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Query: UMLS:C1332347 (ADH)
 2,230 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The three-dimensional structure of rat liver formaldehyde dehydrogenase (FALDH), previously known as class III alcohol dehydrogenase, was constructed using computer graphics and computer programs developed for model building. The construction is based on horse liver alcohol dehydrogenase (EE-ADH), whose structure has been elucidated by X-ray crystallography. The high sequence homology between the two enzymes makes knowledge-based modelling feasible in this case. The model shows a remarkable similarity to horse liver alcohol dehydrogenase especially in the NAD-binding domain. Certain mutations, and the one insertion in FALDH compared to EE-ADH in particular, have cause important changes in the substrate binding site, and thus aliphatic alcohols have been replaced by hemi-thioacetals as favourable substrates.
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PMID:Model for the structure of formaldehyde dehydrogenase based on alcohol dehydrogenase. 188 14

Three amino acid residues (glycine-14, cysteine-135, and cysteine-218) previously speculated to be important for the structure and function of Drosophila melanogaster alcohol dehydrogenase have been investigated by using site-directed mutagenesis followed by kinetic analysis and chemical modification. Mutating glycine-14 to valine (G14V) virtually inactivates Drosophila ADH, and substitution of alanine at this position (G14A) causes a 31% decrease in activity. Thermal denaturation and kinetic and inhibition studies further demonstrate that replacing glycine-14 with either alanine or valine leads to structural changes in the NAD binding domain. These results provide direct evidence for the role played by glycine-14 in maintaining the correct conformation in the NAD binding domain. On the other hand, changing of cysteine-135, -218, or both to alanine (C135A, C218A, and C135A/C218A) causes no decrease in the catalytic activity of the enzyme, indicating that neither of the cysteinyl residues is essential for catalysis. C135A and wild-type enzyme are both inactivated by DTNB. In contrast, C218A and C135A/C218A are unaffected by DTNB treatment. DTNB modification of cysteine-218 can be prevented by the substrates NAD and 2-propanol, suggesting that cysteine-218 may be in the vicinity of the active site. Cysteine-135 which is normally insensitive to DTNB becomes accessible in the presence of 2-propanol and/or NAD, suggesting a conformational change induced by binding of these substrates.
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PMID:Site-directed mutagenesis of glycine-14 and two "critical" cysteinyl residues in Drosophila alcohol dehydrogenase. 210 21

Three different dehydrogenases able to oxidize formaldehyde were found in the Gram-positive methylotroph, Nocardia sp. 239: an NAD-dependent aldehyde dehydrogenase (NA-ADH), and NAD- and factor-dependent formaldehyde dehydrogenase (FD-FDH), and a dye-linked aldehyde dehydrogenase (DL-ADH). The ratio of the activities observed for the two NAD-linked enzymes varied with growth conditions: batch-wise grown cells had nearly the same activities for both enzymes; in fed batch-wise grown cells (methanol limitation) only FD-FDH was detected. The latter is clearly involved in formaldehyde oxidation, since the enzyme and the factor were found only in methanol-grown cells and the enzyme is specific for formaldehyde. In contrast, the two aldehyde dehydrogenases may have significance for aldehyde dissimilation in general, since both activities could also be demonstrated in ethanol-grown cells (but not in glucose-grown cells) and higher aldehydes are even better substrates than formaldehyde. NA-ADH was purified to homogeneity. The enzyme seems to be a homotetramer since it showed a relative molecular mass of 200,000 and the denaturated form of 55,000. Other characteristics are as follows: the enzyme showed substrate inhibition for the aldehydes tested; optimal activity was found at pH 9.2; the reverse reaction was not observed; the enzyme was specific for NAD; GSH, K+, or NH4+ addition did not stimulate formaldehyde oxidation; the order of NAD and substrate addition to the enzyme was not important; several compounds able to block SH groups were inhibitory. Comparison with NAD-linked aldehyde dehydrogenases from Gram-negative bacteria showed that the Nocardia enzyme is distinct from the enzyme of Pseudomonas putida (EC 1.2.1.46) and of Hyphomicrobium X.
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PMID:Different types of formaldehyde-oxidizing dehydrogenases in Nocardia species 239: purification and characterization of an NAD-dependent aldehyde dehydrogenase. 224 Nov 49

