Human liver aldehyde dehydrogenase in Chinese and Asiatic Indians: Gene deletion and its possible implications in alcohol metabolism

Ys, Teng

doi:10.1007/bf00486141

Cited by 78 publications

(28 citation statements)

References 13 publications

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“…ALDH1 is cytosolic in origin, has a low Km for NAD and a high Km for acetaldehyde, and is inactivated by disulfiraih; ALDH2 is mitochondrial in origin, has a high Km for NAD and a low Km for acetaldehyde, and is resistant to disulfiram (15,16). The two isozymes exhibit certain serological homology, indicating that they probably differentiated from a common ancester (6,17 (3,4). The frequency of the mutant ALDH22 gene is estimated to be about 70% and that of the usual ALDH12 gene is estimated to be about 30% in Japanese and Chinese.…”

Section: Resultsmentioning

confidence: 99%

“…Virtually all Caucasians have two major ALDH isozymes-i.e., ALDH1 and ALDH2 in their livers-whereas =50% of Orientals are "atypical" in that they have only ALDH1 and are missing ALDH2 (3,4). A very high incidence (50-80%) of acute alcohol intoxication in Orientals could be related to the absence of active ALDH2 and the presence of superactive PA22 alcohol dehydrogenase isozyme (1,3).…”

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confidence: 99%

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Molecular abnormality of an inactive aldehyde dehydrogenase variant commonly found in Orientals.

Yoshida¹,

Huang²,

Ikawa³

1984

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

402

249

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Usual human livers contain two major aldehyde dehydrogenase [(ALDH) aldehyde:NAD+ oxidoreductase] isozymes-i.e., a cytosolic ALDH1 component and a mitochondrial ALDH2 component-whereas o50% of Orientals are "atypical" and have only the ALDH1 isozyme and are missing the ALDH2 isozyme. We previously demonstrated that atypical livers contain an enzymatically inactive but immunologically crossreactive material (CRM) corresponding to the ALDH2 component. The enzymatically active ALDH2 obtained from a usual liver and the CRM obtained from an atypical liver were reduced, S-carboxymethylated, and digested by trypsin. Separation of their digests by high-performance reverse-phase chromatography and by two-dimensional paper chromatography and electrophoresis revealed that ALDH2 contained a peptide sequence of -Glu-Leu-Gly-Glu-Ala-GlyLeu-Gln-Ala-Asn-Val-Gln-Val-Lys-and that the glutamine adjacent to lysine was substituted by lysine in CRM. AU other tryptic peptides, including eight peptides containing S-carboxymethylcysteine, were common in ALDH2 and CRM. It is concluded that a point mutation in the human ALDH2 locus produced the glutamine -I lysine substitution and enzyme inactivation. (1, 2). The specific activity of the atypical /82P2 isozyme is nearly 100 times higher than that of the usual P1P, isozyme (2). It has been shown that the active site cysteine of the usual P, subunit is replaced by histidine in the superactive atypical P2 subunit (2).Virtually all Caucasians have two major ALDH isozymes-i.e., ALDH1 and ALDH2 in their livers-whereas =50% of Orientals are "atypical" in that they have only ALDH1 and are missing ALDH2 (3, 4). A very high incidence (50-80%) of acute alcohol intoxication in Orientals could be related to the absence of active ALDH2 and the presence of superactive PA22 alcohol dehydrogenase isozyme (1, 3). However, the atypical Orientals have an enzymatically inactive but immunologically crossreactive material (CRM) in their livers (5). The amino acid composition, subunit molecular size, and immunological characteristics of CRM were indistinguishable from the corresponding properties of ALDH2 but differed from those of ALDH1 (6). Therefore, CRM should be an abnormal defective protein resulting from a mutation of the ALDH2 locus. Genetic study indicates that two common alleles-i.e., ALDH12 for the usual ALDH2 isozyme and atypical ALDH22 for the defective CRM at the same locus-are codominantly expressed in Orientals (7). The present paper reports the molecular difference between the usual ALDH2 and the enzymatically inactive CRM. MATERIALS AND METHODSALDH and CRM. Two ALDH isozymes-i.e., ALDH1 and ALDH,-were purified from autopsy specimens of human liver as described (6). CRM and ALDH1 were purified from atypical Japanese livers, which contained the ALDH1 isozyme but not the active ALDH2 isozyme, as described (6). Purities of the samples were checked by polyacrylamide gel electrophoresis in the presence of NaDodSO4 as described (6). The proteins were thoroughly dialyzed against water and lyoph...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Molecular abnormality of an inactive aldehyde dehydrogenase variant commonly found in Orientals.

