Reversible acetylation and inactivation of Mycobacterium tuberculosis acetyl-CoA synthetase is dependent on cAMP

Hua Xu, Subray S. Hegde, John S. Blanchard

Research output: Contribution to journalArticlepeer-review

92 Scopus citations


Recent proteomics studies have revealed that protein acetylation is an abundant and evolutionarily conserved post-translational modification from prokaryotes to eukaryotes. Although an astonishing number of acetylated proteins have been identified in those studies, the acetyltransferases that target these proteins remain largely unknown. Here we characterized MSMEG-5458, one of the GCN5-related N-acetyltransferases (GNAT's) in Mycobacterium smegmatis, and show that it is a protein acetyltransferase (MsPat) that specifically acetylates the ε-amino group of a highly conserved lysine residue in acetyl-CoA synthetase (ACS) with a kcat/Km of nearly 104 M -1 s-1. This acetylation results in the inactivation of ACS activity. Lysine acetylation by MsPat is dependent on 3′,5′- cyclic adenosine monophosphate (cAMP), an important second messenger, indicating that MsPat is a downstream target of the intracellular cAMP signaling pathway. To the best of our knowledge, this is the first protein acetyltransferase in mycobacteria that both is dependent on cAMP and targets a central metabolic enzyme by a specific post-translational modification. Since cAMP is synthesized by adenylate cyclases (AC's) that sense various environmental signals, we hypothesize that the acetylation and inactivation of ACS is important for mycobacteria to adjust to environmental changes. In addition, we show that Rv1151c, a sirtuin-like deacetylase in Mycobacterium tuberculosis, reactivates acetylated ACS through an NAD+-dependent deacetylation. Therefore, Pat and the sirtuin-like deacetylase in mycobacteria constitute a reversible acetylation system that regulates the activity of ACS.

Original languageEnglish (US)
Pages (from-to)5883-5892
Number of pages10
Issue number26
StatePublished - Jul 5 2011

ASJC Scopus subject areas

  • Biochemistry


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