Abstract
In the central nervous system, the flavoprotein D-amino acid oxidase is responsible for catabolizing D-serine, the main endogenous coagonist of N-methyl-D-aspartate receptor. Dysregulation of D-serine brain levels in humans has been associated with neurodegenerative and psychiatric disorders. This D-amino acid is synthesized by the enzyme serine racemase, starting from the corresponding L-enantiomer, and degraded by both serine racemase (via an elimination reaction) and the flavoenzyme D-amino acid oxidase. To shed light on the role of human D-amino acid oxidase (hDAAO) in D-serine metabolism, the structural/functional relationships of this enzyme have been investigated in depth and several strategies aimed at controlling the enzymatic activity have been identified. Here, we focused on the effect of post-translational modifications: by using a combination of structural analyses, biochemical methods, and cellular studies, we investigated whether hDAAO is subjected to nitrosylation, sulfhydration, and phosphorylation. hDAAO is S-nitrosylated and this negatively affects its activity. In contrast, the hydrogen sulfide donor NaHS seems to alter the enzyme conformation, stabilizing a species with higher affinity for the flavin adenine dinucleotide cofactor and thus positively affecting enzymatic activity. Moreover, hDAAO is phosphorylated in cerebellum; however, the protein kinase involved is still unknown. Taken together, these findings indicate that D-serine levels can be also modulated by post-translational modifications of hDAAO as also known for the D-serine synthetic enzyme serine racemase.
Highlights
The FAD-dependent enzyme D-amino acid oxidase (DAAO, EC 1.4.3.3) catalyzes the degradation of D-amino acids, the only exception being aspartate and glutamate (Pollegioni et al, 2007)
A relevant physiological role was highlighted for human D-amino acid oxidase (hDAAO) in the central nervous system: in several areas, it is responsible for catabolizing the key endogenous NMDAr coagonist D-Ser (Sacchi et al, 2012; Murtas et al, 2017; Pollegioni et al, 2018)
The chemical modification of cysteine residues can result from different processes: the direct reaction with nitric oxide (NO) followed by oxidation (Hess et al, 2005) and the transnitrosylation either by S-nitrosylated proteins (Nakamura and Lipton, 2013) or by Snitrosylated peptides, (GSNO) being among them (Broniowska et al, 2013)
Summary
The FAD-dependent enzyme D-amino acid oxidase (DAAO, EC 1.4.3.3) catalyzes the degradation of D-amino acids, the only exception being aspartate and glutamate (Pollegioni et al, 2007). D-serine (D-Ser) represents the physiological substrate of DAAO. Post-Translational Modifications of Human DAAO receptors (NMDAr): it binds the glycine site of these receptors, which regulate activity (Mothet et al, 2000) and physiological functions (Collingridge et al, 2013). D-Ser metabolism in the brain is due to the activity of two enzymes: in addition to DAAO, serine racemase (SR, EC 5.1.1.18) catalyzes both the synthesis of D-Ser from the L-enantiomer and its degradation via an α,β-elimination reaction (Wolosker et al, 1999). DAAO is the main enzyme involved in D-Ser catabolism since SR is only marginally expressed
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