d-Amino acids are the "wrong" enantiomers of amino acids as they are not used in proteins synthesis but evolved in selected functions. On this side, d-aspartate (d-Asp) plays several significant roles in mammals, especially as an agonist of N-methyl-d-aspartate receptors (NMDAR), and is involved in relevant diseases, such as schizophrenia and Alzheimer's disease. In vivo modulation of d-Asp levels represents an intriguing task to cope with such pathological states. As little is known about d-Asp synthesis, the only option for modulating the levels is via degradation, which is due to the flavoenzyme d-aspartate oxidase (DASPO). Here we present the first three-dimensional structure of a DASPO enzyme (from human) which belongs to the d-amino acid oxidase family. Notably, human DASPO differs from human d-amino acid oxidase (attributed to d-serine degradation, the main coagonist of NMDAR) showing peculiar structural features (a specific active site charge distribution), oligomeric state and kinetic mechanism, and a higher FAD affinity and activity. These results provide useful insights into the structure-function relationships of human DASPO: modulating its activity represents now a feasible novel therapeutic target.
Structure and kinetic properties of human d-aspartate oxidase, the enzyme-controlling d-aspartate levels in brain / G. Molla, A. Chaves-Sanjuan, A. Savinelli, M. Nardini, L. Pollegioni. - In: FASEB JOURNAL. - ISSN 1530-6860. - 34:1(2020 Jan), pp. 1182-1197.
|Titolo:||Structure and kinetic properties of human d-aspartate oxidase, the enzyme-controlling d-aspartate levels in brain|
CHAVES SANJUAN, ANTONIO (Secondo)
NARDINI, MARCO (Corresponding)
|Parole Chiave:||d‐aspartate; d‐aspartate oxidase; flavoprotein; NMDA receptor; structure‐function relationships|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
|Data di pubblicazione:||gen-2020|
|Data ahead of print / Data di stampa:||29-nov-2019|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1096/fj.201901703R|
|Appare nelle tipologie:||01 - Articolo su periodico|