The effect of alcohol dehydrogenase (ADH/NAD) from yeast and horse liver was tested on the induction of chromosomal mutations and sister chromatid exchanges (SCE) by N-nitrosodiethanolamine (NDELA) in human lymphocyte cultures. BrdUrd (27 micrograms) was added 24 h after starting the cultures to allow visualisation of SCE. ADH/NAD and NDELA were added 24 h later in different concentrations. No significantly higher level of numerical or structural chromosome aberrations was observed. However, the SCE frequency per cell was significantly increased by adding NAD (31.25 mumol and 62.5 mumol). The exclusive addition of 220 units ADH from yeast as well as 1.8 units ADH from horse liver also raised the number of SCE highly significantly. The combination of NAD and ADH was more effective than each substances alone in the yeast but not in the horse liver system. NDELA in a range of 12.5-62.5 mumol, given to cultures with ADH/NAD from yeast, additionally increased the SCE frequencies in a dose-dependent way. Similar results were found in cultures containing ADH/NAD from horse liver and 6.25-31.25 mumol NDELA, but the total numbers of SCE were distinctly higher. These results indicate that NDELA is strongly activated by ADH from yeast but even more by ADH from horse liver.
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PMID:Increased mutagenicity of N-nitrosodiethanolamine in human lymphocyte cultures after activation by alcohol dehydrogenase. 280 83

The potent carcinogen N-nitrosodiethanolamine (NDELA) which is nonmutagenic in standard modifications of the S. typhimurium/mammalian microsome assay, can be activated effectively by alcohol dehydrogenase/NAD (ADH/NAD) to intermediates which are directly mutagenic in strains TA 98 and TA 100. The expected metabolites N-nitroso-2-hydroxymorpholine (NHMor), N-nitroso-(2-hydroxyethyl)-glycine (NHEG), N-nitrosoiminodiacetic acid (NIDA), and glycolaldehyde were assayed for their direct mutagenic activities in S. typhimurium TA 1535, TA 98, and TA 100. All compounds were clearly mutagenic in TA 100, but different specificities were observed for the other strains. NDELA and its putative mutagenic metabolites were also tested for induction of genotoxic activities by determination of DNA single strand breaks in primary rat hepatocytes. In these cells, NDELA and NHMor were clearly genotoxic, whereas NHEG and NIDA were inactive. In contrast, when assayed for the induction of selective DNA amplification NDELA and its metabolites were not found to induce SV40 DNA synthesis in SV40-transformed Chinese Hamster cells. The compounds were also assayed for induction of DNA single strand breaks in the liver after a single oral application to rats. NDELA and NHMor were about equally active in this in vivo test, whereas NHEG, NIDA and glycolaldehyde were inactive. Differences in biological activity in the cultivated cells, as compared to hepatocytes or to the in vivo situation may most probably be due to differences in metabolism and/or pharmacokinetics.
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PMID:Biological activity of N-nitrosodiethanolamine and of potential metabolites which may arise after activation by alcohol dehydrogenase in Salmonella typhimurium, in mammalian cells, and in vivo. 300 88

The sorption of a model ferment-cofactor system ADH-NAD on hydrophobic carbon carriers and its electrocatalytic properties have been investigated. On the basis of obtained experimental data a model of the structure of inner mitochondrial membrane and a mechanism of transfer of hydrogen through it have been proposed.
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PMID:[Study of the sorption immobilization of coenzyme-dependent oxidoreductases and their functions in electro-enzymatic processes and biological membranes]. 316 93

The beta 3 beta 3 (formerly called beta Indianapolis) and beta 1 beta 1 isoenzymes of human alcohol dehydrogenase differ substantially in their catalytic properties. Specifically, the KM value for NAD+ of beta 3 beta 3 is 70 times greater than that of beta 1 beta 1, and the Ki value for NADH is 35 times greater than that of beta 1 beta 1. To identify the structural basis of these catalytic differences, we sequenced regions of the beta 3 subunit and the beta 3 gene. beta 3 differs from beta 1 by the substitution of Cys for Arg-369. Based on x-ray crystallography of horse ADH, Arg-369 should interact with the nicotinamide phosphate moiety of NAD(H). The Cys for Arg-369 substitution would decrease the enzyme's affinity for coenzyme and, thus, account for the observed kinetic differences between beta 3 beta 3 and beta 1 beta 1.
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PMID:The human beta 3 alcohol dehydrogenase subunit differs from beta 1 by a Cys for Arg-369 substitution which decreases NAD(H) binding. 361 18

The effects of taurine, its initial precursor L-cysteine, and the major metabolite taurocholic acid on two ethanol-mediated responses in rodents were studied. Administration of a single dose of taurocholic acid reduced voluntary intake of a 5% ethanol solution by the rat. In the mouse, taurine had no effect on alcohol drinking or on the central depressant action of ethanol, as measured by the duration of ET-produced loss of the righting reflex. Likewise, taurocholic acid and L-cysteine did not significantly influence the duration of ethanol-narcosis time from control mice. Also studied were the effects of acute and short-term (7 or 10 days) administration of these compounds on hepatic ethanol and acetaldehyde metabolizing enzymes. Short-term administration of an equimolar concentration of taurine enhanced endogenous NADP-linked rat liver aldehyde dehydrogenase (L-ALDH) as contrasted with inhibition of the same enzyme by L-cysteine. Short-term (7 days) treatment with L-cysteine induced rat liver NAD-linked ALDH, but acute (single dose) treatment did not. Taurocholic acid short-term administration caused an induction and an inhibition of endogenous mouse liver alcohol dehydrogenase (L-ADH) and L-ALDH, respectively. The results suggest that taurine does not directly interact with ethanol. However, its major metabolite, taurocholic acid, may cause rapid metabolic conversion of ethanol to acetaldehyde by induction of L-ADH, which is then slowly metabolized due to a concomitant inhibition of L-ALDH. This may cause a build-up of acetaldehyde and thereby produce adverse reactions similar to those resulting from the combination of disulfiram and ethanol.
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PMID:Differential response of NADP-linked hepatic aldehyde dehydrogenase toward taurine: implication for behavioural effects of ethanol. 362 78

