Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.1.1.1 (alcohol dehydrogenase)
9,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NADPH-dependent enzymatic reduction of aromatic aldehydes and ketones observed in the cytosol of guinea pig liver was mediated by at least three distinct reductases (AR 1, AR 2, and AR 3), which were separated by DEAE-cellulose chromatography. By several procedures AR 2 and AR 3 were purified to homogeneity, but AR 1 could be purified only 30-fold because of the small amount. These enzymes were found to have similar molecular weights of 34,000 to 36,000 and similar Stokes radii of about 2.5 nm. AR 3 was identical to aldehyde reductase [EC 1.1.1.2] in substrate specificity for aromatic aldehydes and D-glucuronate and specific inhibition by barbiturates. AR 1 and AR 2 acted on aromatic ketones and cyclohexanone as well as aromatic aldehydes at optimal pHs of 5.4 and 6.0, respectively, and were immunochemically distinguished from AR 3. AR 1 was the most sensitive to sulfhydryl reagents, and AR 2 was more stable at 50 degrees C than the other enzymes. Similar heterogeneity was observed in the kidney enzymes, but other tissues had little aldehyde reductase activity and contained only AR 3. In addition, lung contained a high molecular weight aromatic ketone reductase different from the above reductases.
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PMID:Purification and properties of reductases for aromatic aldehydes and ketones from guinea pig liver. 11 54

The transfer of deuterium from [1 R-2H]ethanol and [1 S-2H]-ethanol to reduced metabolites of administered compounds was measured in female rats provided with bile fistulas. Administered cyclohexanone was reduced to cyclohexanol, and in this reduction hydrogen was transferred only from the 1-pro-R position of the ethanol. The deuterium content in the cyclohexanol was about 67% of that in the ethanol. In the reduction of the 17-oxo group in 3beta-hydroxy-5alpha-androstan-17-one, hydrogen was transferred both from the 1-pro-R position and the 1-pro-S position, resulting in degrees of labelling that were about 25% and 2%, respectively, of those in the specific positions of the ethanols. The 1-pro-R and 1-pro-S positions of ethanol contributed about 9% and 5%, respectively, of the 3beta hydrogen in lithocholic acid formed from 3-oxo-5beta-cholanoic acid. The results indicate that alcohol dehydrogenase and aldehyde dehydrogenase do not share a common pool of NAD, and that NADH formed during acetaldehyde oxidation is utilized for reductions in the cytosol to a smaller extent than the NADH formed in the alcohol dehydrogenase reaction. This result supports the concept that aldehyde oxidation is mainly an intramitochondrial process. The relatively extensive utilization of the 1-pro-S hydrogen of ethanol in the reduction of 3-oxo-5beta-cholanoic acid, that is probably NADPH-dependent, indicates that cytosolic NADPH may be produced from malate or isocitrate formed intramitochondrially.
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PMID:Transfer of the 1-pro-R and the 1-pro-S hydrogen atoms of ethanol in metabolic reductions in vivo. 100 35

Secondary 15N isotope effects at the N-1 position of 3-acetylpyridine adenine dinucleotide have been determined, by using the internal competition technique, for horse liver alcohol dehydrogenase (LADH) with cyclohexanol as a substrate and yeast formate dehydrogenase (FDH) with formate as a substrate. On the basis of less precise previous measurements of these 15N isotope effects, the nicotinamide ring of NAD has been suggested to adopt a boat conformation with carbonium ion character at C-4 during hydride transfer [Cook, P. F., Oppenheimer, N. J. & Cleland, W. W. (1981) Biochemistry 20, 1817]. If this mechanism were valid, as N-1 becomes pyramidal an 15N isotope effect of up to 2-3% would be observed. In the present study the equilibrium 15N isotope effect for the reaction catalyzed by LADH was measured as 1.0042 +/- 0.0007. The kinetic 15N isotope effect for LADH catalysis was 0.9989 +/- 0.0006 for cyclohexanol oxidation and 0.997 +/- 0.002 for cyclohexanone reduction. The kinetic 15N isotope effect for FDH catalysis was 1.004 +/- 0.001. These values suggest that a significant 15N kinetic isotope effect is not associated with hydride transfer for LADH and FDH. Thus, in contrast with the deformation mechanism previously postulated, the pyridine ring of the nucleotide apparently remains planar during these dehydrogenase reactions.
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PMID:Secondary 15N isotope effects on the reactions catalyzed by alcohol and formate dehydrogenases. 201 72

