Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.1.1.1 (alcohol dehydrogenase)
 9,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stereospecificities are reported for seven dehydrogenases from Acholeplasma laidlawii, an organism from an evolutionarily distinct branch of life which has not previously been studied from a stereochemical point of view. Three of the activities examined (alcohol dehydrogenase, lactate dehydrogenase, and alanine dehydrogenase) catalyze the transfer of the pro-R (A) hydrogen from NADH. Four other activities (3-hydroxy-3-methylglutaryl-CoA reductase, glyceraldehyde-3-phosphate dehydrogenase, glucose-6-phosphate dehydrogenase, and NADH oxidase) catalyze the transfer of the pro-S (B) hydrogen from NAD(P)H. The stereospecificity of hydroxymethylglutaryl-CoA reductase is notable because it is the opposite of that of hydroxymethylglutaryl-CoA reductases from yeast and rat. These data are used to derive the simplest historical model capable of explaining available experimental facts.
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PMID:The stereospecificities of seven dehydrogenases from Acholeplasma laidlawii. The simplest historical model that explains dehydrogenase stereospecificity. 236 93

Addition of ethanol (0.2%) to cultures of the yeast Phaffia rhodozyma increased the specific rate of carotenoid production [(carotenoid)(cell mass)-1(time)-1]. The incremental increase in carotenoid synthesis with ethanol was highest in carotenoid-hyperproducing strains. Ethanol increased carotenoid production when it was added at various points during the lag and active growth phases. Ethanol increased alcohol dehydrogenase and hydroxy-methylglutaryl-CoA (HMG-CoA) reductase activities. Our results indicate that increased carotenoid production by ethanol is associated with induction of HMG-CoA reductase and possibly activation of oxidative metabolism.
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PMID:Ethanol increases carotenoid production in Phaffia rhodozyma. 936 93

The objective of this study was to determine the effects of a country liquor Toddy (Coconut palm wine) and an equivalent quantity of ethanol on liver function and lipid metabolism in utero. Female albino rats with an average weight of 125 +/- 5 g were exposed to Toddy from coconut palm (24.5 ml/kg body weight/day) and ethanol (0.52 ml/kg body weight/day) for 15 days before conception and during pregnancy. On day 13 and day 19 of gestation, altered liver function and hyperlipidemia were seen in the fetuses of both the treated groups. Altered liver function was evidenced by the increased activity of alcohol dehydrogenase, aldehyde dehydrogenase, glutamic oxaloacetic transaminase (aspartate amino transferase (GOT)), glutamic pyruvic transaminase (alanine amino transferase (GPT)). Hyperlipidemia was caused by increased biosynthesis since the incorporation of 14C acetate into lipids and activities of HMG CoA reductase and lipogenic enzymes were elevated. Toddy treated fetuses were more severely affected than those exposed to an equivalent quantity of ethanol. Toddy seemed to potentiate the toxicity induced by alcohol suggesting the role of non alcoholic components. Hepatic functions of the day 13 fetuses were effected to a lesser degree than those in the day 19 hepatic liver.
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PMID:Effect of in utero exposure of Toddy (coconut palm wine) on liver function and lipid metabolism in rat fetuses. 995 82

The objective of this study was to determine the effects of a country liquor (Arrack) and the equivalent quantity of ethanol on liver function and lipid metabolism in utero. Female rats of average weight 125 g were exposed to Arrack (12 ml/kg body weight/day) and ethanol (3.2 ml/kg body weight/day) for 15 days before conception and throughout gestation. On 13th day and 19th day of gestation, altered liver function and hyperlipidemia was seen in the fetus of both the treated groups. Altered liver function was evidenced by the increased activity of alcohol dehydrogenase and glutamic pyruvic transaminase or alanine amino transferase (GPT). Hyperlipidemia was caused by increased biosynthesis since the incorporation of 14C acetate to lipids and activities of HMG CoA reductase and lipogenic enzymes were elevated. Arrack seemed to potentiate the toxicity induced by alcohol indicating the role of non ethanolic portion. Hepatic functions of the 13th day fetuses were effected to a lesser degree than the 19th day hepatic liver.
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PMID:Prenatal exposure of an alcoholic beverage (Arrack) on fetal lipid metabolism in rats. 1094 14

