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Class II alcohol dehydrogenase (ADH2) — adding the structure

Authors
Journal
Chemico-Biological Interactions
0009-2797
Publisher
Elsevier
Publication Date
Identifiers
DOI: 10.1016/s0009-2797(00)00276-3
Keywords
  • Alcohol Dehydrogenase
  • Crystal Structure
  • Hydrogen Transfer
  • Mutagenesis
Disciplines
  • Biology

Abstract

Abstract Class II alcohol dehydrogenase (ADH2) represents a highly divergent class of alcohol dehydrogenases predominantly found in liver. Several species variants of ADH2 have been described, and the rodent enzymes form a functionally distinct subgroup with interesting catalytic properties. First, as compared with other ADHs, the catalytic efficiency is low for this subgroup. Second, the substrate repertoire is unique, e.g. rodent ADH2s are not saturated with ethanol as substrate, and while ω-hydroxy fatty acids are common substrates for the human ADH1–ADH4 isoenzymes, including ADH2, these compounds function as inhibitors rather than substrates. The recently determined structure of mouse ADH2 reveals a novel substrate-pocket topography that accounts for the observed substrate specificity and may, therefore, be important for the exploration of orphan substrates of ADH2. It is possible to improve the catalytic efficiency of mouse ADH2 by an array of mutations at position 47. Residue Pro47 of the wild type ADH2 enzyme seems to strain the binding of coenzyme, which prevents a close approach between the coenzyme and substrate for efficient hydrogen transfer. Based on crystallographic and mechanistic investigations, the effects of residue replacements at position 47 are multiple, affecting the distance for hydride transfer, the p K a of the bound alcohol substrate as well as the affinity for coenzyme.

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