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

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.

The Role of Host-Generated H2S in Microbial Pathogenesis: New Perspectives on Tuberculosis

“…In contrast, a pathway which does not require PLP for H 2 S synthesis involves two enzymes, D-amino acid oxidase (DAO) and 3-MST. Here, DAO catalyzes D-cysteine to 3-mercaptopyruvate, the substrate for 3-MST ( Figure 1 ) ( Shibuya et al., 2013 ; Pollegioni et al., 2018 ).…”

“…In the cysteine catabolism pathway, CAT converts L-cysteine and α-ketoglutarate into glutamate and 3-mercaptopyruvate (3-MP), as stated above. 3-MP is also generated from D-cysteine by D-amino acid oxidase (DAO) ( Shibuya et al., 2013 ; Pollegioni et al., 2018 ). 3-MST then transfers the sulfur atom from 3-MP to a nucleophilic Cys 248 (the catalytic site in human 3-MST) to generate a 3-MST-bound persulfide and pyruvate.…”

Natural Occurrence, Biological Functions, and Analysis of D-Amino Acids

“…The structures and functions of DAAO have received intense attention in recent years due to its versatility. [26][27][28][29][30] In 1995, Schell et al discovered that D-Ser was localized principally within glial cells. Specifically, they found that type-2 astrocytes, which were cultured from cerebral cortex, expressed particularly high levels of D-Ser.…”

Development of Chemical Biology Tools Focusing on Peptide/Amide Bond Cleavage Reaction

“…11C (depicted as predicted binding site A and B). The site A is reasonable because there is an entrance of a substratebinding pocket, in which inhibitors such as benzoate are known to bind 68) ; however, the site B was unexpected. The predicted pockets were then verified using the SEAL technology.…”

“…ClarificationofLigand-BindingPocketsofhDAODimierA) Structure of 4-bromo-3-nitrobenzoic acid (BNBA); B) Structure of SEAL with a BNBA-derived ligand moiety; C) Labeled residues and computationally predicted BNBA-bindingpocketsofhDAOdimer(PDBID:2du868) ).…”