NOVEL METHYLENECYCLOPROPYL-BASED ACYL-COA DEHYDROGENASE INHIBITOR

A novel hexyl-substituted methylenecyclopropyl acetyl-CoA was tested a s an enzyme-specific acyl-CoA dehydrogenase inhibitor. Its CoA ester g enerated in situ from the carboxylic acid and CoASH, displayed marked differences in inhibition specificity as compared to methylenecyclopro pyl acetyl-CoA, consistent with. the substrate specificities of the ta rget enzymes. Thus methylenecyclopropyl acetyl-CoA inactivated short-c hain-specific acyl-CoA dehydrogenase rapidly, medium-chain-specific ac yl-CoA dehydrogenase much more slowly and had no effect on long-chain- or very long-chain-specific acyl-CoA dehydrogenases. The hexyl-substi tutent on the methylenecyclopropyl ring gave an inhibitor which rapidl y inactivated MCAD and LCAD whilst VLCAD was inhibited more slowly and SCAD was essentially unaffected. In some cases (e.g, SCAD and MCPA-Co A) inhibition was accompanied by flavin bleaching. In other cases (e,g , LCAD and C(6)MCPA) less pronounced bleaching suggests a different ch emistry of inhibition. (C) 1998 Federation of European Biochemical Soc ieties.