Regulation of Ergothioneine Biosynthesis and Its Effect on Mycobacterium tuberculosis Growth and Infectivity

J Biol Chem. 2015 Sep 18;290(38):23064-76. doi: 10.1074/jbc.M115.648642. Epub 2015 Jul 30.


Ergothioneine (EGT) is synthesized in mycobacteria, but limited knowledge exists regarding its synthesis, physiological role, and regulation. We have identified Rv3701c from Mycobacterium tuberculosis to encode for EgtD, a required histidine methyltransferase that catalyzes first biosynthesis step in EGT biosynthesis. EgtD was found to be phosphorylated by the serine/threonine protein kinase PknD. PknD phosphorylates EgtD both in vitro and in a cell-based system on Thr(213). The phosphomimetic (T213E) but not the phosphoablative (T213A) mutant of EgtD failed to restore EGT synthesis in a ΔegtD mutant. The findings together with observed elevated levels of EGT in a pknD transposon mutant during in vitro growth suggests that EgtD phosphorylation by PknD negatively regulates EGT biosynthesis. We further showed that EGT is required in a nutrient-starved model of persistence and is needed for long term infection of murine macrophages.

Keywords: Mycobacterium tuberculosis; bacterial protein kinase; bacterial signal transduction; ergothioneine; histidine methylation; microbiology; thiol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Ergothioneine / biosynthesis*
  • Ergothioneine / genetics
  • Mice
  • Models, Biological*
  • Mycobacterium tuberculosis / genetics
  • Mycobacterium tuberculosis / metabolism*
  • Mycobacterium tuberculosis / pathogenicity*
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Tuberculosis / genetics
  • Tuberculosis / metabolism*
  • Tuberculosis / pathology


  • Ergothioneine
  • Protein Kinases
  • PknD protein, Nostoc sp. PCC 7120