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Human ζ-crystallin is a Zn(2+)-lacking medium-chain dehydrogenase/reductase (MDR) included in the quinone oxidoreductase (QOR) family because of its activity with quinones. In the present work a novel enzymatic activity was characterized: the double bond α,β-hydrogenation of medium-chain 2-alkenals and 3-alkenones. The enzyme is especially active with lipid peroxidation products such as 4-hydroxyhexenal, and a role in their detoxification is discussed. This specificity is novel in the QOR family, and it is similar to that described in the distantly related alkenal/one reductase family. Moreover, we report the X-ray structure of ζ-crystallin, which represents the first structure solved for a tetrameric Zn(2+)-lacking MDR, and which allowed the identification of the active-site lining residues. Docking simulations suggest a role for Tyr53 and Tyr59 in catalysis. The kinetics of Tyr53Phe and Tyr59Phe mutants support the implication of Tyr53 in binding/catalysis of alkenal/one substrates, while Tyr59 is involved in the recognition of 4-OH-alkenals.

Original publication

DOI

10.1007/s00018-010-0508-2

Type

Journal article

Journal

Cell Mol Life Sci

Publication Date

03/2011

Volume

68

Pages

1065 - 1077

Keywords

Aldehydes, Catalysis, Cloning, Molecular, Crystallography, X-Ray, DNA Primers, Gas Chromatography-Mass Spectrometry, Humans, Hydrogenation, Kinetics, Models, Molecular, Molecular Structure, Mutagenesis, Site-Directed, Protein Binding, Protein Conformation, Substrate Specificity, zeta-Crystallins