Metabolism of 4-pentenoic acid and inhibition of thiolase by metabolites of 4-pentenoic acid

Abstract

The metabolism of 4-pentenoic acid, a hypoglycemic agent and inhibitor of fatty acid oxidation, was studied in rat heart mitochondria. Confirmed was the conversion of 4-pentenoic acid to 2,4-pentadienoyl coenzyme A (CoA), which either is directly degraded via .beta.-oxidation or is first reduced in a NADPH-dependent reaction before it is further degraded by .beta.-oxidation. At pH 6.9, the NADPH-dependent reduction of 2,4-pentadienoyl-CoA proceeds 10 times faster than its degradation by .beta.-oxidation. At pH 7.8, this ratio is only 2 to 1. The direct .beta.-oxidation of 2,4-pentadienoyl-CoA leads to the formation of 3-keto-4-pentenoylCoA, which is highly reactive and spontaneously converts to another 3-ketoacyl-CoA derivative (compound X). 3-Keto-4-pentenoyl-CoA is a poor substrate of 3-ketoacyl-CoA thiolase (EC 2.3.1.16) whereas compound X is not measurably acted upon by this enzyme. The effects of several metabolites of 4-pentenoic acid on the activity of 3-ketoacyl-CoA thiolase were studied. 2,4-Pentadienoyl-CoA is a weak inhibitor of this enzyme that is protected against the inhibition by acetoacetyl-CoA. The most effective inhibitor of 3-ketoacyl-CoA thiolase was 3-keto-4-pentenoyl-CoA, which inhibits the enzyme in both a reversible and irreversible manner. The reversible inhibition is possibly a consequence of the inhibitor being a poor substrate of 3-ketoacyl-CoA thiolase. Evidently, 4-pentenoic acid is metabolized in mitochondria by 2 pathways. The minor yields 3-keto-4-pentenoyl-CoA, which acts both as a reversible and as an irreversible inhibitor of 3-ketoacyl-CoA thiolase and consequently of fatty acid oxidation.