Inhibitors of Thermus thermophilus isopropylmalate dehydrogenase

In an attempt to use mechanism-based design for the discovery of inhibitors of the isopropylmalate dehydrogenase from T. thermophilus, we have prepared and studied a number of potential mimics for an intermediate in the oxidative decarboxylation of isopropyl malate, the enol or enolate 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 suggested that the reaction involves the enolate. The uncompetitive inhibition by a number of anionic compounds suggests, in combination with previous studies on other laboratories, that they mimic the enolate product of the decarboxylation. An explanation for the potency of the inhibition of IMDH by these compounds is proposed based on the electrostatic interaction of product and cofactor.