The objective of this study was to determine the effects of country liquor Toddy and its equivalent quantity of ethanol on lipid metabolism during gestation in rats. Female rats weighing an average of 125 g were exposed to Toddy (24.5 ml/body weight/day) and ethanol (0.52 ml/kg body weight/day) for 15 days before conception and throughout gestation. On the 19th day of gestation, altered liver function and hyperlipidemia was seen in both the treated groups. Altered liver function was evidenced by the increased activity of alcohol dehydrogenase, aldehyde dehydrogenase, glutamic oxaloacetic transaminase or aspartate amino transferase (GOT), glutamic pyruvic transaminase or alanine amino transferase (GPT) and gamma glutamyl transpeptidase (GGT). Hyperlipidemia was caused by increased biosynthesis and decreased degradation of lipids. The incorporation of 14C acetate in lipids and activities of HMG CoA reductase and lipogenic enzymes were elevated and activity of LPL and bile acids contents were decreased. Toddy treated rats were more severely affected than those receiving an equivalent quantity of ethanol. Toddy seemed to potentiate the toxicity induced by alcohol indicating the role of the nonethanolic portion. Hepatic functions were also affected.
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PMID:Effect of exposure to a country liquor (Toddy) during gestation on lipid metabolism in rats. 1131 2

Mevalonic acid derivatives are required for the isoprenylation of a variety of growth-regulating proteins. Treatment of NIH3T3 cells with lovastatin (LOV), an HMG-CoA reductase inhibitor, depletes cells of these derivatives and impairs isoprenylation of RAS and RAS-related proteins. In LOV-treated cells, farnesol (FOH) and geranylgeraniol (GGOH) restore RAS and Rap1 isoprenylation, respectively. In this study, we further characterize the manner in which these isoprenoid alcohols are utilized for protein isoprenylation. Over a 48-h time span, FOH is unable to maintain RAS isoprenylation in the continuing presence of LOV, whereas GGOH is able to maintain Rap1 isoprenylation in the presence of LOV at all times tested. When cells are pretreated with LOV, the ability of both FOH and GGOH to restore protein isoprenylation is time dependent; as the LOV pretreatment time increases, the time required for FOH and GGOH to restore isoprenylation also increases. Despite this time dependence, the ability of FOH and GGOH to restore protein isoprenylation is not dependent on new protein synthesis and does not require alcohol dehydrogenase. These data support the existence of and further characterize the isoprenoid shunt, a novel metabolic pathway that utilizes FOH and GGOH for protein isoprenylation. The enzymes of the isoprenoid shunt are constitutively expressed, their activity may be modulated by isoprenoid depletion, and they are differentially regulated.
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PMID:Isoprenoid alcohols restore protein isoprenylation in a time-dependent manner independent of protein synthesis. 1450 38

Alcohol consumption has been implicated to cause severe hepatic steatosis which is mediated by alcohol dehydrogenase (ADH) activity and CYP(450) 2E1 expression. In this context, the effect of ethanol was studied for its influence on lipogenesis in HepG2 cell which is deficient of ADH and does not express CYP(450) 2E1. The results showed that ethanol at 100mM concentration caused 40% cytotoxicity at 72h as determined by MTT assay. The incorporation of labeled [2-(14)C] acetate into triacylglycerol and phospholipid was increased by 40% and 26% respectively upon 24h incubation, whereas incorporation of labeled [2-(14)C] acetate into cholesterol was not significantly increased. Further, ethanol inhibited HMG-CoA reductase which is a rate-limiting enzyme in the cholesterol biosynthesis. It was observed that, HMG-CoA reductase inhibition was brought about by ethanol as a consequence of decreased cell viability, since incubation of HepG2 cells with mevalonate could not increase the cholesterol content and increase the cell viability. Addition of ethanol significantly increased TNF-alpha secretion and depleted mitochondrial coenzyme-Q(10) which is detrimental for cell viability. But vitamin E (10mM) could partially restore coenzyme-Q(10) and glutathione content with decreased TNF-alpha secretion in ethanol treated cells. Further, lipid peroxidation, glutathione peroxidase and superoxide dismutase enzyme activities remained unaffected. Ethanol decreased glutathione content while, GSH/GSSG ratio was significantly higher compared to other groups showing cellular pro-oxidant and antioxidant balance remained intact. Alanine amino transferase activity was increased by 4.85 folds in cells treated with ethanol confirming hepatocyte damage. Hence, it is inferred that ethanol induced cytotoxicity in HepG2 cells due to coenzyme-Q(10) depletion and increased TNF-alpha secretion.
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PMID:Alcohol depletes coenzyme-Q(10) associated with increased TNF-alpha secretion to induce cytotoxicity in HepG2 cells. 2284 63

