Stimulation of retinoic acid production and growth by ubiquitously expressed alcohol dehydrogenase Adh3.
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.
Molotkov
Andrei
A
Gene Regulation Program, Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Fan
Xiaohong
X
Deltour
Louise
L
Foglio
Mario H
MH
Martras
Silvia
S
Farrés
Jaume
J
Parés
Xavier
X
Duester
Gregg
G
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
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