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)

1. Kinetic relationships referring to multiple-turnover conditions have been derived for the slowest exponential transient appearing in two-substrate enzyme reactions proceeding by an ordered ternary-complex mechanism. The validity of these and previously derived theoretical relationships for this mechanism has been tested by application to the liver alcohol dehydrogenase reaction. 2. All essential features of the transient-state kinetics of alcohol oxidation by NAD+ in the liver alcohol dehydrogenase system can be qualitatively and quantitatively explained in view of the compulsory-order mechanism in the proposed scheme. There is no kinetic evidence for any half-of-the-sites reactivity of the enzyme. A consistent set of rate constants is reported for the enzymic oxidation of benzyl alcohol at pH 8.75. 3. Transient-state rate parameters for benzyl alcohol/benzaldehyde catalysis by liver alcohol dehydrogenase have been determined at different pH. The interpretation of such rate parameters is critically discussed with reference to their informative value for the purpose of determination of rate constants (k and k') for the process of ternary-complex interconversion in the proposed scheme. It is concluded that the apparent rate constant (k') for hydride transfer from benzyl alcohol to NAD+ is dependent on a proton dissociation step with a pKa of 6.4, whereas the rate constant (k) for hydride transfer from NADH to benzaldehyde exhibits no corresponding dependence on proton association. 4. The asymmetric pH dependence of the forward and reverse rate of ternary-complex interconversion during liver alcohol dehydrogenase catalysis appears to reflect an obligatory step of alcohol/alcoholate ion equilibration occurring at the ternary-complex level. It is suggested that the observed pKa 6.4 dependence of the transient rate of alcohol oxidation can be attributed to a coupled acid-base system involving minimally the enzyme-bound alcohol and the protein residues Ser-48 and His-51.
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PMID:Effect of pH on the process of ternary-complex interconversion in the liver-alcohol-dehydrogenase reaction. 2 59

Starch and polyacrylamide gel electrophoresis were used to ascertain the substrate specificities of alcohol-oxidizing enzymes in 13 Drosophila species. The substrates used were a variety of long- and short-chain aliphatic alcohols, one aromatic alcohol, and benzaldehyde. Only one enzyme (product of a single-gene locus) showed significant NAD+-dependent alcohol dehydrogenase activity with short-chain aliphatic alcohols. The 13 species, belonging to four different Drosophila groups, all showed a similar complement of alcohol-oxidizing enzymes, although differences in electrophoretic mobility and in levels of activity existed from species to species. These findings are relevant to the adaptation of Drosophila to alcohol environments.
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PMID:Alcohol-oxidizing enzymes in 13 Drosophila species. 10 41

The reduction, catalysed by liver alcohol dehydrogenase, of benzaldehyde in the presence and absence of pyrazole, and the oxidation of benzyl alcohol and cyclohexanol in the presence of isobutyramide, has been measured by the stopped-flow technique. In performing these experiments particular care was taken to purify the enzyme, coenzymes, substrates and inhibitors, and to minimise as much as possible the effects of a blank substrate reaction. The calculation of the amount of substrate converted to product during the various phases of the transient process was based on the absorption coefficients for the enzyme-coenzyme and enzyme-coenzyme-inhibitor complexes determined in the absence of substrate. The results show that the two active sites of liver alcohol dehydrogenase are kinetically equivalent and that the enzyme does not exhibit half-of-the-sites reactivity.
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PMID:Kinetic equivalence of the active sites of alcohol dehydrogenase from horse liver. 16 81

The transient-state kinetics of enzymic reduction of acetaldehyde and benzaldehyde by NADH, catalyzed by horse liver alcohol dehydrogenase, have been examined under single-turnover conditions, obtained by carrying out reactions either with limiting amounts of enzyme in the presence of 20 mM pyrazole or with limiting amounts of substrate. Analysis of the variation with substrate, coenzyme, and enzyme concentrations of amplitudes and time constants for the exponential transients observed at 328 nm and 300 nm shows that the kinetics of enzymic aldehyde reduction are qualitatively and quantitatively consistent with the relationships derived in the preceding paper for an ordered ternary-complex mechanism involving identical and independent catalytic sites. It is concluded that there is no evidence whatsoever for the kinetic significance of a half-of-the-sites reactivity or any other kind of subunit interaction in the liver alcohol dehydrogenase system. The biphasic transients observed at 328 nm for the reduction of aromatic aldehydes such as benzaldehyde are a normal kinetic characteristic of the ordered ternary-complex mechanism, being attributable to accumulation of the ternary enzyme-NAD-product complex when product dissociation from this complex is slow in comparison to its formation by ternary-complex interconversion.
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PMID:Kinetic transients in the reduction of aldehydes catalysed by liver alcohol dehydrogenase. 18 64

