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Journal ArticleDOI

Human D-Amino Acid Oxidase: Structure, Function, and Regulation

28 Nov 2018-Frontiers in Molecular Biosciences (Frontiers Media SA)-Vol. 5, pp 107-107
TL;DR: 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.

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Citations
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Journal ArticleDOI
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.
Abstract: L-serine is a nonessential amino acid in eukaryotic cells, used for protein synthesis and in producing phosphoglycerides, glycerides, sphingolipids, phosphatidylserine, and methylenetetrahydrofolate Moreover, L-serine is the precursor of two relevant coagonists of NMDA receptors: glycine (through the enzyme serine hydroxymethyltransferase), which preferentially acts on extrasynaptic receptors and D-serine (through the enzyme serine racemase), dominant at synaptic receptors The cytosolic "phosphorylated pathway" regulates de novo biosynthesis of L-serine, employing 3-phosphoglycerate generated by glycolysis and the enzymes 3-phosphoglycerate dehydrogenase, phosphoserine aminotransferase, and phosphoserine phosphatase (the latter representing the irreversible step) In the human brain, L-serine is primarily found in glial cells and is supplied to neurons for D-serine synthesis Serine-deficient patients show severe neurological symptoms, including congenital microcephaly, psychomotor retardation, and intractable seizures, thus highlighting the relevance of de novo production of this amino acid in brain development and morphogenesis Indeed, the phosphorylated pathway is strictly linked to cancer Moreover, L-serine has been suggested as a ready-to-use treatment, as also recently proposed for Alzheimer's disease Here, we present our current state of knowledge concerning the three mammalian enzymes of the phosphorylated pathway and known mutations related to pathological conditions: although the structure of these enzymes has been solved, how enzyme activity is regulated remains largely unknown We believe 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

36 citations


Cites background from "Human D-Amino Acid Oxidase: Structu..."

  • ...Here, D-serine cellular concentration is modulated by the catabolic activity of DAAO [27, 28]....

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  • ...Here, D-serine cellular concentration is modulated by the catabolic activity of DAAO [27, 28]....

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  • ...1 3 Taken together, elucidating the mechanisms affecting the function of enzymes belonging to the phosphorylated pathway and those related to serine metabolism (namely, SR, DAAO, and SHMT) might provide key information for designing specific molecular approaches/tools by which cellular concentrations of serine could be finely tuned....

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  • ...D-Serine is then degraded by both the α and β-elimination reaction catalyzed by SR and oxidative deamination catalyzed by d-amino acid oxidase (DAAO, EC 1.4.3.3) [25–28] (Fig....

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Journal ArticleDOI
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.
Abstract: d-amino acids are increasingly recognized as important signaling molecules in the mammalian central nervous system. However, the d-stereoisomer of the amino acid with the fastest spontaneous racemization ratein vitro in vitro, cysteine, has not been examined in mammals. Using chiral high-performance liquid chromatography and a stereospecific luciferase assay, we identify endogenous d-cysteine in the mammalian brain. We identify serine racemase (SR), which generates the N-methyl-d-aspartate (NMDA) glutamate receptor coagonist d-serine, as a candidate biosynthetic enzyme for d-cysteine. d-cysteine is enriched more than 20-fold in the embryonic mouse brain compared with the adult brain. d-cysteine reduces the proliferation of cultured mouse embryonic neural progenitor cells (NPCs) by ∼50%, effects not shared with d-serine or l-cysteine. The antiproliferative effect of d-cysteine is mediated by the transcription factors FoxO1 and FoxO3a. The selective influence of d-cysteine on NPC proliferation is reflected in overgrowth and aberrant lamination of the cerebral cortex in neonatal SR knockout mice. Finally, we perform an unbiased screen for d-cysteine-binding proteins in NPCs by immunoprecipitation with a d-cysteine-specific antibody followed by mass spectrometry. This approach identifies myristoylated alanine-rich C-kinase substrate (MARCKS) as a putative d-cysteine-binding protein. Together, these results establish endogenous mammalian d-cysteine and implicate it as a physiologic regulator of NPC homeostasis in the developing brain.

