Three-dimensional structures of the three human class I alcohol dehydrogenases

Citation
Ms. Niederhut et al., Three-dimensional structures of the three human class I alcohol dehydrogenases, PROTEIN SCI, 10(4), 2001, pp. 697-706
Citations number
46
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
PROTEIN SCIENCE
ISSN journal
0961-8368 → ACNP
Volume
10
Issue
4
Year of publication
2001
Pages
697 - 706
Database
ISI
SICI code
0961-8368(200104)10:4<697:TSOTTH>2.0.ZU;2-F
Abstract
In contrast with other animal species, humans possess three distinct genes for class I alcohol dehydrogenase and show polymorphic variation in the ADH 1B and ADH1C genes. The three class I alcohol dehydrogenase isoenzymes shar e similar to 93% sequence identity but differ in their substrate specificit y and their developmental expression. We report here the first three-dimens ional structures for the ADH1A and ADH1C*2 gene products at 2.5 and 2.0 Ang strom, respectively, and the structure of the ADH1B*1 gene product in a bin ary complex with cofactor at 2.2 Angstrom. Not surprisingly, the overall st ructure of each isoenzyme is highly similar to the others. However, the sub stitution of Gly for Arg at position 47 in the ADH1A isoenzyme promotes a g reater extent of domain closure in the ADH1A isoenzyme, whereas substitutio n at position 271 may account for the lower turnover rate for the ADH1C*2 i soenzyme relative to its polymorphic variant, ADH1C*1. The substrate-bindin g pockets of each isoenzyme possess a unique topology that dictates each is oenzyme's distinct but overlapping substrate preferences. ADH1*B1 has the m ost restrictive substrate-binding site near the catalytic zinc atom, wherea s both ADH1A and ADH1C*2 possess amino acid substitutions that correlate wi th their better efficiency for the oxidation of secondary alcohols. These s tructures describe the nature of their individual substrate-binding pockets and will improve our understanding of how the metabolism of beverage ethan ol affects the normal metabolic processes performed by these isoenzymes.