Atypical human liver alcohol dehydrogenase: the β2‐Bern subunit has an amino acid exchange that is identical to the one in the β2‐Oriental chain

Bühler, Rolf E.; Hempel, John; Wartburg, Jean‐Pierre von; Jörnvall, Hans

doi:10.1016/0014-5793(84)80806-6

Cited by 20 publications

(8 citation statements)

References 24 publications

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“…The data explain the functional differences between the isozymes containing the "atypical" 82-Oriental and the "typical" 81 subunits. They also confirm the structure at the active site region of the f81 chain (17), which has been questioned, and relate the ,82-Oriental amino acid substitution to that of P2-Bern chains (33). Hence, the genetic origin of 82-Oriental and 132-Bern can be identical.…”

supporting

confidence: 58%

“…NatL Acad Sd USA 81 (1984) 67, also remains unchanged. Finally, the sequence around cysteine-46 shows that the isozyme subunits investigated previously (17) were P1 and y and that 32-Oriental and 132-Bern chains have the same amino acid exchange (33). Thus, 32-Oriental and ,82-Bern can have the same mutational origin.…”

Section: Resultsmentioning

confidence: 59%

“…Therefore, the report suggesting an inversion of residues 46 and 47 due to separate but adjacent mutations (27) is without support. § The data establish that cysteine-46, the protein ligand to the catalytic zinc atom in other liver alcohol dehydrogenases (33), is conserved also in human liver alcohol dehydrogenases, including the Oriental P2P32 allelic variant. As shown in Table 2, the second ligand to the active-site atom, histidine§Those assignments were based on tryptic analyses of the aminoethylated enzymes (27).…”

Section: Resultsmentioning

confidence: 71%

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Human liver alcohol dehydrogenase: amino acid substitution in the beta 2 beta 2 Oriental isozyme explains functional properties, establishes an active site structure, and parallels mutational exchanges in the yeast enzyme.

Jörnvall¹,

Hempel²,

Vallée³

et al. 1984

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

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The homodimeric Oriental 132132 isozyme of human liver alcohol dehydrogenase, corresponding to an allelic variant at the ADH2 gene locus, was studied in order to define the amino acid exchange in relation to the .813f3 isozyme, the predominant allelic form among Caucasians. Sequence analysis reveals that the amino acid substitution occurs at position 7 of the largest CNBr fragment, corresponding to position 47 of the whole protein chain. Here, the P2 form has a histidine residue, while, in common with other characterized mammalian liver alcohol dehydrogenases, the 81, form has an arginine residue. This exchange does not affect the adjacent cysteine-46 residue, which is a protein ligand to the active-site zinc atom, thus clarifying previously inconsistent results. The histidine/arginine-47 mutational replacement corresponds to a position that binds the pyrophosphate group of the coenzyme NAD(H); this explains the functional differences between the P13f1 and 82182 isozymes, including both a lower pH optimum and higher turnover number of 382132, which is likely to be the mutant form. The exchange demonstrates the existence of parallel but separate mutations in the evolution of alcohol dehydrogenases because these mammalian enzymes differ at exactly the same position by the same type of substitution as is found between a mutant and the wild-type constitutive forms of the corresponding yeast enzyme.

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supporting

confidence: 58%

Section: Resultsmentioning

confidence: 59%

Section: Resultsmentioning

confidence: 71%

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Human liver alcohol dehydrogenase: amino acid substitution in the beta 2 beta 2 Oriental isozyme explains functional properties, establishes an active site structure, and parallels mutational exchanges in the yeast enzyme.

Jörnvall¹,

Hempel²,

Vallée³

et al. 1984

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

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“…Atypical 02-subunits have been differently reported from livers of Caucasians and Asians (12-lern and f2-Oriental) (9,10), but both of these 2 types are now known to be structurally identical (11,12), differing from typical (1 subunits by a single His/Arg exchange at position 47. Another type of ADH, ADHIndianapolis, is probably derived from a further variant of the ADH2 locus (13).…”

mentioning

confidence: 99%

Human alcohol dehydrogenase: structural differences between the beta and gamma subunits suggest parallel duplications in isoenzyme evolution and predominant expression of separate gene descendants in livers of different mammals.

