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Cyclic AMP-dependent Protein Lysine Acylation in Mycobacteria Regulates Fatty Acid and Propionate Metabolism*

S. Nambi,Kallol Gupta,Moitrayee Bhattacharyya,P. Ramakrishnan,Vaishnavi Ravikumar,N. Siddiqui,A. Thomas,S. Visweswariah

Published 2013 in Journal of Biological Chemistry

ABSTRACT

Background: KATmt is the first identified cAMP-regulated protein lysine acetylase in mycobacteria. Results: KATmt acylates fatty acyl CoA ligases in vivo in a cAMP-dependent manner, thus regulating their activity. Conclusion: Mycobacteria utilize KATmt to regulate the metabolic pool of acetyl and propionyl CoA. Significance: We provide novel paradigms for linking cAMP signaling and fatty acid metabolism in mycobacteria. Acetylation of lysine residues is a posttranslational modification that is used by both eukaryotes and prokaryotes to regulate a variety of biological processes. Here we identify multiple substrates for the cAMP-dependent protein lysine acetyltransferase from Mycobacterium tuberculosis (KATmt). We demonstrate that a catalytically important lysine residue in a number of FadD (fatty acyl CoA synthetase) enzymes is acetylated by KATmt in a cAMP-dependent manner and that acetylation inhibits the activity of FadD enzymes. A sirtuin-like enzyme can deacetylate multiple FadDs, thus completing the regulatory cycle. Using a strain deleted for the KATmt ortholog in Mycobacterium bovis Bacillus Calmette-Guérin (BCG), we show for the first time that acetylation is dependent on intracellular cAMP levels. KATmt can utilize propionyl CoA as a substrate and, therefore, plays a critical role in alleviating propionyl CoA toxicity in mycobacteria by inactivating acyl CoA synthetase (ACS). The precision by which mycobacteria can regulate the metabolism of fatty acids in a cAMP-dependent manner appears to be unparalleled in other biological organisms and is ideally suited to adapt to the complex environment that pathogenic mycobacteria experience in the host.

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