Basic features of class‐I alcohol dehydrogenase: variable and constant segments coordinated by inter‐class and intra‐class variability

Persson, Bengt; Bergman, Tomas; Keung, Wing Ming; Waldenström, Ulrika; Holmquist, Barton; Vallée, Bert L.; Jörnvall, Hans

doi:10.1111/j.1432-1033.1993.tb18115.x

Cited by 31 publications

(19 citation statements)

References 21 publications

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“…(31,32). Their properties can be compared with those of the classical liver alcohol dehydrogenase ofclass I, whose structure, within the same family, has been analyzed recently to a level showing approximately the same residue divergence (conserved residues, 42%) by analysis of five major vertebrate lines (40).…”

Section: Resultsmentioning

confidence: 99%

Fundamental molecular differences between alcohol dehydrogenase classes.

Danielsson

Atrian

Luque

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

135

128

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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...

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Section: Resultsmentioning

confidence: 99%

Fundamental molecular differences between alcohol dehydrogenase classes.

Danielsson

Atrian

Luque

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

135

128

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“…Although this is still in the millimolar range typical of class I enzymes, as noted above, the value is considerably higher than, for example, for chicken (0.5 mM), alligator (1.2 mM), and the human PIP, (1.2mM) and ylyl (1.1 mM) enzymes (at pH 10.0) [3,21,281. They all have Arg at position 271, instead of the less basic His271 unique to ostrich, and branched-chain residues at position 141, instead of the smaller Ala seen in the ostrich form.…”

Section: H F N Y G V S V I V G V P P a A E K L S F D P M L L F S G R mentioning

confidence: 93%

“…Thus, it has a K,, for ethanol in the millimolar range at pH 10 and a K, for 4-methylpyrazole with ethanol in the micromolar range (see above). Furthermore, it has a residue identity with class I enzymes of 86-87% toward those characterized from two other birds [21, 221, of 82% toward that characterized from one reptile (alligator) [3], and of 72-76% toward those 14 subunits characterized from 8 mammals (18, lo].…”

Section: Relationship To Other Alcohol Dehydrogenasesmentioning

confidence: 99%

“…Reagents and buffers were removed by dialysis. Separate batches of the carboxymethylated protein were cleaved with CNBr (0.2 g / d in 70% formic acid), or digested with Achromobacter lysine-specific protease (Wako Chemicals), Pseudomonas aspartic-acid-specific and Staphylococcal glutamic-acid-specific proteases (Boehringer Mannheim), and bovine chymotrypsin (Merck), all in 0.1 M ammonium bicarbonate, pH 8, frequently in the presence of low concentrations of urea [3]. The resulting peptide pools were fractionated by reverse-phase HPLC on Vydac C, and C8, and TSK ODs-120T C,8.…”

Section: Structural Analysismentioning

confidence: 99%

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Diversity of Vertebrate Class I Alcohol Dehydrogenase

Estonius

Jörnvall

1994

European Journal of Biochemistry

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Class I alcohol dehydrogenase has been characterized from ostrich liver in order to evaluate enzyme variability between two independent lines, mammalian forms of class I alcohol dehydrogenase as a group, and a sufficient number of the enzyme from the most recent animal class (Aves, birds) as another. Between the two enzyme groups, patterns are consistent and mutually similar. This indicates conserved metabolic and catalytic properties of class I alcohol dehydrogenase, suggesting its metabolic role to be distinct, in spite of its protein variability. The new structure has a microheterogeneity (position 112, Arg/Cys) in a variable Zn-binding loop. In addition, it also establishes further native variants at active-site positions, including one thus far unique residue at the inner part of the substrate-binding pocket (Ala141), and a replacement at position 271 (giving His271), which is also the site of a human alcohol dehydrogenase y,Iy2 isozyme variability. The data correlate with functional differences in catalytic properties, the ostrich enzyme having a comparatively high K , for ethanol (5.9 mM at pH lo), and emphasize the importance of single positions in substrate and coenzyme binding, paralleling isozyme variability with protein variability within the class I enzymes.

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“…However, this requires knowledge of variants in each case. Regarding classes I and P, many species variants have long been known (Sun and Plapp, 1992;Yokoyama and Harry, 1993;Persson et al, 1993;Shafqat et al, 1996b), although the internal patterns of class I/P molecular variation have not been compared. Regarding class I11 in plants, glutathione-dependent formaldehyde dehydrogenase activity has been reported for a few species (Uotila and Koivusalo, 1979;Giese et al, 1994) and recently also amino acid sequences for pea and maize class 111 alcohol dehydrogenases (Shafqat et al, 1996a;Sugaya and Sakai, 1996), but further variants and intra-class divergence are unknown.…”

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confidence: 99%

Arabidopsis Formaldehyde Dehydrogenase

Martínez

Achkor

Persson

et al. 1996

European Journal of Biochemistry

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A glutathione-dependent formaldehyde dehydrogenase (class I11 alcohol dehydrogenase) has been characterized from Arubidopsis thulium. This plant enzyme exhibits kinetic and molecular properties in common with the class I11 forms from mammals, with a K,, for S-hydroxymethylglutathione of 1.4 pM, an anodic electrophoretic mobility (PI: 5.3-5.6) and a cross-reaction with anti-(rat class I11 alcohol dehydrogenase) antibodies. The enzyme structure, deduced from the cDNA sequence, fits into the complex system of alcohol dehydrogenases and shows that all life forms share the class I11 protein type. The corresponding mRNA is 1.4 kb and present in all plant organs; a single copy of the gene is found in the genome. The class I11 structural variability is different from that of the ethanol-active enzyme types in both vertebrates (class I) and plants (class P), although class P conserves more of the class 111 properties than class I does. Also the enzymatic properties differ between the two ethanol-active classes. Activesite variability and exchanges at essential residues (Leu/Gly57, AsplArgll5) may explain the distinct kinetics. These patterns are consistent with two different metabolic roles for the ethanol-active enzymes, a more constant function, reduction of acetaldehyde during hypoxia, for class P, and a more variable function, the detoxication of alcohols and participation in metabolic conversions, for class I. A sequence motif, Pro-Xaa-IleNal-Xaa-Gly-His-Glu-Xaa-Xaa-Gly, common to all medium-chain alcohol dehydrogenases is defined.

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Basic features of class‐I alcohol dehydrogenase: variable and constant segments coordinated by inter‐class and intra‐class variability

Cited by 31 publications

References 21 publications

Fundamental molecular differences between alcohol dehydrogenase classes.

Fundamental molecular differences between alcohol dehydrogenase classes.

Diversity of Vertebrate Class I Alcohol Dehydrogenase

Arabidopsis Formaldehyde Dehydrogenase

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