title: Activities of human alcohol dehydrogenases in the metabolic pathways of ethanol and serotonin.
abstract: Alcohols and aldehydes in the metabolic pathways of ethanol and serotonin are substrates for alcohol dehydrogenases (ADH) of class I and II. In addition to the reversible alcohol oxidation/aldehyde reduction, these enzymes catalyse aldehyde oxidation. Class-I gammagamma ADH catalyses the dismutation of both acetaldehyde and 5-hydroxyindole-3-acetaldehyde (5-HIAL) into their corresponding alcohols and carboxylic acids. The turnover of acetaldehyde dismutation is high (kcat = 180 min-1) but saturation is reached first at high concentrations (Km = 30 mm) while dismutation of 5-HIAL is saturated at lower concentrations and is thereby more efficient (Km = 150 microm; kcat = 40 min-1). In a system where NAD+ is regenerated, the oxidation of 5-hydroxytryptophol to 5-hydroxyindole-3-acetic acid proceeds with concentration levels of the intermediary 5-HIAL expected for a two-step oxidation. Butanal and 5-HIAL oxidation is also observed for class-I ADH in the presence of NADH. The class-II enzyme is less efficient in aldehyde oxidation, and the ethanol-oxidation activity of this enzyme is competitively inhibited by acetate (Ki = 12 mm) and 5-hydroxyindole-3-acetic acid (Ki = 2 mm). Reduction of 5-HIAL is efficiently catalysed by class-I gammagamma ADH (kcat = 400 min-1; Km = 33 microm) in the presence of NADH. This indicates that the increased 5-hydroxytryptophol/5-hydroxyindole-3-acetic acid ratio observed after ethanol intake may be due to the increased NADH/NAD+ ratio on the class-I ADH.
authors.affiliation: Department of Medical Biochemistry, Karolinska Institutet, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Svensson
authors.forename: M
authors.initials: M
authors.lastname: Some
authors.forename: A
authors.initials: A
authors.lastname: Lundsjö
authors.forename: A
authors.initials: A
authors.lastname: Helander
authors.forename: T
authors.initials: T
authors.lastname: Cronholm
authors.forename: J O
authors.initials: JO
authors.lastname: Höög
mesh_terms: D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism; D000431:Ethanol / Q000378:metabolism*; D006801:Humans; D006859:Hydrogen / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D006917:Hydroxytryptophol / Q000378:metabolism; D007700:Kinetics; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D012701:Serotonin / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D009243:NAD; D006917:Hydroxytryptophol; D012701:Serotonin; D000431:Ethanol; D006897:Hydroxyindoleacetic Acid; D006859:Hydrogen; D000426:Alcohol Dehydrogenase