HMG-CoA reductase catalyzes the four-electron reduction of HMG-CoA to mevalonate and is an enzyme of considerable biomedical relevance because of the impact of its statin inhibitors on public health. Although the reaction has been studied extensively using X-ray crystallography, there are surprisingly no computational studies that test the mechanistic hypotheses suggested for this complex reaction. Theozyme and quantum mechanical (QM)/molecular mechanical (MM) calculations up to the B3LYP/6-31g(d,p)//B3LYP/6-311++g(2d,2p) level of theory were employed to generate an atomistic description of the enzymatic reaction process and its energy profile. The models generated here predict that the catalytically important Glu83 is protonated prior to hydride transfer and that it acts as the general acid or base in the reaction. With Glu83 protonated, the activation energies calculated for the sequential hydride transfer reactions, 21.8 and 19.3 kcal/mol, are in qualitative agreement with the experimentally determined rate constant for the entire reaction (1 s(-1) to 1 min(-1)). When Glu83 is not protonated, the first hydride transfer reaction is predicted to be disfavored by >20 kcal/mol, and the activation energy is predicted to be higher by >10 kcal/mol. While not involved in the reaction as an acid or base, Lys267 is critical for stabilization of the transition state in forming an oxyanion hole with the protonated Glu83. Molecular dynamics simulations and MM/Poisson-Boltzmann surface area free energy calculations predict that the enzyme active site stabilizes the hemithioacetal intermediate better than the aldehyde intermediate. This suggests a mechanism in which cofactor exchange occurs before the breakdown of the hemithioacetal. Slowing the conversion to aldehyde would provide the enzyme with a mechanism to protect it from solvent and explain why the free aldehyde is not observed experimentally. Our results support the hypothesis that the pK(a) of an active site acidic group is modulated by the redox state of the cofactor. The oxidized cofactor and deprotonated Glu83 are closer in space after hydride transfer, indicating that indeed the cofactor may influence the pK(a) of Glu83 through an electrostatic interaction. The enzyme is able to catalyze the transfer of a hydride to the structurally and electronically distinct substrates by maintaining the general shape of the active site and adjusting the electrostatic environment through acid-base chemistry. Our results are in good agreement with the well-studied hydride transfer reactions catalyzed by liver alcohol dehydrogenase in calculated energy profile and reaction geometries despite different mechanistic functionalities.
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PMID:Molecular modeling of the reaction pathway and hydride transfer reactions of HMG-CoA reductase. 2297 Dec 2

Squalene has wide applications in the food and pharmaceutical industries. Engineering microbes to produce squalene is a promising alternative for traditional production approaches. In this study, squalene production was enhanced to 978.24 mg/L through stepwise overexpression of the enzymes that catalyze acetyl-CoA to squalene. Subsequently, to increase the activity of HMG-CoA reductase and alleviate the high dependence on NADPH, the HMG-CoA reductase (NADH-HMGR) from Silicibacter pomeroyi, highly specific for NADH, was introduced, which increased squalene production to 1086.31 mg/L. Native ethanol dehydrogenase ADH2 and acetaldehyde dehydrogenase ADA from Dickeya zeae were further overexpressed, which enhanced the capability to utilize ethanol for squalene synthesis and endowed the engineered strain with greater adaptability to high ethanol concentrations. Finally, a remarkable squalene production of 9472 mg/L was obtained from ethanol via carbon source-controlled fed-batch fermentation. This study will greatly accelerate the process of developing microbial cell factories for squalene production.
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PMID:Metabolic Engineering of Saccharomyces cerevisiae To Overproduce Squalene. 3198 19