PMID: 2492793Feb 15, 1989Paper

Inhibition of pyruvate carboxylase by sequestration of coenzyme A with sodium benzoate

Archives of Biochemistry and Biophysics
A D GriffithG C Tremblay

Abstract

Pyruvate-dependent CO2 fixation by isolated mitochondria was strongly inhibited by sodium benzoate. Pyruvate carboxylase was identified as a site of inhibition by limiting flux measurements to assays of pyruvate carboxylase coupled with malate dehydrogenase. Benzoate reduced pyruvate-dependent incorporation of [14C]KHCO3 into malate and pyruvate-dependent malate accumulation by 74 and 72%, respectively. Aspartate-dependent malate accumulation was insensitive to benzoate, ruling out malate dehydrogenase as a site of action. Inhibition by benzoate was antagonized by glycine, which sharply accelerated conversion of benzoate to hippurate. Assays of coenzyme A and its acyl derivatives revealed inhibition to correlate with depletion of acetyl CoA and accumulation of benzoyl CoA. Depletion of acetyl CoA was sufficient to account for greater than 50% reduction in pyruvate carboxylase activity. Competition between acetyl CoA and benzoyl CoA for the activator site on pyruvate carboxylase was insignificant. Results support the interpretation that the observed inhibition of pyruvate carboxylase occurred primarily by depletion of the activator, acetyl CoA, through sequestration of coenzyme A during benzoate metabolism.

References

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Citations

Jan 1, 1991·European Journal of Clinical Pharmacology·K Kubota, T Ishizaki
Jul 15, 1991·Biochemical Pharmacology·D M CyrG C Tremblay
Mar 1, 1997·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·P Nasseri-SinaJ Caldwell
Mar 1, 1992·The Journal of Clinical Investigation·R R Russell, H Taegtmeyer
May 31, 2012·Orphanet Journal of Rare Diseases·Johannes HäberleCarlo Dionisi-Vici
Apr 24, 2014·Drug Metabolism Reviews·Christoffel Petrus Stephanus BadenhorstAlberdina Aike van Dijk
Dec 2, 2004·Canadian Journal of Physiology and Pharmacology·Thomas DanielsRobert L Rodgers
Dec 4, 1995·American Journal of Medical Genetics·J L Van HoveS G Kahler
Apr 16, 2019·Journal of Inherited Metabolic Disease·Johannes HäberleCarlo Dionisi-Vici
Aug 1, 1998·Journal of Inherited Metabolic Disease·F Feillet, J V Leonard
Mar 18, 2003·Journal of Inherited Metabolic Disease·V PrietschG F Hoffmann
Jan 10, 2001·The Journal of Pediatrics·M L BatshawM Tuchman

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