Abstract
Biosynthesis of coenzyme A (CoA) requires a five-step process using pantothenate and cysteine in the fission yeast Schizosaccharomyces pombe. CoA contains a thiol (SH) group, which reacts with carboxylic acid to form thioesters, giving rise to acyl-activated CoAs such as acetyl-CoA. Acetyl-CoA is essential for energy metabolism and protein acetylation, and, in higher eukaryotes, for the production of neurotransmitters. We isolated a novel S. pombe temperature-sensitive strain ppc1-537 mutated in the catalytic region of phosphopantothenoylcysteine synthetase (designated Ppc1), which is essential for CoA synthesis. The mutant becomes auxotrophic to pantothenate at permissive temperature, displaying greatly decreased levels of CoA, acetyl-CoA and histone acetylation. Moreover, ppc1-537 mutant cells failed to restore proliferation from quiescence. Ppc1 is thus the product of a super-housekeeping gene. The ppc1-537 mutant showed combined synthetic lethal defects with five of six histone deacetylase mutants, whereas sir2 deletion exceptionally rescued the ppc1-537 phenotype. In synchronous cultures, ppc1-537 cells can proceed to the S phase, but lose viability during mitosis failing in sister centromere/kinetochore segregation and nuclear division. Additionally, double-strand break repair is defective in the ppc1-537 mutant, producing fragile broken DNA, probably owing to diminished histone acetylation. The CoA-supported metabolism thus controls the state of chromosome DNA.
Highlights
Coenzyme A (CoA) is a ubiquitous, essential cofactor that plays a central role in the metabolism of carboxylic acids and lipids [1]
One thousand and fifteen ts strains of S. pombe were previously isolated, their phenotypes characterized, and some of the genes essential for mitosis, cell growth, cellular quiescence maintenance, glucose metabolism and gene silencing were determined through phenotypic characterizations followed by gene identification and gene product analyses [26,27,28,29,30]
Diminished histone H3 and H4 acetylation in ppc1-537 cells. Because both levels of CoA and acetyl-CoA were greatly diminished in ppc1-537 mutant cells even under permissive temperature, in the step we examined whether histone acetylation decreased in mutant cells
Summary
Coenzyme A (CoA) is a ubiquitous, essential cofactor that plays a central role in the metabolism of carboxylic acids and lipids [1]. About 4 per cent of all known enzymes use CoA as an obligate cofactor. CoA is involved in over 100 different reactions of intermediary metabolism [2,3]. CoA was discovered through a study on amino group acetylation of small molecules [4,5]. CoA was subsequently shown to be composed of adenosine 50-phosphate, pantothenate and a sulphhydryl moiety. Acylation (thioesterification) of CoA at the sulphhydryl group by various carboxylic acids results in the production of many important acylated CoAs, including acetyl-CoA.
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