Yoshida¹,

Huang²,

Ikawa³

1984

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

402

249

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“…About half of Orientals lack ALDH2 activity, as assayed in hair root or liver specimens (4)(5)(6), and experience facial flushing, dysphoria, tachycardia, nausea, and hypotension owing to acetaldehyde accumulation when they drink (7,8). The ALDH2-deficient phenotype appears to be very uncommon in Caucasian and Black Americans, Europeans, and most North American Indians, but it has been detected in -40% of some South American Indians (9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity. The inactive ALDH2(2) allele is dominant.

Crabb¹,

Edenberg²,

Bosron³

et al. 1989

J. Clin. Invest.

546

305

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Many Orientals lack the mitochondrial aldehyde dehydrogenase (ALDH2) activity responsible for the oxidation of acetaldehyde produced during ethanol metabolism. These individuals suffer the alcohol-flush reaction when they drink alcoholic beverages. The alcohol-flush reaction is the result of excessive acetaldehyde accumulation, and the unpleasant symptoms tend to reduce alcohol consumption. The subunit of this homotetrameric enzyme was sequenced and the abnormality in the inactive enzyme shown to be a substitution of lysine for glutamate at position 487. We have used the polymerase chain reaction to determine the genotypes of 24 livers from Japanese individuals. Correlating genotype with phenotype leads to the conclusion that the allele (ALDH22) encoding the abnormal subunit is dominant.

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“…The existence of CRM corresponding to ALDH-2 in an atypical liver leads us to conclude that the absence of ALDH-2 isozyme in about 50~ of Japanese is not due to regulatory mutation, nonsense mutation, or gene deletion, as previously proposed (Teng, 1981), but it must be due to a structural mutation in a gene for ALDH-2 locus, resulting in the formation of enzymatically inactive abnormal protein. It would be interesting to investigate an exact amino acid substitution which caused the total loss of enzymatic activity in the mutant ALDH-2 protein.…”

mentioning

confidence: 51%

“…Virtually all Caucasians have two major isozymes, i.e., ALDH-1 and ALDH-2, while approximately 50~ of Orientals have only ALDH-1 isozyme, missing ALDH-2 isozyme (Goedde et al, 1979a, Teng, 1981. Since ALDH-2 has a high affinity to acetaldehyde, an absence of this isozyme could induce elevation of acetaldehyde concentration in the atypical subjects.…”

Section: Introduc~onmentioning

confidence: 99%

Molecular basis of difference in alcohol metabolism between Orientals and Caucasians

Yoshida

1982

Jap J Human Genet

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SummaryThe human cytosol alcohol dehydrogenase(ADH) controlled by ADH2 locus is known to be polymorphic. Most Caucasians have the usual enzyme consisting of the usual ~1 subunit, while nearly 90~ of Orientals have the atypical /~2 subunit. At the physiological pH, the cytosol enzyme activity of the atypical liver is much higher than that of the typical liver. It has been suggested that a high frequency of acute alcohol intoxication among Orientals could be related to the rapid accumulation of acetaldehyde due to the atypical ADH. Human liver aldehyde dehydrogenase (ALDH) is also polymorphic. Virtually all Caucasians have two major isozymes, i.e., ALDH-1 and ALDH-2, while about 50~ of Orientals have only ALDH-1, missing ALDH-2 component. Since ALDH-2 has high affinity to acetaldehyde, the high incidence of alcohol sensitivity in Orientals could be related to the accumulation of acetaldehyde due to the lack of ALDH-2 component. The usual ADH homodimer ~1/71 and the atypical homodimer ~2/~2 were purified to homogeneity. The specific activity of the atypical enzyme was nearly three orders of magnitude higher than the usual enzyme at the physiological pH. The usual enzyme was rapidly inactivated by iodoacetate, indicating an existence of the "active site cysteine'" in the molecule. In contrast, the atypical enzyme was resistant against the iodoacetate inactivation. Peptide mapping analysis revealed that the active site cysteine in the usual ~1 subunit is replaced by histidine in the atypical 82 subunit. In the usual ~1~1 enzyme, like horse enzyme, the catalytic Zn is expected to link to the sensitive cysteine at position 47, histidine at position 67, and cysteine at presumably position 174, thus making up the active site. In contrast, the active site of the atypical ~2~2 enzyme is expected to consist of the catalytic Zn linked to histidine at position 47, histidine at position 67, and cysteine at position around 174. The functional abnormalities of the atypical enzyme can be correlated to its molecular abnormality. 55

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Human liver aldehyde dehydrogenase in Chinese and Asiatic Indians: Gene deletion and its possible implications in alcohol metabolism

Cited by 78 publications

References 13 publications

Molecular abnormality of an inactive aldehyde dehydrogenase variant commonly found in Orientals.

Molecular abnormality of an inactive aldehyde dehydrogenase variant commonly found in Orientals.

Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity. The inactive ALDH2(2) allele is dominant.

Molecular basis of difference in alcohol metabolism between Orientals and Caucasians

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