Mammalian alcohol dehydrogenase 3 (ADH3) has several essential functions

The human alcohol dehydrogenase 3 enzyme (ADH3) has been assigned two essential roles, besides a general action in oxidation or reduction of alcohols and aldehydes. These are glutathione-dependent oxidation of formaldehyde and glutathione-dependent reduction of nitric oxide (NO), where the actual substrates are hydroxymethylglutathione (HMGSH) and S-nitrosoglutathione (GSNO), respectively. ADH3 mRNA associates with proliferative keratinocytes where it exhibits a comparatively short half-life and may be used as a marker for cell proliferation. However, the ADH3 protein as such is extremely stable and shows substantial capacity for formaldehyde detoxification, indicating that ADH3 is the major enzyme involved in formaldehyde oxidation. Furthermore, ADH3 rapidly catalyzes the reductive breakdown of GSNO to glutathione sulfinamide. Human ADH3 reduces GSNO with a k(cat)/K-m approximately 50% higher than that for HMGSH oxidation, resulting in the highest catalytic efficiency yet identified for the enzyme. An argument against an ADH3 mediated reduction of GSNO is the low NADH/NAD(+) ratio in the cell. However, at least two observations support such a function. Firstly, the major product of GSNO reduction neither serves as substrate nor inhibitor for the enzyme. Hence, the reaction products are not substrates for ADH3, and the overall reaction is therefore irreversible. Secondly, we have shown that alcohol oxidation, corresponding to physiologically relevant levels, will produce enough reduced coenzyme to drive the reduction of GSNO. Altogether this indicates the essential functions of ADH3 acting upon a large set of interacting substrates, which probably depends on the cellular status particularly with respect to the redox levels. Finally, identified allele variants may affect ADH3 expression levels in individuals, adding further complexity to understanding the metabolic functions of the ADH3 enzyme.