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Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2.

ABSTRACT: We report that human acetyl-CoA synthetase 2 (AceCS2) is a mitochondrial matrix protein. AceCS2 is reversibly acetylated at Lys-642 in the active site of the enzyme. The mitochondrial sirtuin SIRT3 interacts with AceCS2 and deacetylates Lys-642 both in vitro and in vivo. Deacetylation of AceCS2 by SIRT3 activates the acetyl-CoA synthetase activity of AceCS2. This report identifies the first acetylated substrate protein of SIRT3. Our findings show that a mammalian sirtuin directly controls the activity of a metabolic enzyme by means of reversible lysine acetylation. Because the activity of a bacterial ortholog of AceCS2, called ACS, is controlled via deacetylation by a bacterial sirtuin protein, our observation highlights the conservation of a metabolic regulatory pathway from bacteria to humans.

SUBMITTER: Schwer B

PROVIDER: S-EPMC1502439 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

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Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2.

Schwer Bjoern B Bunkenborg Jakob J Verdin Regis O RO Andersen Jens S JS Verdin Eric E

Proceedings of the National Academy of Sciences of the United States of America 20060620 27

We report that human acetyl-CoA synthetase 2 (AceCS2) is a mitochondrial matrix protein. AceCS2 is reversibly acetylated at Lys-642 in the active site of the enzyme. The mitochondrial sirtuin SIRT3 interacts with AceCS2 and deacetylates Lys-642 both in vitro and in vivo. Deacetylation of AceCS2 by SIRT3 activates the acetyl-CoA synthetase activity of AceCS2. This report identifies the first acetylated substrate protein of SIRT3. Our findings show that a mammalian sirtuin directly controls the ac ...[more]

PMID: 16788062

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Project description:UnlabelledIn Salmonella enterica, the reversible lysine acetylation (RLA) system is comprised of the protein acetyltransferase (Pat) and sirtuin deacetylase (CobB). RLA controls the activities of many proteins, including the acetyl coenzyme A (acetyl-CoA) synthetase (Acs), by modulating the degree of Acs acetylation. We report that IolR, a myo-inositol catabolism repressor, activates the expression of genes encoding components of the RLA system. In vitro evidence shows that the IolR protein directly regulates pat expression. An iolR mutant strain displayed a growth defect in minimal medium containing 10 mM acetate, a condition under which RLA function is critical to control Acs activity. Increased levels of Pat, CobB, or Acs activity reversed the growth defect, suggesting the Pat/CobB ratio in an iolR strain is altered and that such a change affects the level of acetylated, inactive Acs. Results of quantitative reverse transcription-PCR (qRT-PCR) analyses of pat, cobB, and acs expression indicated that expression of the genes alluded to in the IolR-deficient strain was reduced 5-, 3-, and 2.6-fold, respectively, relative to the levels present in the strain carrying the iolR(+) allele. Acs activity in cell-free extracts from an iolR mutant strain was reduced ~25% relative to that of the iolR(+) strain. Glucose differentially regulated expression of pat, cobB, and acs. The catabolite repressor protein (Crp) positively regulated expression of pat while having no effect on cobB.ImportanceReversible lysine acylation is used by cells of all domains of life to modulate the function of proteins involved in diverse cellular processes. Work reported herein begins to outline the regulatory circuitry that integrates the expression of genes encoding enzymes that control the activity of a central metabolic enzyme in C2 metabolism. Genetic analyses revealed effects on reversible lysine acylation that greatly impacted the growth behavior of the cell. This work provides the first insights into the complexities of the system responsible for controlling reversible lysine acylation at the transcriptional level in the enteropathogenic bacterium Salmonella enterica.

Dataset Information

Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2.

Publications

Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2.

Similar Datasets

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