title: Site-directed inhibition of Haemophilus influenzae malate dehydrogenase.
abstract: Previous studies of Haemophilus organisms documented the importance of an NAD+-dependent malate dehydrogenase in the incomplete tricarboxylic acid cycle present in these organisms. Selective interactions occurring at the coenzyme and substrate binding sites of a purified Haemophilus influenzae malate dehydrogenase were investigated. Coenzyme-competitive inhibition by adenosine derivatives demonstrated the presence of regions in the coenzyme binding site that interacted with the adenosine and pyrophosphate moieties of the coenzyme. Positive chainlength effects in the coenzyme-competitive inhibition by aliphatic carboxylic acids indicated the presence of a hydrophobic region at this site that was close to the pyrophosphate region. Seven analogues of NAD+ that were structurally altered in either the pyridine or purine ring were evaluated as selective inhibitors of the enzyme. The three most effective inhibitors of the purified malate dehydrogenase inhibited the growth of H. influenzae when the organism was grown on a limiting concentration of NAD+.
authors.affiliation: Department of Biochemistry and Nutrition, Virginia Polytechnic Institute and State University, Blacksburg 24061.
authors.forename: H
authors.initials: H
authors.lastname: Yoon
authors.forename: B M
authors.initials: BM
authors.lastname: Anderson
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000249:Adenosine Monophosphate / Q000494:pharmacology; D001667:Binding, Competitive; D002208:Caproates / Q000494:pharmacology; D002264:Carboxylic Acids / Q000494:pharmacology; D003067:Coenzymes / Q000494:pharmacology; D006193:Haemophilus influenzae / Q000201:enzymology* / Q000254:growth & development; D008291:Malate Dehydrogenase / Q000037:antagonists & inhibitors*; D009243:NAD / Q000378:metabolism
chemical_list: D002208:Caproates; D002264:Carboxylic Acids; D003067:Coenzymes; D009243:NAD; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D008291:Malate Dehydrogenase