Inactivation of medium-chain acyl-CoA dehydrogenase by oct-4-en-2-ynoyl-CoA

Mitochondrial medium-chain acyl-CoA dehydrogenase is a key enzyme for the beta-oxidation of fatty acids, which catalyzes the FAD-dependent oxidation of a variety of acyl-CoA Substrates to the corresponding trans-2-enoyl-CoA thioesters. Oct-4-en-2-ynoyl-CoA was identified as a new irreversible inhibitor of acyl-CoA dehydrogenase, and kinetic parameters K-I and k(inact) were determined to be 11 mu M and 0.025 min(-1), respectively. Triple bond between C2 and C3 of the inhibitor was identified as the functional group responsible for enzyme inactivation, and Michael addition is proposed as the mechanism for this inactivation, which is a new pathway for inactivation of MCAD by inhibitors. The inhibitor may become a lead for further development for treating non-insulin dependent diabetes mellitus. (C) 2005 Elsevier Ltd. All rights reserved.