INHIBITORS OF THERMUS-THERMOPHILUS ISOPROPYLMALATE DEHYDROGENASE

In an attempt to use mechanism-based design for the discovery of inhib itors of the isopropylmalate dehydrogenase from T. thermophilus, we ha ve prepared and studied a number of potential mimics for an intermedia te in the oxidative decarboxylation of isopropyl malate, the enol or e nolate of alpha-ketoisocaproate. Because hydroxamate and dicarboxylate enolate mimics are strong, uncompetitive inhibitors of the enzyme and vinyl fluoride enol mimics are weak, competitive inhibitors, it is su ggested that the reaction involves the enolate. The uncompetitive inhi bition by a number of anionic compounds suggests, in combination with previous studies in other laboratories, that they mimic the enolate pr oduct of the decarboxylation. An explanation for the potency of the in hibition of IMDH by these compounds is proposed based on the electrost atic interaction of product and cofactor.