24 citations

Journal ArticleDOI
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.
Abstract: Alzheimer's disease (AD), the main cause of dementia worldwide, is characterized by a complex and multifactorial etiology In large part, excitatory neurotransmission in the central nervous system is mediated by glutamate and its receptors are involved in synaptic plasticity The N-methyl-D-aspartate (NMDA) receptors, which require the agonist glutamate and a coagonist such as glycine or the D-enantiomer of serine for activation, play a main role here A second D-amino acid, D-aspartate, acts as agonist of NMDA receptors D-amino acids, present in low amounts in nature and long considered to be of bacterial origin, have distinctive functions in mammals In recent years, alterations in physiological levels of various D-amino acids have been linked to various pathological states, ranging from chronic kidney disease to neurological disorders Actually, the level of NMDA receptor signaling must be balanced to promote neuronal survival and prevent neurodegeneration: this signaling in AD is affected mainly by glutamate availability and modulation of the receptor's functions Here, we report the experimental findings linking D-serine and D-aspartate, through NMDA receptor modulation, to AD and cognitive functions Interestingly, AD progression has been also associated with the enzymes related to D-amino acid metabolism as well as with glucose and serine metabolism Furthermore, the D-serine and D-/total serine ratio in serum have been recently proposed as biomarkers of AD progression A greater understanding of the role of D-amino acids in excitotoxicity related to the pathogenesis of AD will facilitate novel therapeutic treatments to cure the disease and improve life expectancy

24 citations

Journal ArticleDOI
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.
Abstract: For centuries, hydrogen sulfide (H2S) was considered primarily as a poisonous gas and environmental hazard. However, with the discovery of prokaryotic and eukaryotic enzymes for H2S production, breakdown, and utilization, H2S has emerged as an important signaling molecule in a wide range of physiological and pathological processes. Hence, H2S is considered a gasotransmitter along with nitric oxide (•NO) and carbon monoxide (CO). Surprisingly, despite having overlapping functions with •NO and CO, the role of host H2S in microbial pathogenesis is understudied and represents a gap in our knowledge. Given the numerous reports that followed the discovery of •NO and CO and their respective roles in microbial pathogenesis, we anticipate a rapid increase in studies that further define the importance of H2S in microbial pathogenesis, which may lead to new virulence paradigms. Therefore, this review provides an overview of sulfide chemistry, enzymatic production of H2S, and the importance of H2S in metabolism and immunity in response to microbial pathogens. We then describe our 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. Finally, this review discusses the utility of H2S-donor compounds, inhibitors of H2S-producing enzymes, and their potential clinical significance.

20 citations


Cites background from "Human D-Amino Acid Oxidase: Structu..."

  • ...Here, DAO catalyzes D- November 2020 | Volume 10 | Article 586923 cysteine to 3-mercaptopyruvate, the substrate for 3-MST (Figure 1) (Shibuya et al., 2013; Pollegioni et al., 2018)....

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  • ...3-MP is also generated from D-cysteine by D-amino acid oxidase (DAO) (Shibuya et al., 2013; Pollegioni et al., 2018)....

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Journal ArticleDOI
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.

17 citations

References
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Journal ArticleDOI
TL;DR: The major triggers that initiate and maintain central sensitization in healthy individuals in response to nociceptor input and in patients with inflammatory and neuropathic pain are reviewed, emphasizing the fundamental contribution and multiple mechanisms of synaptic plasticity caused by changes in the density, nature, and properties of ionotropic and metabotropic glutamate receptors.

2,803 citations

Journal ArticleDOI
TL;DR: Hypofunction of the NMDA receptor, possibly on critical GABAergic inter-neurons, may contribute to the pathophysiology of schizophrenia.
Abstract: 1. After 50 years of antipsychotic drug development focused on the dopamine D2 receptor, schizophrenia remains a chronic, disabling disorder for most affected individuals.

886 citations


"Human D-Amino Acid Oxidase: Structu..." refers background in this paper

  • ...An NMDAR hypofunction was also related to schizophrenia (Coyle et al., 2003; Coyle, 2006; Stone and Pilowsky, 2007): the altered activation state of the receptor was proposed to depend on a deficiency in D-serine signaling (Hashimoto et al....

