title: Unexpected N-acetylation of capreomycin by mycobacterial Eis enzymes.
abstract: OBJECTIVE
  The enhanced intracellular survival (Eis) protein from Mycobacterium tuberculosis (Eis_Mtb), a regio-versatile N-acetyltransferase active towards many aminoglycosides (AGs), confers resistance to kanamycin A in some cases of extensively drug-resistant tuberculosis (XDR-TB). We assessed the activity of Eis_Mtb and of its homologue from Mycobacterium smegmatis (Eis_Msm) against a panel of anti-tuberculosis (TB) drugs and lysine-containing compounds.
  
  
  RESULTS
  Both enzymes acetylated capreomycin and some lysine-containing compounds, but not other non-AG non-lysine-containing drugs tested. Modelling studies predicted the site of modification on capreomycin to be one of the two primary amines in its β-lysine side chain. Using Eis_Mtb, we established via nuclear magnetic resonance (NMR) spectroscopy that acetylation of capreomycin occurs on the ε-amine of the β-lysine side chain. Using Msm, we also demonstrated for the first time to our knowledge that acetylation of capreomycin results in deactivation of the drug.
  
  
  CONCLUSIONS
  Eis is a unique acetyltransferase capable of inactivating the anti-TB drug capreomycin, AGs and other lysine-containing compounds.
authors.affiliation: Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jacob L
authors.initials: JL
authors.lastname: Houghton
authors.forename: Keith D
authors.initials: KD
authors.lastname: Green
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Pricer
authors.forename: Abdelrahman S
authors.initials: AS
authors.lastname: Mayhoub
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garneau-Tsodikova
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases; D000942:Antigens, Bacterial / Q000378:metabolism*; D000995:Antitubercular Agents / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D002207:Capreomycin / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D020102:Mycobacterium smegmatis / Q000201:enzymology* / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D002207:Capreomycin; D000123:Acetyltransferases; C430563:Eis protein, Mycobacterium tuberculosis