Bühler¹,

Hempel²,

Kaiser³

et al. 1984

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

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ABSTRACTlibman alcohol dehydrogenase (ADH; alcohol:NAD+ oxidoreductase, EC 1.1.1.1) occurs in multiple forms, which exhibit distinct electrophoretic mobilities and enzymatic properties. The homogeneous isoenzymes I3P, and y1yi were isolated from livers of Caucasians with "tyrpical" ADH phenotype by double ternary complex affinity chromatography and ion exchange chromatography. The differences between the PI and Vi subunits were determined by structural analysis of all tryptic peptides from the carboxymethylated proteins. The human f3I and Vi chains differ at 21 of the 373 positions (5.6%). Ten tryptic peptides account for the differences. All residue substitutions are compatible with one-base mutations and result in largely unaltered properties, but five lead to charge differences. Sixteen substitutions are at positions corresponding to the catalytic domain of the well-known horse enzyme; five correspond to the coepzyme-binding domain. Substitutions adjacent to important regions may correlate with differences in coenzyme binding, substrate specificities, and active-site relationships. The residue replacements between the PI and yV subunits of human ADH are not identical to the known substitutions between ethanol-active (E) and steroid-active (S) subunits of horse ADH. Thus, the duplication leading to human pi and yi subunits is separate and different from that leading to equine E and S subunits. Both duplications are likely to have occurred after the ancestral separation of human and equine ADH. Of the 21 residues that are different between P1I/ yi, 13 in y'but only 6 in flu are identical to those of the horse E chain. This suggests a closer relationship between yV and E, although .81 in mah and E in the horse are the subunits recovered in highest yield from liver ADH preparations. Consequently, in these two mammalian species, relative activities of genes for an isoenzyme family appear to be different.Human and horse alcohol dehydrogenases (ADH; alcohol:

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“…Beside the major groups, some atypical alcohol dehydrogenases are known as well. As an example, atypical alcohol dehydrogenase from the liver of some Caucasians has been shown to have higher specificity and lower pH optimum than the common alcohol dehydrogenases 44,45 . The enzyme uses NAD + as a co-substrate and it contains Zn II+ .…”

Section: Metabolism and Toxicity Arisingmentioning

confidence: 99%

Toxicology and the biological role of methanol and ethanol: Current view

Pohanka¹

2016

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Background. Alcohol variants such as ethanol and methanol are simple organic compounds widely used in foods, pharmaceuticals, chemical synthesis, etc. Both are becoming an emerging health problem; abuse of ethanol containing beverages can lead to disparate health problems and methanol is highly toxic and unfit for consumption. Methods and Results. This review summarizes the basic knowledge about ethanol and methanol toxicity, the effect mechanism on the body, the current care of poisoned individuals and the implication of alcohols in the development of diseases. Alcohol related dementia, stroke, metabolic syndrome and hepatitis are discussed as well. Besides ethanol, methanol toxicity and its biodegradation pathways are addressed. Conclusions. The impact of ethanol and methanol on the body is shown as case reports, along with a discussion on the possible implication of alcohol in Alzheimer's disease and antidotal therapy for methanol poisoning. The role of ethanol in cancer and degenerative disorders seems to be underestimated given the current knowledge. Treatment in case of poisoning is another issue that remains unresolved even though effective protocols and drugs exist.

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Atypical human liver alcohol dehydrogenase: the β₂‐Bern subunit has an amino acid exchange that is identical to the one in the β₂‐Oriental chain

Abstract: Alcohol dehydrogenase Human liver isoenzyme Primary structure Mutation

Cited by 20 publications

References 24 publications

Human liver alcohol dehydrogenase: amino acid substitution in the beta 2 beta 2 Oriental isozyme explains functional properties, establishes an active site structure, and parallels mutational exchanges in the yeast enzyme.

Human liver alcohol dehydrogenase: amino acid substitution in the beta 2 beta 2 Oriental isozyme explains functional properties, establishes an active site structure, and parallels mutational exchanges in the yeast enzyme.

Human alcohol dehydrogenase: structural differences between the beta and gamma subunits suggest parallel duplications in isoenzyme evolution and predominant expression of separate gene descendants in livers of different mammals.

Toxicology and the biological role of methanol and ethanol: Current view

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