Research communications in chemical pathology and pharmacology 1993-12-01

Differential effects of fatty acyl coenzyme A derivatives on citrate synthase and glutamate dehydrogenase.

J C Lai, B B Liang, E J Jarvi, A J Cooper, D R Lu

Index: Res. Commun. Chem. Pathol. Pharmacol. 82(3) , 331-8, (1993)

Full Text: HTML

Abstract

We investigated the hypothesis that one mechanism underlying fatty acid toxicity is the selective inhibition of rate-limiting and/or regulated tricarboxylic acid cycle and related enzymes by fatty acyl coenzyme A (CoA) derivatives by examining the effects of several fatty acyl CoAs on purified citrate synthase (CS) and glutamate dehydrogenase (GDH). The results indicate that, at pathophysiological levels, palmitoyl CoA, a long-chain acyl CoA, is a potent inhibitor of CS and GDH with IC50 values of 3-15 microM. At much higher levels (in the pathological and toxicological range), octanoyl and decanoyl CoA (medium-chain acyl CoAs) 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 pathophysiological importance in fatty acid toxicity and in metabolic encephalopathies in which organic acidemia is persistent. The findings also provide additional support for the original hypothesis.


Related Compounds

Related Articles:

Effect of pH and acyl-CoA chain length on the conversion of heart mitochondrial CPT-I/CPTo to a high affinity, malonyl-CoA-inhibited state.

1996-08-13

[Biochim. Biophys. Acta 1290(3) , 261-6, (1996)]

Mechanism of Vibrio cholerae autoinducer-1 biosynthesis.

2011-04-15

[ACS Chem. Biol. 6 , 356-365, (2011)]

Insights into the biosynthesis of the Vibrio cholerae major autoinducer CAI-1 from the crystal structure of the PLP-dependent enzyme CqsA.

2009-09-25

[J. Mol. Biol. 392 , 763-773, (2009)]

Unexpected stereoselective exchange of straight-chain fatty acyl-CoA alpha-protons by human alpha-methylacyl-CoA racemase 1A (P504S).

2010-05-21

[Chem. Commun. (Camb.) 46 , 3348-3350, (2010)]

Acyl coenzyme A esters differentially activate cardiac and beta-cell adenosine triphosphate-sensitive potassium channels in a side-chain length-specific manner.

2003-10-01

[Metab. Clin. Exp. 52(10) , 1313-9, (2003)]

More Articles...