An Atypical Human Alcohol Dehydrogenase

Wartburg, J. P. von; Papenberg, J.; Aebi, H.

doi:10.1139/o65-102

Cited by 180 publications

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“…Horse liver alcohol dehydrogenase and the normal human liver enzyme, which have the same tertiary structure [21], have an alanine residue in this position [22]. This residue is exchanged for proline in the atypical human enzyme [23] which has a different activity and pH optimum. Apparently this region plays an important role in the rate-limiting step of the catalytic mechanism.…”

Section: Discussionmentioning

confidence: 99%

The Crystal Structure of Complexes between Horse Liver Alcohol Dehydrogenase and the Coenzyme Analogues 3‐Iodopyridine‐adenine Dinucleotide and Pyridine‐adenine Dinucleotide

Samama

Zeppezauer

Biellmann

et al. 1977

European Journal of Biochemistry

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We have studied the binding of the enzymatically active NAD + analogue, 3-iodopyridine-adenine dinucleotide, and the inactive analogue, pyridine-adenine dinucleotide to the enzyme horse liver alcohol dehydrogenase using X-ray crystallographic methods. These studies were made under such conditions that crystals of the complexes were isomorphous to apocnzyme crystals. Both analogues bind in the same conformation. The binding of the adenosine moiety is very similar to that of ADP-ribose or NADH bound to the enzyme. The conformation and mode of binding of the remaining portions of the analogue molecules is, however, quite different. The pyridine ring is not situated in the active-site pocket as the nicotinamide group in thc isomorphous enzyme -NADH . imidazole complex but lies at the surface of the crevice between the two domains of the subunit, approximately 1.5 nm away from the catalytically active zinc atom. Lys-228 which has been shown to be important for NADH dissociation is in this region of the molecule.A large number of analogues to the coenzyme NAD' have been investigated [l] in order to delineate the role of the various moieties of the dinucleotide in the interaction of this coenzyme with the NAD+-dependent dehydrogenases. We have been particularly interested in the enzymatic effects of substitutions on the nicotinamide ring. As part of these studies, and also for thc use as heavy-atom derivatives in protein Crystallography, we synthesized 3-iOdO and subsequently 3-bromo and 3-chloro derivatives of pyridineadenine dinucleotide which were active in enzymatic hydrogen transfer reactions. Synthesis of these analogues and their kinetic properties for some NAD+-dependent dehydrogenase-catalysed reactions is presented elsewhere [2].The present study describes the binding of the 3-iodo analogue to one of these enzymes, horse liver alcohol dehydrogenase, as studied by X-ray crystallographic methods. Furthermore, the results of that Abbreviations.Pd AD + . pyridine-adenine dinucleot ide ; io3PdAD+, 3-iodopyridine-adenine dinucleotide; Tes, 2-([tris-(hydroxymethyl)methyi]amino)ethane sulfonic acid.

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Section: Discussionmentioning

confidence: 99%

The Crystal Structure of Complexes between Horse Liver Alcohol Dehydrogenase and the Coenzyme Analogues 3‐Iodopyridine‐adenine Dinucleotide and Pyridine‐adenine Dinucleotide

Samama

Zeppezauer

Biellmann

et al. 1977

European Journal of Biochemistry

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“…Allelic variants are known both for the ADHz locus (coding for ,@I and possibly several fl2 polypeptides [2]); and for the ADH3 locus (coding for the yl and y2 subunits [2]). The 'atypical' human liver alcohol dehydrogenase of Caucasian origin [3] is such a variant from the AD& locus [2] and the corresponding protein chain has been called the &-Bern subunit. Isoenzymes with ,&-Oriental subunits, isolated from livers of Oriental origin, have also been described t To whom correspondence shoufd be addressed [4,5], as well as forms with ~K~dj~~~~~l~~ chains from livers of African ancestry [6].…”

Section: Introductionmentioning

confidence: 99%

“…Thus, alcohol dehydrogen~e preparations ~ont~ning either of these two atypical ~2-subunits distinctly differ in enzymatic properties from other preparations, The specific activity is considerably higher and the pHoptimum for ethanol oxidation is shifted from the normal pH around 10.5 down to about pH 8 [7,9]. Also, the susceptibility to inhibitors is significantly altered [3].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 1984

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“…One of them exhibits a single activity optimum at pH 7.0, whereas the other two have dual pH optima at 7.0 and 10.0. Based on the pH-dependence of their activities, their Km values for ethanol, and their mobility on starch gel electrophoresis, these newly discovered forms can be differentiated from both the "typical" and "atypical" enzyme forms described previously (5)(6)(7)(8)(9). Clearly, the molecular heterogeneity of human liver ADH is much more complex and diverse than had been appreciated, which calls for a more searching examination of the molecular and genetic basis of ADH isoenzymes.…”

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confidence: 96%

New molecular forms of human liver alcohol dehydrogenase: isolation and characterization of ADHIndianapolis.

