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)

We have synthesized phenyl adenine dinucleotide (P1-adenosine-5')-P2-(beta-D-ribofuranosylbenzene-5')-pyrophosphate (PhAD), a novel analog of pyridine nucleotide coenzymes. This compound contains a planar aromatic ring, as does NAD+, but lacks a positive charge. PhAD is an inhibitor of horse liver alcohol dehydrogenase, competitive with NADH. PhAD is very similar to NAD+ sterically since both compounds have a planar aromatic ring. However, PhAD resembles NADH in binding to the enzyme because the dissociation constants of both compounds show a parallel increase as the pH is raised, whereas those of NAD+ behave in the opposite manner. These observations indicate that the enzyme differentiates between NAD+ and NADH on the basis of the positive charge on the molecule and not the stereochemical orientation of the reduced nicotinamide ring.
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PMID:The interaction of liver alcohol dehydrogenase with phenyl adenine dinucleotide, a novel analog of pyridine nucleotide coenzymes. 21 Jan 61

The apoenzyme and holoenzyme structures of liver alcohol dehydrogenase have been determined by X-ray methods to obtain details about coenzyme binding, substrate specificity and the catalytic mechanism. Coenzyme binding induces a conformational change of the protein which partly shields the active site from the solution. The reduced coenzyme binds in an open conformation similar to that of NAD bound to malate dehydrogenase. A hydrogen bond between Thr-178 and the carboxamide group of the coenzyme is essential for proper positioning of the nicotinamide in the active site. Coenzyme analogues in which the carboxamide group is absent or substituted with iodine bind in a different conformation and do not induce the structural change of the protein. Binding of substrate molecules has been studied in crystals obtained from an equilibrium mixture of enzyme, coenzyme and p-bromobenzyl alcohol. The oxygen atom of this substrate as well as that of the inhibitor molecules trifluoroethanol and dimethyl sulphoxide bind directly to the catalytic zinc atom. The substrate-binding region is a deep hydrophobic pocket at the bottom of which the zinc atom mediates electrophilic catalysis of alcohol oxidation.
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PMID:Coenzyme-induced conformational changes and substrate binding in liver alcohol dehydrogenase. 21 94

The three-dimensional structure of a ternary complex of horse liver alcohol dehydrogenase with reduced nicotinamide adenine dinucleotide and the inhibitor dimethyl sulfoxide has been determined to 4.5 A resolution independently of the apoenzyme structure. The electron density maps of both structures have been compared. The two coenzyme binding domains which form the center of the dimer molecular have retained their conformation and orientation within the molecule whereas the catalytic domains rotate and narrow the cleft between the domains. The active site becomes shielded from the solution by a combination of this rotation, local movements of a loop from residues 53 to 57 and coenzyme and substrate binding. Both subunits bind coenzyme and inhibitor to the same extent. The nicotinamide ring of the coenzyme is positioned close to the active zinc atom and the inhibitor is bound to this zinc atom. The difference between the two crystallographically independent subunits is small. The proposed mechanisms of action for the enzyme based on the apoenzyme structure are confirmed by the present investigation.
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PMID:Structural differences between apo- and holoenzyme of horse liver alcohol dehydrogenase. 21 69

A potent new enzyme-antibody conjugate system for amplifying cytotoxicity was tested in a well-defined model of hapten [2,4,6-trinitrophenyl (TNP)]-substituted tumor cells (HEp2) and purified anti-hapten antibody. Brief treatment of TNP-HEp2 cells with low concentrations (0.05 to 0.74 micrograms/ml) of antihapten antibody-alcohol dehydrogenase conjugate (Ab-ADH) followed by culture in complement-free medium containing nicotinamide adenine dinucleotide and allyl alcohol or 2-fluoroethanol resulted in 15 to 90% cell killing as measured by 5-[125l]iodo'-2-deoxyuridine uptake assay. The importance of the complete enzyme system was indicated by reduced or absent cytotoxicity if Ab-ADH, nicotinamide adenine dinucleotide, or allyl alcohol (or 2-fluorethanol) were omitted. Immunological specificity of the Ab-ADH was demonstrated by reduced or absent cytotoxicity when: (a) HEp2 cells were not coated with TNP; (b) Ab-ADH binding onto TNP-cells was blocked by free hapten (2,4-dinitrophenyllysine); or (c) unconjugated alcohol dehydrogenase and anti-TNP purified IgG anti-2,4,6-trinitrophenyl antibody with NAD+ and allyl alcohol or anti-TNP antibody with complement were used.
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PMID:Affinity cytotoxicity with an alcohol dehydrogenase-antibody conjugate and allyl alcohol. 22 Nov 2

Butylated hydroxyanisole (BHA), a widely used food additive, previously was found to inhibit various chemical carcinogens. In the present work, BHA, when added to the diet, inhibited the carcinogenic action of methylazoxymethanol (MAM) acetate on the large intestine of female CF1 mice. The effects of BHA on nicotinamide adenine dinucleotide (NAD+)-dependent alcohol dehydrogenase, a postulated activating enzyme for MAM, were determined. BHA reduced this enzyme activity in vitro in crude tissue preparations of large intestine and liver. The parallel finding of BHA inhibition of MAM acetate carcinogenesis of the large bowel and of NAD'-dependent dehydrogenase activity lends support to the postulated role of the dehydrogenase activity in activating MAM to an ultimate carcinogenic form. However, BHA has multiple biologic actions so that its inhibitory effect on MAM acetate-induced neoplasia of the large intestine may entail some other mechanism.
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PMID:Inhibitory effects of butylated hydroxyanisole on methylazoxymethanol acetate-induced neoplasia of the large intestine and on nicotinamide adenine dinucleotide-dependent alcohol dehydrogenase activity in mice. 22 17