Acute alcohol intoxication is far more commonly observed in Orientals than Caucasians. The human liver contains several cytosolic and microsomal ADHs. One of the major cytosolic ADH isozymes controlled by a gene at the ADH2 locus differs between Caucasians and Orientals. Most Caucasians have the usual enzyme consisting of usual beta 1 subunit, while nearly 90% of Orientals have the atypical enzyme consisting of the atypical beta 2 subunit. The specific activity of the atypical enzyme is several times higher at pH 10 and nearly 100 times higher at physiologic pH than the usual enzyme. Km values for ethanol, NAD, acetaldehyde, and NADH are several times higher for the atypical enzyme than for the usual enzyme. The usual enzyme is rapidly inactivated by iodoacetate, indicating the existence of an "active-site cysteine" in the molecule. In contrast, the atypical enzyme is resistant to iodoacetate inactivation. Peptide mapping analysis revealed that the active site Cys in the usual beta 1 subunit is replaced by His in the atypical beta 2 subunit. A remarkable structural homology exists at the active site of horse and human enzymes. In the usual beta 1 beta 1 enzyme, as in the horse enzyme, the catalytic Zn is expected to link to the sensitive Cys at position 47, His at position 67, and Cys (presumably) at position 174, thus forming the active site. In contrast, the active site of the atypical beta 2 beta 2 enzyme is expected to consist of the catalytic Zn linked to His at position 47, His at position 67, and Cys (presumably) at position 174. The resistance of the atypical beta 2 beta 2 to inactivation by iodoacetate is a direct consequence of the replacement of the sensitive Cys at position 47 by His. Liver ALDH components also differ between Caucasians and Orientals. Virtually all Caucasians have two major ALDH isozymes, ALDH1 and ALDH2, while approximately 50% of Orientals have only the ALDH1 isozyme (cytosolic) missing ALDH2 isozyme (presumably mitochondrial). ALDH1 consists of four subunits with a molecular weight of 56,500, and ALDH2 consists of four subunits with a molecular weight of 52,600. The two isozymes do not share any common subunit. Examination of liver extracts by two-dimensional crossed immunoelectrophoresis revealed that an atypical Oriental liver with no ALDH2 isozyme contained an enzymatically inactive but immunologically cross-reactive material corresponding to ALDH2, besides the active ALDH1 isozyme.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differences in the isozymes involved in alcohol metabolism between caucasians and orientals. 635 99

The NAD-dependent oxidation of ethanol, 2,3-butanediol, and other primary and secondary alcohols, catalyzed by alcohol dehydrogenases derived from Penicillium charlesii, was investigated. Alcohol dehydrogenase, ADH-I, was purified to homogeneity in a yield of 54%. The enzyme utilizes several primary alcohols as substrates, with Km values of the order of 10(-4) M. A Km value of 60 mM was obtained for R,R,-2,3-butanediol. The stereospecificity of the oxidation of 2-butanol was investigated, and S-(+)-2-butanol was found to be oxidized 2.4 times faster than was R-(-)-2-butanol. The reduction of 2-butanone was shown to produce S-(+)-2-butanol and R-(-)-butanol in a ratio of 7:3. ADH-I is the primary isozyme of alcohol dehydrogenase present in cultures utilizing glucose as the sole carbon source. The level of alcohol dehydrogenase activity increased 7.6-fold in mycelia from cultures grown with glucose and 2,3-butanediol (0.5%) as carbon sources compared with the activity in cultures grown on only glucose. Two additional forms of alcohol dehydrogenase, ADH-II and ADH-III, were present in the cultures supplemented with 2,3-butanediol. These forms of alcohol dehydrogenase catalyze the oxidation of ethanol and 2,3-butanediol. These data suggest that P. charlesii carries out an oxidation of 2,3-butanediol which may constitute the first reaction in the degradation of 2,3-butanediol as well as the last reaction in the mixed-acid fermentation. Alcohol dehydrogenase activities in P. charlesii may be encoded by multiple genes, one which is expressed constitutively and others whose expression is inducible by 2,3-butanediol.
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PMID:Occurrence of multiple forms of alcohol dehydrogenase in Penicillium supplemented with 2,3-butanediol. 638 55


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