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  • ...An NMDAR hypofunction was also related to schizophrenia (Coyle et al., 2003; Coyle, 2006; Stone and Pilowsky, 2007): the altered activation state of the receptor was proposed to depend on a deficiency in D-serine signaling (Hashimoto et al., 2003, 2005; Verrall et al., 2010)....

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Journal ArticleDOI
TL;DR: The first update of BindingDB since 2007 is provided, focusing on new and unique features and highlighting directions of importance to the field as a whole.
Abstract: BindingDB, www.bindingdb.org, is a publicly accessible database of experimental protein-small molecule interaction data. Its collection of over a million data entries derives primarily from scientific articles and, increasingly, US patents. BindingDB provides many ways to browse and search for data of interest, including an advanced search tool, which can cross searches of multiple query types, including text, chemical structure, protein sequence and numerical affinities. The PDB and PubMed provide links to data in BindingDB, and vice versa; and BindingDB provides links to pathway information, the ZINC catalog of available compounds, and other resources. The BindingDB website offers specialized tools that take advantage of its large data collection, including ones to generate hypotheses for the protein targets bound by a bioactive compound, and for the compounds bound by a new protein of known sequence; and virtual compound screening by maximal chemical similarity, binary kernel discrimination, and support vector machine methods. Specialized data sets are also available, such as binding data for hundreds of congeneric series of ligands, drawn from BindingDB and organized for use in validating drug design methods. BindingDB offers several forms of programmatic access, and comes with extensive background material and documentation. Here, we provide the first update of BindingDB since 2007, focusing on new and unique features and highlighting directions of importance to the field as a whole.

871 citations


"Human D-Amino Acid Oxidase: Structu..." refers background in this paper

  • ...More than 500 substrate-competitive inhibitors have been identified so far (Gilson et al., 2016)....

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Journal ArticleDOI
27 Mar 2015-Science
TL;DR: A moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS found several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene.
Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.

813 citations


"Human D-Amino Acid Oxidase: Structu..." refers background in this paper

  • ...A recent, comprehensive, exomesequencing study revealed that the only DNA variants associated with clinical outcome of ALS and with lower rates of survival are located on the DAO gene (Cirulli et al., 2015)....

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Journal ArticleDOI
TL;DR: A map of 191 single-nucleotide polymorphism (SNPs) was built across a 5-Mb segment from chromosome 13q34 that has been genetically linked to schizophrenia, pointing to the involvement of this N-methyl-d-aspartate receptor regulation pathway in schizophrenia.
Abstract: A map of 191 single-nucleotide polymorphism (SNPs) was built across a 5-Mb segment from chromosome 13q34 that has been genetically linked to schizophrenia. DNA from 213 schizophrenic patients and 241 normal individuals from Canada were genotyped with this marker set. Two 1,400- and 65-kb regions contained markers associated with the disease. Two markers from the 65-kb region were also found to be associated to schizophrenia in a Russian sample. Two overlapping genes G72 and G30 transcribed in brain were experimentally annotated in this 65-kb region. Transfection experiments point to the existence of a 153-aa protein coded by the G72 gene. This protein is rapidly evolving in primates, is localized to endoplasmic reticulum/Golgi in transfected cells, is able to form multimers and specifically binds to carbohydrates. Yeast two-hybrid experiments with the G72 protein identified the enzyme d-amino acid oxidase (DAAO) as an interacting partner. DAAO is expressed in human brain where it oxidizes d-serine, a potent activator of N-methyl-D-aspartate type glutamate receptor. The interaction between G72 and DAAO was confirmed in vitro and resulted in activation of DAAO. Four SNP markers from DAAO were found to be associated with schizophrenia in the Canadian samples. Logistic regression revealed genetic interaction between associated SNPs in vicinity of two genes. The association of both DAAO and a new gene G72 from 13q34 with schizophrenia together with activation of DAAO activity by a G72 protein product points to the involvement of this N-methyl-d-aspartate receptor regulation pathway in schizophrenia.

802 citations


"Human D-Amino Acid Oxidase: Structu..." refers background in this paper

  • ...Further support comes from the discovery that the G72 gene, encoding the small protein pLG72, the main hDAAO-specific binding protein (see below), has been linked to schizophrenia (Chumakov et al., 2002; Sacchi et al., 2008, 2016; Pollegioni et al., 2018)....

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