Dataset Information

Competitive Inhibitors Unveil Structure/Function Relationships in Human D-Amino Acid Oxidase.

ABSTRACT: D-amino acid oxidase (DAAO) catalyzes the oxidative deamination of several neutral D-amino acids and is the enzyme mainly responsible (together with serine racemase) for degrading D-serine (D-Ser) in the central nervous system of mammals. This D-amino acid, which binds the coagonist site of the N-methyl-D-aspartate receptor, is thus a key neuromodulator of glutamatergic neurotransmission. Altered D-Ser metabolism results in several pathological conditions (e.g., amylotrophic lateral sclerosis or schizophrenia, SZ) for which effective "broad spectrum" pharmaceutical drugs are not yet available. In particular, the correlation between reduced D-Ser concentration and SZ led to a renaissance of biochemical interest in human DAAO (hDAAO). In the last 10 years, public and corporate research laboratories undertook huge efforts to study the structural, enzymatic, and physiological properties of the human flavoenzyme and to identify novel effective inhibitors which, acting as pharmaceutical drugs, could decrease hDAAO activity, thus restoring the physiological concentration of D-Ser. Although, none of the identified hDAAO inhibitors has reached the market yet, from a biochemical point of view, these compounds turned out to be invaluable for gaining a detailed understanding of the structure/function relationships at the molecular level in the mammalian DAAO, in particular of the interaction between ligand and the enzyme. This detailed knowledge, together with several recent studies concerning the interaction of the human enzyme with other protein regulative partners, its subcellular localization, and in vivo degradation, contributed to gaining comprehensive knowledge of the structure, function, and physiopathological role of this important human enzyme.

SUBMITTER: Molla G

PROVIDER: S-EPMC5715370 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Competitive Inhibitors Unveil Structure/Function Relationships in Human D-Amino Acid Oxidase.

Molla Gianluca G

Frontiers in molecular biosciences 20171127

D-amino acid oxidase (DAAO) catalyzes the oxidative deamination of several neutral D-amino acids and is the enzyme mainly responsible (together with serine racemase) for degrading D-serine (D-Ser) in the central nervous system of mammals. This D-amino acid, which binds the coagonist site of the N-methyl-D-aspartate receptor, is thus a key neuromodulator of glutamatergic neurotransmission. Altered D-Ser metabolism results in several pathological conditions (e.g., amylotrophic lateral sclerosis or ...[more]

PMID: 29250527

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Project description:Glutamine together with glucose is essential for body's homeostasis. It is the most abundant amino acid and is involved in many biosynthetic, regulatory and energy production processes. Several membrane transporters which differ in transport modes, ensure glutamine homeostasis by coordinating its absorption, reabsorption and delivery to tissues. These transporters belong to different protein families, are redundant and ubiquitous. Their classification, originally based on functional properties, has recently been associated with the SLC nomenclature. Function of glutamine transporters is studied in cells over-expressing the transporters or, more recently in proteoliposomes harboring the proteins extracted from animal tissues or over-expressed in microorganisms. The role of the glutamine transporters is linked to their transport modes and coupling with Na(+) and H(+). Most transporters share specificity for other neutral or cationic amino acids. Na(+)-dependent co-transporters efficiently accumulate glutamine while antiporters regulate the pools of glutamine and other amino acids. The most acknowledged glutamine transporters belong to the SLC1, 6, 7, and 38 families. The members involved in the homeostasis are the co-transporters B0AT1 and the SNAT members 1, 2, 3, 5, and 7; the antiporters ASCT2, LAT1 and 2. The last two are associated to the ancillary CD98 protein. Some information on regulation of the glutamine transporters exist, which, however, need to be deepened. No information at all is available on structures, besides some homology models obtained using similar bacterial transporters as templates. Some models of rat and human glutamine transporters highlight very similar structures between the orthologs. Moreover the presence of glycosylation and/or phosphorylation sites located at the extracellular or intracellular faces has been predicted. ASCT2 and LAT1 are over-expressed in several cancers, thus representing potential targets for pharmacological intervention.

Project description:Amino acid residues critical for a protein's structure-function are retained by natural selection and these residues are identified by the level of variance in co-aligned homologous protein sequences. The relevant residues in the nitrogen fixation Component 1 α- and β-subunits were identified by the alignment of 95 protein sequences. Proteins were included from species encompassing multiple microbial phyla and diverse ecological niches as well as the nitrogen fixation genotypes, anf, nif, and vnf, which encode proteins associated with cofactors differing at one metal site. After adjusting for differences in sequence length, insertions, and deletions, the remaining >85% of the sequence co-aligned the subunits from the three genotypes. Six Groups, designated Anf, Vnf , and Nif I-IV, were assigned based upon genetic origin, sequence adjustments, and conserved residues. Both subunits subdivided into the same groups. Invariant and single variant residues were identified and were defined as "core" for nitrogenase function. Three species in Group Nif-III, Candidatus Desulforudis audaxviator, Desulfotomaculum kuznetsovii, and Thermodesulfatator indicus, were found to have a seleno-cysteine that replaces one cysteinyl ligand of the 8Fe:7S, P-cluster. Subsets of invariant residues, limited to individual groups, were identified; these unique residues help identify the gene of origin (anf, nif, or vnf) yet should not be considered diagnostic of the metal content of associated cofactors. Fourteen of the 19 residues that compose the cofactor pocket are invariant or single variant; the other five residues are highly variable but do not correlate with the putative metal content of the cofactor. The variable residues are clustered on one side of the cofactor, away from other functional centers in the three dimensional structure. Many of the invariant and single variant residues were not previously recognized as potentially critical and their identification provides the bases for new analyses of the three-dimensional structure and for mutagenesis studies.

Dataset Information

Competitive Inhibitors Unveil Structure/Function Relationships in Human D-Amino Acid Oxidase.

Publications

Competitive Inhibitors Unveil Structure/Function Relationships in Human D-Amino Acid Oxidase.

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