| 1931995 |
Tserng KY, Jin SJ, Hoppel CL: Spiropentaneacetic acid as a specific inhibitor of medium-chain acyl-CoA dehydrogenase. Biochemistry. 1991 Nov 5;30(44):10755-60.
To study the structure-activity relationship between pentanoic acid analogues and the inhibition of fatty acid oxidation, a number of 4-pentenoic and methylenecyclopropaneacetic acid derivatives were prepared. All compounds inhibited palmitoylcarnitine oxidation in rat liver mitochondria, with 50% inhibition occurring at a concentration between 6 and 100 microM. However, only methylenecyclopropaneacetic acid (MCPA) and spiropentaneacetic acid (SPA) showed in vivo inhibitory activity in rats as indicated by the occurrence of dicarboxylic aciduria. Rats treated with SPA excreted metabolites derived only from fatty acid oxidation whereas MCPA-treated rats also excreted metabolites derived from branch-chained amino acid and lysine metabolism. SPA is a specific inhibitor of fatty acid oxidation without affecting amino acid metabolism. The site of inhibition is medium-chain acyl-CoA dehydrogenase (MCAD). In contrast, MCPA inhibited both MCAD and short-chain acyl-CoA dehydrogenase with a stronger inhibition toward the latter. The inhibition of fatty acid oxidation by both inhibitors was partially reversible by glycine or l-carnitine. Since SPA does not form a ring-opened nucleophile such as that proposed for MCPA in the inhibition of FAD prosthetic group in acyl-CoA dehydrogenases, we propose that the irreversible inhibition by SPA occurs by a tight complex without forming a covalent bond to the isoalloxazine ring in FAD. |
81(1,1,1,1) |