Fundamental molecular differences between alcohol dehydrogenase classes.

Abstract

Two types of alcohol dehydrogenase in separate protein families are the "medium-chain" zinc enzymes (including the classical liver and yeast forms) and the "shortchain" enzymes (including the insect form). Although the medium-chain family has been characterized in prokaryotes and many eukaryotes (fungi, plants, cephalopods, and verte-brates), insects have seemed to possess only the short-chain enzyme. We have now also characterized a medium-chain alcohol dehydrogenase in Drosophila. The developmental stages of the fly, compatible with the constitutive nature of the vertebrate enzyme. Taken together, the results bridge a previously apparent gap in the distribution of medium-chain alcohol dehydrogenases and establish a strictly conserved class m enzyme, consistent with an important role for this enzyme in cellular metabolism.The "classical" alcohol dehydrogenase is part of a widespread system of zinc-containing enzymes (1). In mammalian tissues, at least six classes of this enzyme occur. They differ considerably and represent stages between separate enzymes and ordinary isozymes. Class I is the well-known liver enzyme with ethanol dehydrogenase activity (2), class III is identical with glutathione-dependent formaldehyde dehydrogenase (3), class IV is a form preferentially expressed in stomach (4, 5), while classes II, V, and VI, although little studied, are known also to exhibit distinct properties (6, 7, 44). The class origins have been traced to gene duplications early in vertebrate evolution [the I/III duplication (8)] or during that evolution [the IV/I duplication (5)], with emerging activities toward ethanol (9); class III corresponds to an ancestral form. These properties and the different evolutionary patterns, with class III being "constant" and class I "variable" (10), result in a consistent picture of the enzyme system and place the classes of medium-chain alcohol dehydrogenases as separate enzymes in the cellular metabolism.Similarly, another protein family, short-chain dehydrogenases, has also evolved into a family comprising many different enzyme activities, including an alcohol dehydrogenase (11). This form operates by means of a completely different catalytic mechanism and is related to mammalian prostaglandin dehydrogenases/carbonyl reductase (12). Thus far, this alcohol dehydrogenase has been found in insects, the Drosophila enzyme being recognized early to differ from the zinc-containing alcohol dehydrogenases (13,14). Its properties in various Drosophila species are well established (15).These two alcohol dehydrogenase types demonstrate that ethanol dehydrogenase activity has evolved in different manners, with many organisms now employing a medium-chain enzyme, while others depend on a short-chain enzyme. The medium-chain family has not been identified in insects, although it is of ancient origin and has been characterized in other eukaryotes and in prokaryotes. We now show that the family is indeed present also in insects and that its major representative is the typical class III t...

Arabidopsis Formaldehyde Dehydrogenase

“…The results show a unique band in both restriction patterns, suggesting that the region of DNA spanned by the clone exists in a single copy in the Arabidopsis genome. Evidence for a single-copy gene has been reported also for Drosophilu class 111 alcohol dehydrogenase (Luque et al, 1994).…”

Two Zebrafish Alcohol Dehydrogenases Share Common Ancestry with Mammalian Class I, II, IV, and V Alcohol Dehydrogenase Genes but Have Distinct Functional Characteristics

“…The human ADH5 mRNA is developmentally expressed in the fetal tissues including the brain, lung, liver, and kidney (32). The medium-chain class III alcohol dehydrogenase in Drosophila melanogaster is expressed throughout the larval, pupal, and adult life stages of the fly (33). In mice, ADH5 mRNA is detected as early as 6.5 days postcoitum and is nearly ubiquitously expressed in adult tissues (31).…”

Differentiation-dependent expression of Adhfe1 in adipogenesis

“…NAD+ or NADP+-dependent alcohol dehydrogenases (ADHs) comprise an enzyme superfamily whose members have been demonstrated to have wide substrate specificities as well as various and extensive metabolic functions [9,30,31,46,54]. ADHs of higher organisms have been broadly classified as the medium-chain dehydrogenases/reductases (MDRs) [30,45] and the short-chain dehydrogenase/reductases (SDRs) [48].…”