title: Oxidation and reduction of 4-hydroxyalkenals catalyzed by isozymes of human alcohol dehydrogenase.
abstract: 4-Hydroxyalkenals, natural cytotoxic products of lipid peroxidation, are substrates for human alcohol dehydrogenases (ADH). Class I and II ADHs reduce aliphatic 4-hydroxyalkenals with chain lengths of from 5 to 15 carbons at pH 7 with kcat and Km values comparable to simple aliphatic aldehydes of the same chain length. Class II is particularly effective in the reduction with kcat values as high as 3300 min-1 for 4-hydroxyundecenal. Class III ADH is essentially inactive toward all of these substrates. The class I and II isozymes also catalyze the oxidation of the 4-hydroxy group at pH 10. However, during the reaction, an NAD(+)-dependent irreversible partial inactivation of the alpha beta 1 isozyme is observed which is attributed, with the aid of computer graphics modeling, to selective modification of the alpha subunit. Both ethanol and 1,10-phenanthroline, known to compete with conventional substrates, instantaneously, reversibly, and competitively inhibit 4-hydroxyalkenal reduction and oxidation, indicating that 4-hydroxyalkenals bind at the same site as do conventional substates. The fact that the class II enzyme pi pi-ADH so far is found only in the liver and that the 4-hydroxyalkenals are the best substrates known for this isozyme suggest that it may play a significant role in cellular defenses in the conversion of the cytotoxic aldehydes to the less reactive alcohols.
authors.affiliation: Department of Biochemistry, University of Uppsala Biomedical Center, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Sellin
authors.forename: B
authors.initials: B
authors.lastname: Holmquist
authors.forename: B
authors.initials: B
authors.lastname: Mannervik
authors.forename: B L
authors.initials: BL
authors.lastname: Vallee
mesh_terms: D000426:Alcohol Dehydrogenase / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D010084:Oxidation-Reduction; D013379:Substrate Specificity
chemical_list: D000447:Aldehydes; D007527:Isoenzymes; D000426:Alcohol Dehydrogenase