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Structure and kinetic properties of human d ‐aspartate oxidase, the enzyme‐controlling d ‐aspartate levels in brain

DOI: 10.1096/fj.201901703R DOI Help

Authors: Gianluca Molla (Università degli studi dell’Insubria) , Antonio Chaves‐sanjuan (Università degli studi di Milano) , Antonio Savinelli (Università degli studi dell’Insubria) , Marco Nardini (Università degli studi di Milano) , Loredano Pollegioni (Università degli studi dell’Insubria)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Faseb Journal , VOL 20

State: Published (Approved)
Published: November 2019

Abstract: 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.

Journal Keywords: d‐aspartate; d‐aspartate oxidase; flavoprotein; NMDA receptor; structure‐function relationships

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I04-Macromolecular Crystallography

Added On: 04/12/2019 14:58

Discipline Tags:

Catalysis Life Sciences & Biotech Health & Wellbeing Neurology Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)