DIFFERENTIAL-EFFECTS OF FATTY ACYL-COENZYME A DERIVATIVES ON CITRATE SYNTHASE AND GLUTAMATE-DEHYDROGENASE

We investigated the hypothesis that one mechanism underlying fatty aci d toxicity is the selective inhibition of rate-limiting and/or regulat ed tricarboxylic acid cycle and related enzymes by fatty acyl coenzyme A (CoA) derivatives by examining the effects of several fatty acyl Co As on purified citrate synthase (CS) and glutamate dehydrogenase (GDH) . The results indicate that, at pathophysiological levels, palmitoyl C oA, a long-chain acyl CoA, is a potent inhibitor of CS and GDH with IC 50 values of 3-15 muM. At much higher levels (in the pathological and toxicological range), octanoyl and decanoyl CoA (medium-chain acyl CoA s) inhibited both enzymes with IC50 values of 0.4-1.6 mM. Butyryl CoA, a short-chain acyl CoA, inhibited CS (IC50 = 0.9 mM) at toxicological levels but inhibited GDH poorly. These results suggest that the long- chain fatty acyl CoA inhibition of CS and GDH may assume some pathophy siological importance in fatty acid toxicity and in metabolic encephal opathies in which organic acidemia is persistent. The findings also pr ovide additional support for the original hypothesis.