Cyclic AMP-dependent protein lysine acylation in mycobacteria regulates fatty acid and propionate metabolism

J Biol Chem. 2013 May 17;288(20):14114-24. doi: 10.1074/jbc.M113.463992. Epub 2013 Apr 3.

Abstract

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.

Keywords: Acetyl Coenzyme A; Actinobacteria; Fatty Acid Metabolism; Mass Spectrometry (MS); Mycobacteria; Prokaryotic Signal Transduction; Protein Acylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylesterase / metabolism*
  • Amino Acid Sequence
  • Bacterial Proteins / metabolism
  • Coenzyme A Ligases / metabolism*
  • Cyclic AMP / metabolism*
  • Fatty Acids / metabolism*
  • Gene Deletion
  • Gene Expression Regulation, Bacterial
  • Lysine / metabolism*
  • Mass Spectrometry
  • Molecular Sequence Data
  • Mutagenesis
  • Mycobacterium bovis / metabolism
  • Mycobacterium tuberculosis / metabolism*
  • Propionates / metabolism*
  • Sequence Homology, Amino Acid
  • Signal Transduction

Substances

  • Bacterial Proteins
  • Fatty Acids
  • Propionates
  • Cyclic AMP
  • Acetylesterase
  • Coenzyme A Ligases
  • Lysine