Bosron¹,

Li²,

Vallée³

1980

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

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The biochemital determinants of alcoholism and genetic correlates for the variability in man's response to alcohol have remained obscure until recently. The identification of genetically determined isoenzymes of alcohol dehydrogenase with different catalytic properties may bear importantly upon this problem. New molecular forms of human liver alcohol dehydrogenase (ADH; alcohol:NAD+ Commun. 91, 1549Commun. 91, -1555. The distinguishing features of these specimens were (i) they showed activity optima for ethanol oxidation at both pH 7.0 and 10.0 and (ii) they formed electrophoretic-bands cathodic to the ,B isoenzyme. From such livers, three new ADH forms have now been iso a, one of which has a single pH optimum at 7.0 and two of which have dual optima at pH 7.0 and 10.0. These new forms were designated ADHlndianapolis forms 1,2, and 3, respectively. They can be differentiated from previously described ADH isoenzymes, including the so-called "atypical" isoenzyme, by their electrophoretic mobility, pH optima, and Km for ethanol (approxi-mately 60 mM at pH 7.5) Based upon the electrophoretic pattern of livers containing ADHirnii and the mobility of the three isolated molecular forms, ADAiLdianapolis may be the result of polymorphism at the ADH2 gene locus, which codes for the , subunit.Humans exhibit large individual differences in their rate of alcohol metabolism and in their physiological, psychological, and pathological response to ethanol consumption (1). The potential relationships between these phenomena and the remarkable variability and large number of alcohol dehydrogenase (ADH; alcohol:NAD+ oxidoreductase, EC 1.1.1.1) isoenzymes in human liver have been discussed (2). Such comparisons are of quite recent origin largely because a means for the isolation and characterization of the molecular properties of human ADH isoenzymes had not been available. Specific affinity chromatographic techniques for ADH isoenzyme purification (3, 4) and electrophoretic procedures capable of resolving hitherto unidentified molecular forms (5, 6) have improved the situation rapidly and significantly.A genetic modelt proposed some years ago (7) has thus far satisfactorily accounted for most variations in ADH isoenzymes observed in earlier studies. It did not encompass -r-ADH (2), however, which was discovered subsequent to the proposal of the model. Most recently, we discovered yet other ADH molecular forms in 16% of autopsy liver specimens from Indianapolis, IN (6), which also could not be classified according to that model. Characteristically these livers manifest two pH optima for ethanol oxidation at pH 7.0 and 10.0 and form electrophoretic bands cathodic to the f3,B isoenzyme (6).The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact. 5784We have now isolated three of these new molecular forms from such liver specimens. One of them exhibits a single activity o...

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An Atypical Human Alcohol Dehydrogenase

Cited by 180 publications

References 0 publications

The Crystal Structure of Complexes between Horse Liver Alcohol Dehydrogenase and the Coenzyme Analogues 3‐Iodopyridine‐adenine Dinucleotide and Pyridine‐adenine Dinucleotide

The Crystal Structure of Complexes between Horse Liver Alcohol Dehydrogenase and the Coenzyme Analogues 3‐Iodopyridine‐adenine Dinucleotide and Pyridine‐adenine Dinucleotide

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

New molecular forms of human liver alcohol dehydrogenase: isolation and characterization of ADHIndianapolis.

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An Atypical Human Alcohol Dehydrogenase

Cited by 180 publications

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The Crystal Structure of Complexes between Horse Liver Alcohol Dehydrogenase and the Coenzyme Analogues 3‐Iodopyridine‐adenine Dinucleotide and Pyridine‐adenine Dinucleotide

The Crystal Structure of Complexes between Horse Liver Alcohol Dehydrogenase and the Coenzyme Analogues 3‐Iodopyridine‐adenine Dinucleotide and Pyridine‐adenine Dinucleotide

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

New molecular forms of human liver alcohol dehydrogenase: isolation and characterization of ADHIndianapolis.

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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