Regulation mechanisms of human D-amino acid oxidase

Abstract

The human peroxisomal FAD-dependent enzyme D-amino acid oxidase (hDAAO, EC 1.4.3.3) plays a key role in important physiological processes by catalyzing the stereospecific degradation of several D-amino acids (D-AAs). A number of studies demonstrated that a dysregulation in processes regulating D-AAs concentration is related to the mechanism(s) predisposing to several pathologies. The important role played by hDAAO in modulating D-AAs levels increased the interest for this flavoenzyme: while structural and biochemical properties have been extensively investigated, several aspects in the modulation of its functionality remain elusive. Furthermore, it has been recently suggested that DAAO could be mistargeted to the nucleus or secreted in the (mouse) intestinal lumen, where it could select the composition of gut microbiota by generating H2O2. Here, some biochemical properties of the recombinant enzyme were investigated. Moreover, we focused on mistargeting of DAAO by studying a variant lacking the N-terminal signal peptide (thus shedding light on the mechanism of microbiota selection) and two variants at position 120 (a residue belonging to a putative nuclear translocation signal): the cellular targeting of the flavoenzyme seems a way to modulate hDAAO functionality. This modulation allows hDAAO to fulfil different physiological functions, such as the control of the level of D-Ser in the brain and of other D-AAs in different tissues or the selection of microbiota in the gut