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)

1. Allyl and allylic compounds may exert alkylating activities by SN1, SN2 and SN2' mechanisms. This direct alkylating potential can be determined quantitatively by a modified 4-NBP (4-nitrobenzyl pyridine) test. 2. The alkylating activities in a systematically selected series of allyl and allylic compounds correlate well with the direct mutagenic potential as determined in the Ames test using Salmonella typhimurium TA 100 as tester strain. 3. The allylic structure is a prerequisite for these types of activities since structurally related molecules lacking the allylic moiety are inactive in this respect. 4. The potency of both the alkylating and mutagenic activity is determined by the strength of the leaving group: --OSO2CH3 greater than I greater than Br greater than Cl greater than--NCS. 5. Indirect mutagenicity, through metabolic activation of the olefinic bond (by addition of S9 mix to the tester medium), can be ruled out for practically all compounds, the only exception found being 2,3-dichloro-1-propene where an increase of mutagenicity is encountered after addition of S9 mix; mechanistic explanations for this exception are provided. 6. Analogous activation is demonstrated for benzyl halides, the alkylating potency of which is even higher than that of genuine allylic compounds. 7. A variety of methyl- and chlorine-substituted allyl compounds has been included in the study: both groups increase activity, either by +I (CH3) or by +M effects (Cl). 8. alpha, beta-Unsaturated carbonyl compounds, e.g. acrolein and crotonaldehyde, also display direct mutagenic activity which is due to a completely different mechanism: covalent binding to nucleophilic sites of DNA bases by Michael addition. Methyl and other alkyl substitutions decrease the mutagenic potential in this type of compound. The corresponding alcohols, also displaying mutagenic activity but to a lesser degree, are metabolically activated by ADH (alcohol dehydrogenase) of the tester strain microbes to the aldehydes or ketones.
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PMID:Mutagenic properties of allylic and alpha, beta-unsaturated compounds: consideration of alkylating mechanisms. 676 6

The role of configuration for the affinity labelling of sheep liver sorbitol dehydrogenase by chloro-substituted analogues of 2-bromo-3-(5-imidazolyl)propionate (BrImPpOH) has been studied. A saturation kinetics mechanism applies which includes formation of a reversible complex with the enzyme prior to alkylation of Cys-43. The pseudo first-order inactivation rate-constant, k2, and the dissociation constant for the reversible enzyme-affinity label complex. KEI, were determined at pH 7.4 and 23.5 degrees C. The stereo isomers of each affinity label exhibit different kinetic characteristics but, unlike with horse liver alcohol dehydrogenase, the discrimination between them is not absolute. For the different affinity labels, k2 varies with 2-chloro-3-(5-imidazolyl)methylpropionate (Me-ClImPpOH) > 2-chloro-3-(5-imidazolyl)propionate (ClImPpOH) > 2-chloro-3-(5-imidazolyl)propanol (ClImPOH), consistent with their order of inherent reactivity, and the specificity constant k2/KEI varies with (S)-Me-ClImPpOH > (S)-ClImPpOH > (S)-ClImPpOH > (R)-Me-ClImPpOH > (R)-ClImPpOH. Models of the affinity labels were built into the active site of the predicted subunit structure of the enzyme by using a computer-controlled display system. In each binary complex, the imidazole moiety of the affinity label was liganded to the catalytic zinc atom, and the angle Scys-C alpha-Cl was linear, in accordance with an SN2 mechanism. Both enantiomers of each label could form plausible complexes with the enzyme model, in agreement with the kinetic data. The enantiomeric selectivity, rather than absolute specificity, of the reaction appears due to the anion-binding site in sorbitol dehydrogenase being less developed than in horse liver alcohol dehydrogenase.
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PMID:Stereo-selective affinity labelling of sheep liver sorbitol dehydrogenase by chloro-substituted analogues of 2-bromo-3-(5-imidazolyl)propionic acid. 862 39