The aldehyde dehydrogenase ALDH2*2 allele exhibits dominance over ALDH2*1 in transduced HeLa cells.

Xiao, Qing; Weiner, Henry; Johnston, Timothy; Crabb, David W.

doi:10.1172/jci118272

Cited by 73 publications

(88 citation statements)

References 21 publications

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“…In all forms of the enzymes assayed, the ratio of 1,2-GDN/1,3-GDN was constant at 8:1. Furthermore, the decreased GTN biotransformation in ALDH2*1/2 heterozygotes was dominant over the ALDH2*1/1 subjects, a finding similar to that of the ALDH2 dehydrogenase activity (12,14). Although the GTN biotransformation catalytic activity was decreased for the heterozygous and homozygous mutants, a relatively higher activity remained, as compared with their respective dehydrogenase activities.…”

Section: Resultssupporting

confidence: 56%

“…ALDH2 is a tetramer, and 1 defective subunit is sufficient to render the entire enzyme inactive; thus, Glu504 homozygotes (ALDH2*1/1) exhibit normal enzymatic activity, Glu504/Lys504 heterozygotes (ALDH2*1/2) show approximately 6% of normal activity, and Lys504 homozygotes (ALDH2*2/2) show negligible activity toward acetaldehyde (12). The ALDH2*2 allele is thus inherited as an autosomal dominant trait (11,12,14). This mutation has been considered as a protective factor against the development of alcoholism and may explain distinct alcohol drinking habits across various ethnic populations (13).…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin

Zhang

Jin³

et al. 2006

Journal of Clinical Investigation

144

101

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Glyceryl trinitrate (GTN), also known as nitroglycerin, has been used to treat angina and heart failure for more than 130 years. Recently, it was shown that mitochondrial aldehyde dehydrogenase-2 (ALDH2) is responsible for formation of NO, the metabolite needed for GTN efficacy. In the present study, we show that the common G-to-A polymorphism in exon 12 of ALDH2 -resulting in a Glu504Lys replacement that virtually eliminates ALDH2 activity in both heterozygotes and homozygotes -is associated with a lack of efficacy of sublingual GTN in Chinese subjects. We also show that the catalytic efficiency (V max /K m ) of GTN metabolism of the Glu504 protein is approximately 10-fold higher than that of the Lys504 enzyme. We conclude that the presence of the Lys504 allele contributes in large part to the lack of an efficacious clinical response to nitroglycerin; we recommend that this genetic factor be considered when administering nitroglycerin to patients, especially Asians, 30-50% of whom possess the inactive ALDH2*2 mutant allele.

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Section: Resultssupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin

Zhang

Jin³

et al. 2006

Journal of Clinical Investigation

144

101

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“…= 22, c 2 = 268.343). The three-group (0, 1-7, [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] or the two-group (0-7, 8-22) score distribution also showed significant proportional differences between AUD Past histories of diabetes mellitus (DM), chronic liver diseases (liver cirrhosis, chronic hepatitis, hepatic dysfunction and alcoholic liver dysfunction), AUD and blood transfusion were more prevalent among AUD patients (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…The variant subunit, encoded by ALDH2*2 , decreases the activity in the tetrameric enzyme. 10 The present matched case-control study was performed to investigate the relationship between the aforementioned potential risk factors, including ADH2 and ALDH2 genotypes, and AUD as diagnosed by psychiatrists in Japan.…”

Section: Introductionmentioning

confidence: 99%

Alcohol drinking frequency is more directly associated with alcohol use disorder than alcohol metabolizing enzymes among male Japanese