Horse liver alcohol dehydrogenase (EC 1.1.1.1) solubilized in sodium dioctylsulfosuccinate (AOT)/cyclohexane reverse micelles was used for the oxidation of ethanol and reduction of cyclohexanone in a coupled substrate/coenzyme recycling system. The activity of the enzyme was studied as a function of pH and water content. The enzyme was optimally active in microemulsions prepared with buffer of pH around 8. An increase in enzymatic activity was observed as a function of increasing water content. The Km values for the substrates were calculated based on the total reaction volume. The apparent Km for ethanol in reverse micelles was about eight times lower as compared to that in buffer solution, whereas the Km for cyclohexanone was almost unaltered. Storage and operational stability were investigated. It was found that the specific activity of the alcohol dehydrogenase operating in reverse micellar solution was good for at least two weeks. The steroid eticholan-3 beta-ol-17-one was also used as a substrate. In this case the reaction rate was approximately five times higher in a reverse micellar solution than in buffer.
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PMID:Activity and stability of horse-liver alcohol dehydrogenase in sodium dioctylsulfosuccinate/cyclohexane reverse micelles. 243 36

Changes in the enzymatic properties of horse liver alcohol dehydrogenase (HLADH; EC 1.1.1.1) were studied as a function of incubation time in Aerosol-OT/isooctane microemulsions. The enzyme was characterized by fluorimetric binding studies of the inhibitor isobutyramide to the binary complex, HLADH-NADH and by determination of Km,app and Vmax,app values for cyclohexanone. The Km,app values for cyclohexanone and the Kd,app for isobutyramide stay constant throughout a 48-h incubation, whereas the Vmax,app and the total number of inhibitor binding sites decrease. Thus the inactivation process previously described corresponds to progressive loss of functional sites, while the properties of the remaining functional sites are unchanged. If no co-enzyme is added to the system, the enzyme loses catalytic activity within less than an hour, but if co-enzyme is added, a fraction of the HLADH enzyme population retains enzyme activity over a long period of time. Hence the presence of bound co-enzyme significantly inhibits the process(es) leading to inactivation of the enzyme in the microemulsions.
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PMID:Analysis of the inactivation of liver alcohol dehydrogenase during storage in Aerosol-OT/isooctane microemulsions. 247 42

A case of coma due to the drinking of a liquid cement for polyvinyl chloride resin, containing acetone, methyl ethyl ketone, cyclohexanone and polyvinyl chloride is described. The patient also simultaneously ingested the alcoholic beverage, sake. After gastric lavage, plasma exchanges and direct hemoperfusions, the patient recovered. The concentrations of these chemicals in plasma and urine were analyzed at various time intervals to estimate the clearance. The elimination half lives for acetone and methyl ethyl ketone were 18 hours and 10 hours, respectively. Although cyclohexanone made up the largest component in the solvents, the blood level was extremely low and a large amount of cyclohexanol, a metabolite of cyclohexanone was detected in the blood and urine. The glucuronide metabolite of cyclohexanol was also estimated after the hydrolysis with beta-glucuronidase. Since the conversion of cyclohexanone to cyclohexanol is known to be catalyzed by alcohol dehydrogenase, possible interactions between sake ingestion and cyclohexanone metabolism is proposed.
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PMID:Disposition of acetone, methyl ethyl ketone and cyclohexanone in acute poisoning. 276 22

On the administration of 3'-methyl-N,N-dimethyl-4-aminoazobenzene to rats pure aminoazo dye-bound alcohol dehydrogenase accounting for 45% of the total soluble protein bound aminoazo dye is isolated from the liver soluble supernatant. Tryptic digestion of that purified aminoazo dye-bound enzyme yields an aminoazo dye-bound nonapeptide which has a sequence identical to amino acids 301-309 in the known sequence of alcohol dehydrogenase (H. Jornvall and O. Markovic, Eur. J. Biochem., 29 (1972) 167-174) with the exception of methionine 306 which is replaced by an aminoazo dye modified amino acid. The nature of the aminoazo dye adduct was determined by studying the structure of the related tetrapeptide obtained by Pronase B digestion and shown by proton NMR spectroscopy and fast atom bombardment mass spectroscopy to have the structure 3-(Val. Asn. Pro. Homocystein-S-yl)-4-methylamino-3'-methylazobenzene. This carcinogen-protein adduct is assumed to arise from attack of the ultimate carcinogenic metabolite, N-sulphonyloxy-4-methylamino-3'-methylazobenzene (FF. Kadlubar, J.A. Miller and E.C. Miller, Cancer Res., 36 (1976) 2350-2359) at the sulphur of methionine 306 followed by spontaneous S-demethylation. This highly specific reaction of carcinogen with alcohol dehydrogenase lowers its Vmax and increases its Km with cyclohexanone thereby reducing its catalytic efficiency for this substrate. This highly specific reaction of the carcinogen with alcohol dehydrogenase may be regarded as a major detoxication reaction.
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PMID:The binding of an aminoazo dye carcinogen to a specific methionine residue in rat liver alcohol dehydrogenase in vivo. 312 Nov 96

