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.
Highlights
Using FAD as cofactor, D-amino acid oxidase (DAAO, EC 1.4.3.3) catalyzes with strict stereoselectivity the oxidative deamination of neutral D-amino acids
We recently proposed that pLG72 might target the cytosolic form of human DAAO (hDAAO) to the ubiquitin-proteasome system, starting its degradation (Cappelletti et al, 2014)
With the final aim to use hDAAO in different tissues responding to several needs, evolution adopted complicated regulatory strategies to modulate the activity of the flavoenzyme
Summary
Using FAD as cofactor, D-amino acid oxidase (DAAO, EC 1.4.3.3) catalyzes with strict stereoselectivity the oxidative deamination of neutral D-amino acids. Appreciable levels of various D-amino acids were determined in brain and other tissues based on improved analytical methods (mainly high-performance liquid chromatography) (Nagata, 1992; Nagata et al, 1992; Hashimoto et al, 1993; Hamase et al, 1997). This cleared the path to identifying specific physiological roles for D-amino acids (Wang et al, 2000; Wolosker et al, 2002; Fuchs et al, 2005) and to propose for DAAO a key role in their metabolic control. SR is poorly expressed in astrocytes, which instead produce DAAO; in these cells the flavoenzyme indirectly controls its availability at the synapse by regulating D-serine cellular concentrations and affects the activation level of NMDAR by modulating the occupancy of the co-agonist site
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