New transient kinetic methods, which allow kinetics to be carried out under conditions of excess substrate, have been employed to investigate the kinetics of hydride transfer from NADH to aromatic aldehydes and from aromatic alcohols to NAD+ as a function of pH. The hydride transfer rate from 4-deuterio-NADH to beta-naphthaldehyde is nearly pH independent from pH 6.0 to pH 9.9; the isotope effect is also pH independent with kappa-H/kappaD congruent to 2.3. Likewise, the rate of oxidation of benzyl alcohol by NAD+ changes little with pH between pH 8.75 and pH 5.9; the isotope effect for this process is between 3.0 and 4.4. Earlier substituent effect studies on the reduction of aromatic aldehydes were consistent with electrophilic catalysis by either zinc or a protonic acid. The pH independence of hydride transfer is consistent with electrophilic catalysis by zinc since such catalysis by protonic acid (with a pK between 6.0 and 10.0) would show strong pH dependence. However, protonic acid catalysis cannot be excluded if the pKa of the acid catalyst in the ternary NADH-E-RCOH complex were smaller than 6.0 or smaller than 10.0. The two kinetic parameters changing significantly with pH are the kinetic binding constant for ternary complex formation with aromatic alcohol and the rate of dissociation of aromatic alcohols from enzyme. This is consistent with base-catalyzed removal of a proton from alcohol substrated and consequent acid catalysis of protonation of a zinc-alcoholate complex. The equilibrium constant for hydride transfer from benzaldehyde to benzyl alcohol at pH 8.75 is K-eq equals kappa-H/kappa-H equals 42; this constant has important consequences concerning subunit interactions during liver alcohol dehydrogenase catalysis.
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PMID:Effect of pH on the liver alcohol dehydrogenase reaction. 23 78

The effect of pH on steady state kinetic parameters for the yeast alcohol dehydrogenase-catalyzed reduction of aldehydes and oxidation of alcohols has been studied. The oxidation of p-CH3 benzyl alcohol-1,1-h2 and -1,1-d2 by NAD+ was found to be characterized by large deuterium isotope effects (kH/kD = 4.1 plus or minus 0.1) between pH 7.5 and 9.5, indicating a rate-limiting hydride trahsfer step in this pH range; a plot of kCAT versus pH could be fit to a theoretical titration curve, pK = 8.25, where kCAT increases with increasing pH. The Michaelis constnat for p-CH3 benzyl alcohol was independent of pH. The reduction of p-CH3 benzaldehyde by NADH and reduced nicotinamide adenine dinucleotide with deuterium in the 4-A position (NADD) cound not be studied below pH 8.5 due to substrate inhibition; however, between pH 8.5 and 9.5, kCAT was found to decrease with increasing pH and to be characterized by significant isotope effects (kH/kD = 3.3 plus or minus 0.3). In the case of acetaldehyde reduction by NADH and NADD, isotope effects were found to be small and exxentially invariant (kH/kD = 2.O plus or minus 0.4) between pH 7.2 and 9.5, suggesting a partially rate-limiting hydride transger step for this substrate; a plot of kCAT/K'b (where K'b is the Michaelis constant for acetaldehyde) versus pH could be fit to a titration curve, pK = 8.25. The titration curve for acetaldehyde reduction has the same pK but is opposite in direction to that observed for p-CH3 benzyl alcohol oxidation. The data presented in this paper indicate a dependence on different enzyme forms for aldehyde reduction and alcohol oxidation and are consistent with a single active site side chain, pK = 8.25, which functions in acid-base catalysis of the hydride transfer step.
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PMID:Acid-base catalysis in the yeast alcohol dehydrogenase reaction. 23 17

