title: Cyclic AMP-dependent protein lysine acylation in mycobacteria regulates fatty acid and propionate metabolism.
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.
authors.affiliation: Department of Molecular Reproduction, Development, and Genetics, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Subhalaxmi
authors.initials: S
authors.lastname: Nambi
authors.affiliation: Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Kallol
authors.initials: K
authors.lastname: Gupta
authors.affiliation: Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Moitrayee
authors.initials: M
authors.lastname: Bhattacharyya
authors.affiliation: Department of Molecular Reproduction, Development, and Genetics, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Parvathy
authors.initials: P
authors.lastname: Ramakrishnan
authors.affiliation: Department of Molecular Reproduction, Development, and Genetics, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Vaishnavi
authors.initials: V
authors.lastname: Ravikumar
authors.affiliation: Department of Molecular Reproduction, Development, and Genetics, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Nida
authors.initials: N
authors.lastname: Siddiqui
authors.affiliation: Department of Molecular Reproduction, Development, and Genetics, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Ann Terene
authors.initials: AT
authors.lastname: Thomas
authors.affiliation: Department of Molecular Reproduction, Development, and Genetics, Indian Institute of Science, Bangalore 560012, India. Electronic address: sandhya@mrdg.iisc.ernet.
authors.forename: Sandhya S
authors.initials: SS
authors.lastname: Visweswariah
mesh_terms: D000115:Acetylesterase / Q000378:metabolism*; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000378:metabolism; D003066:Coenzyme A Ligases / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D017353:Gene Deletion; D015964:Gene Expression Regulation, Bacterial; D008239:Lysine / Q000378:metabolism*; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009163:Mycobacterium bovis / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D011422:Propionates / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: D001426:Bacterial Proteins; D005227:Fatty Acids; D011422:Propionates; D000242:Cyclic AMP; D000115:Acetylesterase; D003066:Coenzyme A Ligases; D008239:Lysine
keywords: Acetyl Coenzyme A; Actinobacteria; Fatty Acid Metabolism; Mass Spectrometry (MS); Mycobacteria; Prokaryotic Signal Transduction; Protein Acylation
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