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

Yeast alcohol dehydrogenase is inactivated and alkylated by styrene oxide in a single exponential kinetic process. The concentration dependence of half-times for inactivation indicates the formation of an enzyme inhibitor complex, KI = 2.5 times 10(-2) M at pH 8.0. Reduced nicotinamide adenine dinucleotide (NADH), at a concentration of 3 times 10(-4) M where Kd congruent to 1 times 10(-5) M, has a small effect on kinetic parameters for inactivation. Although benzyl alcohol and acetamide-NADH increase the KI for styrene oxide in a manner consistent with their dissociation constants, substrate also increases the rate of inactivation at high styrene oxide concentrations. The reciprocal of half-times for inactivation, extrapolated to infinite styrene oxide concentration, increases with pH between 7.6 and 9.0, pK congruent to 8.5. The stoichiometry of alkylation by [3H]styrene oxide is 2.2 mol of reagent incorporated/mol of subunit, and is accompanied by the loss of 1.9 mol of sulfhydryl/mol of subunit; prior alkylation with iodoacetamide reduces the stoichiometry to 0.88:1, and increases the rate of labeling. Tryptic digests of enzyme modified with [14C]iodoacetamide or [3H]styrene oxide produce two major peptides which cochromatograph, indicating that styrene oxide and iodoacetamide modify the same cysteine residues. Previous investigators have reported that iodoacetate, iodoacetamide, and butyl isocyanate alkylate either of two reactive cysteines of yeast alcohol dehydrogenase; both cysteines cannot be modified simultaneously [Belke et al. (1974), Biochemistry 13, 3418]. The inactivation of enzyme by p-chloromercuribenzoate (PCMB) is reported here to be accompanied by the incorporation of 2.3 mol of PCMB/mol of enzyme subunits, in analogy with styrene oxide; the planarity of the alkylating agent appears to be an important factor in determining the stoichiometry of labeling.
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PMID:The interaction of an epoxide with yeast alcohol dehydrogenase: evidence for binding and the modification of two active site cysteines by styrene oxide. 23 61

1,4,5,6-Tetrahydronicotinamide adenine dinucleotide (H2NADH) has been investigated as a reduced coenzyme analog in the reaction between trans-4-N,N-dimethylaminocinnamaldehyde (I) (lambdamax 398 nm, epsilonmax 3.15 X 10-4 M-minus 1 cm-minus 1) and the horse liver alcohol dehydrogenase-NADH complex. These equilibrium binding and temperature-jump kinetic studies establish the following. (i) Substitution of H2NADH for NADH limits reaction to the reversible formation of a new chromophoric species, lambdamax 468 nm, epsilonmax 5.8 x 10-4 M-minus 1 cm-minus 1. This chromophore is demonstrated to be structurally analogous to the transient intermediate formed during the reaction of I with the enzyme-NADH complex [Dunn, M. F., and Hutchison, J. S. (1973), Biochemistry 12, 4882]. (ii) The process of intermediate formation with the enzyme-NADH complex is independent of pH over the range 6.13-10.54. Although studies were limited to the pH range 5.98-8.72, a similar pH independence appears to hold for the H2NADH system. (iii) Within the ternary complex, I is bound within van der Waal's contact distance of the coenzyme nicotinamide ring. (iv) Formation of the transient intermediate does not involve covalent modification of coenzyme. Based on these findings, we conclude that zinc ion has a Lewis acid function in facilitating the chemical activation of the aldehyde carbonyl for reduction, and that reduced coenzyme plays a noncovalent effector role in this substrate activating step.
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PMID:Roles of zinc ion and reduced coenzyme in horse liver alcohol dehydrogenase catalysis. The mechanism of aldehyde activation. 23 85

The binding of Cibacron F3GA to orthorhombic crystals of liver alcohol dehydrogenase has been studied to 0.37-nm resolution. Similarities in the binding of this dye were found for rings B, C and D with the binding of the coenzyme NAD+. However, ring A of the dye and the nicotinamide ribose part of the coenzyme are quite differently bound to the enzyme.
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PMID:X-ray studies of the binding of Cibacron blue F3GA to liver alcohol dehydrogenase. 52 Mar 14

A nicotinamide adenine dinucleotide (NAD)-dependent n-alkane dehydrogenase and an NAD phosphate (reduced form)-dependent alkane hydroxylase have been purified from cell-free extracts of Pseudomonas sp. strain 196Aa grown anaerobically on n-alkane. The n-alkane dehydrogenase (fraction R-3), obtained as a single peak from Bio-Gel P-60, showed an overall 135-fold purification and was demonstrated by infrared spectroscopy and gas chromatography to convert n-decane to 1-decene. The alkene hydroxylase activity in the S-3 fraction, purified 167 times from diethylaminoethyl-cellulose, was shown by the same methodology to convert decene to decanol. Commercial ferredoxin has been shown to increase the alkane dehydrogenase activity. An NAD-, flavine adenine dinucleotide-, and iron-dependent alcohol dehydrogenase was demonstrated in the R-3 fraction. A mechanism for the anaerobic conversion of n-alkane to fatty acid has been proposed.
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PMID:N-Alkane oxidation enzymes of a pseudomonad. 86 35


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