Nishiyori

Shibata

Ogimoto

et al. 2005

Psychiatry Clin Neurosci

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The development of alcohol use disorder (AUD) is related to various social, economic, cultural, environmental and hereditary factors. Several potential risk factors have been proposed for AUD in addition to alcohol consumption, including alcohol dehydrogenase2 (ADH2), acetaldehyde dehydrogenase2 (ALDH2), marital status, educational, occupational or past medical history (e.g. diabetes mellitus, hypertension, lung, digestive tract, or chronic liver disease) or smoking habits. The present study was performed to investigate the relationship between the aforementioned potential risk factors and AUD in Japan. A case-control study was performed on 153 male Japanese AUD patients and age-, gender-, or other confounder-matched controls to investigate the relation multivariately between ADH2 , ALDH2 or alcohol drinking and AUD. Genomic DNA were extracted from nail clippings by the guanidium method, and genotyping of ADH2 and ALDH2 were performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Univariate analyses by the conditional logistic regression model revealed statistically significant odds ratios due to ADH2*1/1 genotype, ALDH2*1/1 genotype, middle school as the final school attended, longest occupations as farmers, fishermen, craftsmen, miners, production process or construction workers, and past histories of chronic liver disease and AUD. However, multivariate analyses under a hierarchically well-formulated model strategy with interaction and confounding assessment indicated that (i) heavy alcohol intake was a significant risk factor (odds ratio per 1.0 g of daily ethanol intake; 1.096, 95% confidence interval; 1.026-1.171) for developing AUD after adjusting for other confounders; and (ii) ADH2*1/1 genotype and ALDH2*1/1 genotype were not risk factors after adjusting for daily ethanol intake and other confounders. The present study shows that AUD was more directly and strongly associated with alcohol drinking than with alcohol metabolizing enzymes among male Japanese.

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“…The binding ability of these proteins depends on the cooperation of two or more motifs belonging to different subunits. Although a dominant negative mutation is not usually expected for diseases involving defects of enzymes, since enzymes are so active that there is no loss of function unless their levels have decreased to less than 10-15% of normal levels, several dominantly inherited metabolic diseases have been reported (Xiao et al 1995, Chamberlin et al 1997. In a heterozygous state, these mutants antagonize the activity of the remaining wild-type allele and give a phenotype approaching a null.…”

Section: Discussionmentioning

confidence: 99%

Both N-terminal and C-terminal regions of steroid sulfatase are important for enzyme activity

Sugawara¹,

Nomura²,

Hoshi³

2006

Journal of Endocrinology

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Steroid sulfatase (STS) is localized in the endoplasmic reticulum and catalyzes desulfation of 3 -hydroxysteroid sulfates. X-linked ichthyosis (XLI) is an inherited skin disorder caused by deficiency of STS enzyme activity. We previously reported a case in which XLI with a one-base change in the STS gene and variation in amino acid Q560P developed. In this study, we performed molecular analysis to determine the importance of terminal regions of STS and the effect of mutant STS on STS enzyme activity. To examine the effect of terminal truncated STS on the enzyme activity, N-and C-terminal truncated STS expression vectors were transfected into COS-1 cells. The activity of truncated STS lacking the N-terminal regions declined, and the activity of C-terminal-truncated STS declined with extension of the truncated C-terminal region. Although the results of pulse-chase experiments showed that a one-base mutant STS (Q560P) and C-terminal-truncated STS (C2 (1-559)) had no effects on protein synthesis and degradation, the mutant STS and C-terminal-truncated STS have dominant negative effect on STS enzyme activity when the STS mutant or truncated STS protein and a wild-type STS protein coexist in cells. Results of coprecipitation of the truncated STS with an STS-FLAG fusion protein showed that STS formed a dimer conformation in cells. In this study, we have shown that both the N-terminal region and C-terminal region are important for STS enzyme activity. The C-terminal mutant has a dominant negative effect on wild-type STS.

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The aldehyde dehydrogenase ALDH22 allele exhibits dominance over ALDH21 in transduced HeLa cells.

Cited by 73 publications

References 21 publications

Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin

Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin

Alcohol drinking frequency is more directly associated with alcohol use disorder than alcohol metabolizing enzymes among male Japanese

Both N-terminal and C-terminal regions of steroid sulfatase are important for enzyme activity

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