Steady-state kinetic parameters for the yeast alcohol dehydrogenase catalyzed oxidation of a series of parasubstituted benzyl alcohols-1, 1-h2 and -1, 1-d2 by NAD+ are reported. Catalytic constants have been found to be characterized by large deuterium isotope effects: kH/kD=4.8, p-Br; 4.2, p-Cl; 3, 4, p-H; 4, 2, p-CH3; 3, 2, p-CH3O. The observed isotope effects on k(cat)/K(A), K(A), and K(B), where K(A) and K(B) are Michaelis constants for NAD+ and alcohol, indicate a borderline rapid equilibrium-steady-state kinetic mechanism involving the random addition of substrate and coenzyme to enzyme. With the exception of p-CH3 and possible p-CH3O substituted benzyl alcohol, k(cat) is concluded to represent a single, rate-limiting hydrogen transfer step. A multiple linear regression analysis of the combined data for benzaldehyde reduction (Klinman, J.P. (1972), J. Biol. Chem. 247, 7977-7987, expanded to include p-CH(CH3) 2-substituted benzaldehyde) and benzyl alcohol oxidation has been carried out to determine the contribution of electronic, hydrophobic, and steric effects to k(cat) and substrate binding. Benzaldehyde binding is concluded to depend on electronic substituent effects as previously reported [log 1/K(ald)=(-0.92 +/- 0.18)sigma+-(0.80 +/- 0.067)], whereas benzyl alcohol binding correlates with substrate hydrophobicity [(log 1/K(alc)=(0.60 +/- 0.14) log P -(1.2 +/- 0.12)]. In the case of benzyl alcohol oxidation, k(cat) is independent of electronic and steric effects; the best of seven equations indicates a small negative dependence of k(cat) on hydrophobicity, which is within experimental error or zero [log k(o)=(-0.075 +/- 0.25) log P -(0.65 +/- 0.19)]. Data for benzaldehyde reduction are correlated at the 99% significance level by a single variable equation [(log k(R)=(2.1 +/- 0.37) sigma+-(0.093 +/- 0.14)] and a two variable equation [(log k(R)=(1.9 +/- 0.33) sigma+ + (0.46 +/- 0.20) log P-(0.46 +/- 0.20)]; these equations indicate (a) a large dependence on electronic substituent as reported previously and (b) a possible role for hydrophobic factors in facilitating catalysis. As the result of the observed hydrophobic substituent effects, different ground-state interactions are suggested for the binding of benzaldehydes and benzyl alcohols. Electronic substituent effects lead to the conclusion that there is little or no change in charge at C-1 of substrate at the transition state, relative to alcohol in the ground state. The significance of these effects to the detailed properties of the hydrogen transfer step is discussed.
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PMID:Isotope effects and structure-reactivity correlations in the yeast alcohol dehydrogenase reaction. A study of the enzyme-catalyzed oxidation of aromatic alcohols. 77 29

Acute IP injection of benzyl alcohol but not benzaldehyde (0.5 g/kg) caused aversion to voluntary drinking of 5% ethanol solution by male rats with preference to ethanol. Benzyl alcohol noncompetitively inhibited hepatic alcohol dehydrogenase of rats maintained for a short term on 5% ethanol compared to control. The results suggest an adverse interaction between benzyl alcohol and ethanol underlying the observed aversion to ethanol.
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PMID:Behavioral and enzymatic interactions between benzyl alcohol and ethanol. 147 90

1. Short-term intake of a 2% benzyl alcohol in the rat drinking fluid resulted in sex-dependent inhibition of hepatic alcohol dehydrogenase. 2. Benzyl alcohol intake also inhibited female but not male mitochondrial aldehyde dehydrogenase isoenzymes with the apparent low and high Km. 3. The benzyl alcohol inhibition kinetics were found non-competitive with the major differences in Vmax being confined to the cytoplasmic enzymes. 4. The velocity of the enzymatic reaction was greater for the substrate benzaldehyde than benzyl alcohol. 5. The results suggest sex-dependent hepatic alcohol dehydrogenase-substrate competition between benzyl alcohol and ethanol which may precipitate adverse metabolic interaction particularly in the susceptible female subject. 6. Modulation of the activity of this enzyme by benzyl alcohol may contribute to its toxicity as preservative in parentral injectable solutions.
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PMID:Benzyl alcohol adverse effects in the rat: implications for toxicity as a preservative in parentral injectable solutions. 168 18

Active site substituted Cd(II) horse liver alcohol dehydrogenase has been studied by Perturbed Angular Correlation of Gamma rays Spectroscopy during turnover conditions for benzaldehyde and 4-trans-(N,N-dimethylamino)cinnamaldehyde. The ternary complex between alcohol dehydrogenase NAD+ and Cl-, and the binary complex between alcohol dehydrogenase and orthophenanthroline have also been studied. The Nuclear Quadrupole Interaction parameters have been interpreted in terms of different coordination geometries for Cd(II) in the catalytic zinc site of the enzyme. Calculation of the nuclear quadrupole interaction for cadmium in the catalytic site of the enzyme with and without coenzyme, based upon the four coordinated geometries determined from X-ray diffraction, agrees with the experimentally determined values. The ternary complexes between enzyme, NAD+ and either Cl- or trifluoroethanol and the binary complex between enzyme and orthophenanthroline have almost identical spectral parameters which are not consistent with a four coordinated geometry, but are consistent with a five coordinated geometry. The non-protein ligands for the ternary complex with trifluoroethanol are suggested to be an alkoxide group and a water molecule. The Nuclear Quadrupole Interaction parameters for the productive ternary complex between enzyme, NADH and an aldehyde is consistent with the four coordinated geometry predicted from X-ray diffraction data having the carbonyl group of the aldehyde substituting the water molecule as ligand to the metal.
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PMID:Coordination geometry for cadmium in the catalytic zinc site of horse liver alcohol dehydrogenase: studies by PAC spectroscopy. 180 73


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