Catalytic Efficiency of Human Alcohol Dehydrogenases for Retinol Oxidation and Retinal Reduction

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Abstract
Mammalian alcohol dehydrogenase (ADH) is thought to be involved in the reversible oxidation of vitamin A or retinol to retinal for retinoic acid synthesis. Retinoic acid is a potent transcriptional regulator and a morphogen. It was proposed that the competition of consumed ethanol with retinol oxidation by ADH might explain developmental disorders seen with fetal alcohol syndrome. We report herein the dative efficiency (V/Km) of eight human ADH isoenzymes for oxidation of all-trans-retinol and reduction of three retinal isomers (all-frans, Scis, and 134s-retinal). Class IV σσ and class II ππ isoenzymes are the most efficient forms, with VIKm values ∼100 and 30 times greater, respectively, than class I β1β1 or γ1,γ1. σσ exhibits the highest V/K, (1–2 μm−1min-−1), followed by ππ, with V/Km of 0.5–0.6 pm−1min−1 for all-trans-retinol, all-trans-retinal, and 9-cis-retinal. ππ also has the lowest Km (11–14 μm) for all-trans-retinol and three retinal isomers. αα shows an intermediate efficiency, with V/Km of 0.09–0.2 am−1min−1 and a relatively low Km of 16–24 μm for all four substrates. αα has the highest efficiency of all tested isoenzymes for 13-cis-retinal. Class 111 xx is inactive with all the tested retinoids. The contribution of class IV σσ, class II ππ, and even class I αα to retinol oxidation and retinal reduction in vivo will depend on expression of these isoenzymes in specific tissues, relative activities toward free retinol/retinal versus that bound to the cellular retinol binding protein (CRBP or CRBP II) and the concentration of free versus bound retinoids.