Synthesis of conformationally restricted substrate analogs and their interaction with 3-isopropylmalate dehydrogenase derived from thermus thermophilus

Article abstract of DOI:10.1016/S0040-4020(97)00104-X

The finding that 2-O-methyl-3-isopropylmalate was an uncompetitive inhibitor of 3-isopropylmalate dehydrogenase (IPMDH, EC 1.1.1.85), involved in the rate-determining step in the biosynthetic pathway of the essential amino acid L-leucine, prompted to design conformationally restricted substrate analogs, in which the hydroxy oxygen is intramolecularly bound to an isopropyl carbon to form a ring structure. The oxirane 2 was the most inhibitory among those synthesized. IPMDH appeared to recognize preferentially the anti-conformation of the butanedioic acid structure.