Hepatocytes were isolated from fed female rats and incubated with a redox indicator system consisting of cyclohexanone and unlabelled or perdeuterated cyclohexanol. The concentrations and deuterium contents of these were measured by g.l.c. and g.l.c.-m.s. of oxime t-butyldimethylsilyl derivatives. The equilibrium composition represented the redox state of the coenzyme bound to alcohol dehydrogenase, since 4-methylpyrazole inhibited the interconversion. Reduction appeared to be catalysed to a small extent also by an NADPH-dependent aldehyde reductase. The NADH/NAD+ ratio on alcohol dehydrogenase was 3 orders of magnitude higher in the presence of ethanol than in its absence. This redox shift has the degree expected from reported kinetic constants. The shift was due both to a decreased rate of oxidation and to an increased rate of reduction in the indicator system. The results indicate that the redox effect of ethanol on the free NAD system is due to efficient removal of acetaldehyde from a near-equilibrium system consisting of ethanol, acetaldehyde and bound coenzymes, together with dissociation of NADH from the enzyme. The effect on the redox state of the bound coenzyme was less marked when the ethanol was deuterated at C-1, indicating an isotope effect. The 2H excess in the cyclohexanol formed was about 70% of that in the [1,1-2H2]ethanol. This dilution, which is caused by binding of free NADH to the enzyme, indicates that reoxidation of cytosolic NADH partly limits the rate of ethanol oxidation.
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PMID:Effect of ethanol on the redox state of the coenzyme bound to alcohol dehydrogenase studied in isolated hepatocytes. 343 67

1. The activity of liver alcohol dehydrogenase with cyclohexanol and cyclohexanone as substrates was studied, and the initial-rate parameters were determined from measurements at low substrate concentrations. In contrast with aliphatic ketones, cyclohexanone is a fairly good substrate, although less active than aliphatic aldehydes. The Michaelis constant for cyclohexanol is of the same order as that for ethanol, and the maximum rate and Michaelis constant for NAD(+) obtained with cyclohexanol are very similar to those obtained with primary aliphatic alcohols. The data for this substrate at low concentrations are therefore consistent with a compulsory-order mechanism in which ternary complexes are not rate-limiting. 2. With large concentrations of NAD(+), substrate activation is observed with increasing concentrations of cyclohexanol, whereas with small NAD(+) concentrations substrate inhibition is observed. This complex behaviour is explained by a mechanism previously proposed for this enzyme, which also satisfactorily described the kinetics of oxidation of primary and secondary aliphatic alcohols and aldehydes, including the substrate inhibition exhibited by primary alcohols, and the reduction of aldehydes. The activation with large concentrations of both NAD(+) and cyclohexanol is attributed to the formation of an abortive complex, E.NADH.ROH, from which NADH dissociates more rapidly than from the normal product complex E.NADH. Substrate inhibition in the presence of small NAD(+) concentrations is attributed to the formation of an active complex E.ROH, with which NAD(+) reacts more slowly than with the free enzyme. 3. Some support for these mechanisms of substrate activation and inhibition is obtained by approximate theoretical calculations, and their applicability to other two-substrate reactions that exhibit complex initial-rate behaviour, as a more likely alternative to the postulate of a second binding site for the substrate, is suggested.
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PMID:Substrate activation and inhibition in coenzyme-substrate reactions cyclohexanol oxidation catalysed by liver alcohol dehydrogenase. 429 Sep 85

The class I (alpha, beta 1, gamma 1, and gamma 2), II (pi), and III (chi) isozymes of human liver alcohol dehydrogenase (ADH) were isolated as electrophoretically homogeneous preparations to examine their kinetics of aldehyde and ketone reduction. While the oxidation of a wide variety of alcohols by ADH has been investigated extensively, the reduction of aldehydes and ketones has received much less attention even though the equilibrium favors the latter process. For each isozyme, the Km and kcat values were measured at pH 7.0 with acetaldehyde, pentanal, octanal, benzaldehyde, and cyclohexanone as substrates. Activity could not be detected with succinic semialdehyde and betaine aldehyde for any of the isozymes. The nonenzymatic hydration, oxidation, and aldol condensation of aldehydes in aqueous solutions present serious experimental obstacles in determining the isozymes' kinetic constants. The effects of these reactions on the enzymatic parameters were studied and compensated for. Michaelis constants for all class I and II isozymes vary by more than 8000-fold, from less than 1 microM for beta 1 gamma 1 and beta 1 beta 1 with octanal to 8.3 mM for pi-ADH for acetaldehyde. However, with any given aldehyde, these values vary by less than 40-fold, and the constants are approximately equal to Km values reported previously for the corresponding alcohols. In contrast, Km values for chi-ADH are extremely high and could be determined accurately only for octanal (75 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human liver alcohol dehydrogenase isozymes: reduction of aldehydes and ketones. 639 29


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