Human α‐amino‐β‐carboxymuconate‐ε‐semialdehyde decarboxylase (ACMSD): A structural and mechanistic unveiling. Issue 1 (21st November 2014)

• Record Type: Journal Article
• Authors: Huo, Lu; Liu, Fange; Iwaki, Hiroaki; Li, Tingfeng; Hasegawa, Yoshie; Liu, Aimin
• Is Part Of: Proteins. Volume 83:Issue 1(2015)
• Page Start: 178
• Page End: 187
• Publication Date: 2014-11-21
• Subjects: Proteins -- Periodicals; Proteins -- Periodicals; 572.6
• DOI: 10.1002/prot.24722
• Languages: English
• ISSNs: 0887-3585

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p>Human α‐amino‐β‐carboxymuconate‐ε‐semialdehyde decarboxylase determines the fate of tryptophan metabolites in the kynurenine pathway by controlling the quinolinate levels for <italic>de novo</italic> nicotinamide adenine dinucleotide biosynthesis. The unstable nature of its substrate has made gaining insight into its reaction mechanism difficult. Our electron paramagnetic resonance (EPR) spectroscopic study on the Cu‐substituted human enzyme suggests that the native substrate does not directly ligate to the metal ion. Substrate binding did not result in a change of either the hyperfine structure or the super‐hyperfine structure of the EPR spectrum. We also determined the crystal structure of the human enzyme in its native catalytically active state (at 1.99 Å resolution), a substrate analogue‐bound form (2.50 Å resolution), and a selected active site mutant form with one of the putative substrate binding residues altered (2.32 Å resolution). These structures illustrate that each asymmetric unit contains three pairs of dimers. Consistent with the EPR findings, the ligand‐bound complex structure shows that the substrate analogue does not directly coordinate to the metal ion but is bound to the active site by two arginine residues through noncovalent interactions. Proteins 2015; 83:178–187. © 2014 Wiley Periodicals, Inc.</p> </abstract>