to AD and cognitive functions, were reported, which was also associated with the enzymes related to D-amino acid metabolism as well as with glucose and serine metabolism.
Journal ArticleDOI
The Role of Host-Generated H2S in Microbial Pathogenesis: New Perspectives on Tuberculosis.
Aejazur Rahman,Joel N. Glasgow,Sajid Nadeem,Vineel P. Reddy,Ritesh R. Sevalkar,Jack R. Lancaster,Adrie J. C. Steyn +6 more
TL;DR: The current understanding of the role of host-derived H2S in tuberculosis (TB) disease, including its influences on host immunity and bioenergetics, and on Mycobacterium tuberculosis (Mtb) growth and survival is described.
Journal ArticleDOI
Cerebrospinal fluid and serum d-serine concentrations are unaltered across the whole clinical spectrum of Alzheimer's disease.
Tommaso Nuzzo,Mattia Miroballo,Alessia Casamassa,Andrea Mancini,Lorenzo Gaetani,Robert Nisticò,Paolo Eusebi,Masumi Katane,Hiroshi Homma,Paolo Calabresi,Francesco Errico,Lucilla Parnetti,Alessandro Usiello +12 more
TL;DR: The results failed to confirm previous findings indicating the CSF d-serine as a novel biomarker for AD, and instead measured blood serum and CSF concentration of two NMDAR modulators, such as d-Serine and d-aspartate, in a cohort of drug-free subjects encompassing the whole AD clinical spectrum.
References
More filters
Journal ArticleDOI
Spinal D-Amino Acid Oxidase Contributes to Neuropathic Pain in Rats
TL;DR: Investigation of the potential role of DAO in neuropathic pain in a rat model of tight L5/L6 spinal nerve ligation concludes that spinal DAO plays a pronociceptive role and might be a target molecule for the treatment of chronic pain of neuropathic origin.
Journal ArticleDOI
Novel targets for drugs in schizophrenia.
James M. Stone,Lyn S. Pilowsky +1 more
TL;DR: This review summarises the main neurochemical theories of schizophrenia, and examines possible therapeutic targets for new antipsychotic drugs including glutamate, acetylcholine and serotonin neurotransmitter systems.
Journal ArticleDOI
Relevance of weak flavin binding in human D-amino acid oxidase.
TL;DR: It is proposed that the absence in vivo of an active site ligand/substrate weakens the cofactor binding, yielding the inactive apoprotein form and thus avoiding excessive D‐serine degradation.
Journal Article
Characterization of D-amino acid oxidase from Trigonopsis variabilis.
TL;DR: D-amino acid oxidase from Trigonopsis variabilis was purified to homogeneity as a well resolved flavoprotein giving typical flavin spectral perturbations.
Journal ArticleDOI
Activity of D-amino acid oxidase is widespread in the human central nervous system
TL;DR: The distribution of DAO activity in cerebral white matter and the motor system in humans is established, providing evidence to support the involvement ofDAO in schizophrenia and ALS and raising further questions about the regulation of D-serine in DAO-rich regions as well as the physiological/pathological roles of DAOs in white matter astrocytes.