Marvin R. Boots

Molecular interactions of six aromatic competitive inhibitors with bovine liver glutamate dehydrogenase

Abstract Six aromatic dicarboxylic acids (isophthalic acid, pyridine-3,5-dicarboxylic acid, and pyridine-2,6-dicarboxylic acid) and bromo-substituted aryl monocarboxylic acids (5-bromofuroic acid, m -bromobenzoic acid, and 5-bromothiophene-2-carboxylic acid) were tested with bovine liver glutamate dehydrogenase [ l -glutamate: NAD(P) + oxidoreductase (deaminating) EC 1.4.1.3] for inhibition against l -glutamate as a function of pH (6.6 to 9.0). These compounds were competitive inhibitors at all pH values tested and the inhibition remained competitive when either NADP + or NAD + was coenzyme. Maximum inhibitor potency (p K 1 ) for the dicarboxylic acids occurred at pH 7.8 and for the monocarboxylic acids occurred at pH 8.7. The relative inhibitor potencies were correlated with the inhibitors‘ “central atom” absolute charge densities | Q T | calculated from molecular orbital theory. This indicated that desolvation of this atom may be important for combination of inhibitor with enzyme. A high degree of solvation as indicated by the magnitude of charge density could have decreased the interaction of inhibitor with enzyme. Similar results had been obtained previously for 4 aliphatic dicarboxylic acid competitive inhibitors

Synthesis of 5-Substituted Isophthalic Acids and Competitive Inhibition Studies with Bovine Liver Glutamate Dehydrogenase

Summary Isophthalic acid, 5-carboxy-, 5-hydroxy-, 5-methoxy-, 5-fluoro-, 5-bromo-, 5-cyano-, and 5-methylisophthalic acid were inhibitors competitive with l-glutamate for bovine liver glutamate dehydrogenase. The extent of inhibition by the derived compounds was not much greater than that obtained with the parent compound, isophthalic acid. A plot of pKi versus pH showed the presence of an ionizable group (pKa 7.4-7.8) at the enzyme active site which interacted with the substitutent at the 5 position of the substituted isophthalates.