Mammalian alcohol dehydrogenase — Functional and structural implications

Abstract

Mammalian alcohol dehydrogenase (ADH) constitutes a complex system with different forms and extensive multiplicity (ADH1-ADH6) that catalyze the oxidation and reduction of a wide variety of alcohols and aldehydes. The ADH1 enzymes, the classical liver forms, are involved in several metabolic pathways beside the oxidation of ethanol, e.g. norepinephrine, dopamine, serotonin and bile acid metabolism. This class is also able to further oxidize aldehydes into the corresponding carboxylic acids, i.e. dismutation. ADH2, can be divided into two subgroups, one group consisting of the human enzyme together with a rabbit form and another consisting of the rodent forms. The rodent enzymes almost lack ethanol-oxidizing capacity in contrast to the human form, indicating that rodents are poor model systems for human ethanol metabolism. ADH3 (identical to glutathione-dependent formaldehyde dehydrogenase) is clearly the ancestral ADH form and S-hydroxymethylglutathione is the main physiological substrate, but the enzyme can still oxidize ethanol at high concentrations. ADH4 is solely extrahepatically expressed and is probably involved in first pass metabolism of ethanol beside its role in retinol metabolism. The higher classes, ADH5 and ADH6, have been poorly investigated and their substrate repertoire is unknown. The entire ADH system can be seen as a general detoxifying system for alcohols and aldehydes without generating toxic radicals in contrast to the cytochrome P450 system.

Conservative evolution in duplicated genes of the primate Class I ADH cluster

“…The second split was between ADH1A and ADH1B. These results agree with our preliminary analyses using the neighbour joining (NJ) tree (Saitou and Nei, 1987) including all ADH classes based on cDNA and amino acid sequences from human, baboon, horse, mouse, rat, fish, amphioxus, and E. coli plasmid (tree not shown) derived from databases, and also with previously reported trees (Yokoyama and Yokoyama, 1987;Höög et al, 2001).…”

“…All ADH classes form dimers and catalyze oxidization of various kinds and concentrations of alcohols using NAD + /NADH as coenzyme (Eklund et al, 1976a,b;Höög et al, 2001). The ADH family is classified into five classes (I-V) based on biochemical properties, and nucleotide/amino acid sequence similarity.…”

Enrichment of ligands with molecular dockings and subsequent characterization for human alcohol dehydrogenase 3

“…Alcohol dehydrogenase 3 (ADH3), the ancestral form within the mammalian alcohol dehydrogenase system, is also known as glutathione-dependent formaldehyde dehydrogenase and S-nitrosoglutathione (GSNO) reductase [1][2][3][4]. The latter reflects the dual function of the enzyme [5].…”

“…Furthermore, the enzyme shows a universal presence and structural conservation that imply that ADH3 performs essential functions in many living organisms [6]. Functions attributed to ADH3 include first-pass ethanol metabolism, detoxification of endogenous and exogenous formaldehyde, nitric oxide (NO) homeostasis, contribution to retinoic acid formation, and oxidation of x-hydroxy fatty acids [1,5,[7][8][9][10].…”

Biomedical Vignette

“…Höög et al [14] reported the functions of ADH1-ADH4 and cautioned that rodents are poor model systems for human ethanol metabolism since the rodent ADH2 enzymes almost lack ethanol-oxidizing capacity in contrast to the human form. The authors further proposed that, in contrast to the cytochrome P450 system, the function of the entire ADH system could be seen as a general detoxifying system for alcohols and aldehydes without generating toxic radicals.…”