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Inhibition effects of furfural on alcohol dehydrogenase, aldehyde dehydrogenase and pyruvate dehydrogenase.

ABSTRACT: The kinetics of furfural inhibition of the enzymes alcohol dehydrogenase (ADH; EC 1.1.1.1), aldehyde dehydrogenase (AlDH; EC 1.2.1.5) and the pyruvate dehydrogenase (PDH) complex were studied in vitro. At a concentration of less than 2 mM furfural was found to decrease the activity of both PDH and AlDH by more than 90%, whereas the ADH activity decreased by less than 20% at the same concentration. Furfural inhibition of ADH and AlDH activities could be described well by a competitive inhibition model, whereas the inhibition of PDH was best described as non-competitive. The estimated K(m) value of AlDH for furfural was found to be about 5 microM, which was lower than that for acetaldehyde (10 microM). For ADH, however, the estimated K(m) value for furfural (1.2 mM) was higher than that for acetaldehyde (0.4 mM). The inhibition of the three enzymes by 5-hydroxymethylfurfural (HMF) was also measured. The inhibition caused by HMF of ADH was very similar to that caused by furfural. However, HMF did not inhibit either AlDH or PDH as severely as furfural. The inhibition effects on the three enzymes could well explain previously reported in vivo effects caused by furfural and HMF on the overall metabolism of Saccharomyces cerevisiae, suggesting a critical role of these enzymes in the observed inhibition.

SUBMITTER: Modig T

PROVIDER: S-EPMC1222530 | biostudies-other | 2002 May

REPOSITORIES: biostudies-other

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Project description:Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are two major alcohol-metabolizing enzymes. Moderate alcohol intake is a protective modified factor in Alzheimer's disease (AD) while heavy alcohol intake and abstinence increased dementia risk. The associations between Alzheimer's disease and alcohol-metabolizing genes are uncertain. This study examined the association of AD with seven ADH/ALDH single-nucleotide polymorphisms (SNPs), ADH1C rs2241894, ADH1B rs1229984, ALDH1B1 rs2073478, ALDH2 rs886205, rs4767944, rs4648328, and rs671. We enrolled 157 AD and 168 age- and sex-matched control subjects in pilot study to examine the association of AD with ADH/ALDH SNPs. Reconstructed ALDH2 haplotypes were performed. We measured plasma level of ADH1C and checked the interaction effect of AD-rs2241894 genotype on plasma ADH1C level. In extension study, we further examined 339 AD and 2,504 healthy control from the Taiwan Biobank. In pilot study, we observed that ADH1C rs2241894 TT genotype was negatively associated with AD in a recessive genetic model (OR = 0.25, 95% CI 0.09-0.75, p < 0.0001) in women. A strong linkage disequilibrium was observed among the four examined SNPs of ALDH2. No haplotype was related to AD. The plasma ADH1C level in AD was higher than that in control. After adjusted by age, sex, hypertension, diabetes mellitus, and alcohol, we found a significant interaction effect of AD-rs2241894 genotype on plasma ADH1C level (p = 0.04). This interaction effect was attributable to the association between AD and plasma ADH1C level (β estimate = 366, 95% CI 92.7∼639.4, p = 0.009). The genetic distribution of ADH1C rs2241894 showed strong ethnic heterogeneity, in which the T allele was the minor allele accounting for 28.5% in our study and 23.6% in East Asians, while it was a major allele in Americans, Europeans, and the global populations. No association was discovered between AD and the five SNPs: rs2241894, rs1229984, rs2073478, rs886205, and rs671 in the extension study. In summary, this study revealed a suggestive association between ADH1C rs2241894 and female AD in the pilot study, but failed to confirm this finding in a population database. Further age-matched and large sample size case-control studies are needed before rs2241894 can be interpreted as a protective genetic factor of AD.

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Inhibition effects of furfural on alcohol dehydrogenase, aldehyde dehydrogenase and pyruvate dehydrogenase.

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