Stereoselective interaction of 2-halo-acyl-CoA derivatives with medium chain acyl-CoA dehydrogenase from pig kidney.

Several 2-halo-acyl-CoA derivatives have been synthesized to examine the interaction of these potential inhibitors of mitochondrial beta-oxidation with the purified medium chain acyl-CoA dehydrogenase from pig kidney. Racemic 2-bromo-, 2-chloro-, and 2-fluoro-octanoyl-CoA thioesters show 6.6, 33, and 3.5% of the activity of octanoyl-CoA in the standard assay system, respectively. Only the S-enantiomer of these 2-substituted analogues is a significant substrate of the dehydrogenase, with S-2-bromo-octanoyl-CoA showing a rate of 18% that of octanoyl-CoA, compared to about 1% for the R-isomer. The observations presented here suggest that a detailed understanding of the mode of action of 2-halo-fatty acids as inhibitors of mammalian beta-oxidation will require consideration of the metabolic fate and inhibitory effects of both enantiomers.