title: Stimulation of retinoic acid production and growth by ubiquitously expressed alcohol dehydrogenase Adh3.
abstract: Influence of vitamin A (retinol) on growth depends on its sequential oxidation to retinal and then to retinoic acid (RA), producing a ligand for RA receptors essential in development of specific tissues. Genetic studies have revealed that aldehyde dehydrogenases function as tissue-specific catalysts for oxidation of retinal to RA. However, enzymes catalyzing the first step of RA synthesis, oxidation of retinol to retinal, remain unclear because none of the present candidate enzymes have expression patterns that fully overlap with those of aldehyde dehydrogenases during development. Here, we provide genetic evidence that alcohol dehydrogenase (ADH) performs this function by demonstrating a role for Adh3, a ubiquitously expressed form. Adh3 null mutant mice exhibit reduced RA generation in vivo, growth deficiency that can be rescued by retinol supplementation, and completely penetrant postnatal lethality during vitamin A deficiency. ADH3 was also shown to have in vitro retinol oxidation activity. Unlike the second step, the first step of RA synthesis is not tissue-restricted because it is catalyzed by ADH3, a ubiquitous enzyme having an ancient origin.
authors.affiliation: Gene Regulation Program, Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Molotkov
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Fan
authors.forename: Louise
authors.initials: L
authors.lastname: Deltour
authors.forename: Mario H
authors.initials: MH
authors.lastname: Foglio
authors.forename: Silvia
authors.initials: S
authors.lastname: Martras
authors.forename: Jaume
authors.initials: J
authors.lastname: Farrés
authors.forename: Xavier
authors.initials: X
authors.lastname: Parés
authors.forename: Gregg
authors.initials: G
authors.lastname: Duester
mesh_terms: D000426:Alcohol Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D000429:Alcohol Oxidoreductases / Q000096:biosynthesis; D000818:Animals; D003600:Cytosol / Q000201:enzymology; D005838:Genotype; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010100:Oxygen / Q000378:metabolism; D012172:Retinaldehyde / Q000378:metabolism; D013997:Time Factors; D014212:Tretinoin / Q000378:metabolism*; D014801:Vitamin A / Q000378:metabolism / Q000494:pharmacology; D014802:Vitamin A Deficiency / Q000378:metabolism
chemical_list: D014801:Vitamin A; D014212:Tretinoin; D000429:Alcohol Oxidoreductases; C420272:ADH1C protein, human; C456281:Adh7 protein, mouse; D000426:Alcohol Dehydrogenase; C022520:retinol dehydrogenase; D012172:Retinaldehyde; D010100:Oxygen