Acetylation of lysine residues is a post translational 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 acetyl transferase (KATmt) from Mycobacterium tuberculosis. We demonstrate that a catalytically important lysine residue in a number of FadD enzymes is acetylated by KATmt in a cAMP dependent manner, and 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 M. bovis 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 synthase. The precision by which mycobacteria can regulate 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.