title: Regulation of Ergothioneine Biosynthesis and Its Effect on Mycobacterium tuberculosis Growth and Infectivity.
abstract: 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.
authors.affiliation: From the Division of Infectious Diseases, Department of Medicine and.
authors.forename: Melissa
authors.initials: M
authors.lastname: Richard-Greenblatt
authors.affiliation: From the Division of Infectious Diseases, Department of Medicine and.
authors.forename: Horacio
authors.initials: H
authors.lastname: Bach
authors.affiliation: Kwazulu-Natal Research Institute for Tuberculosis and HIV, Durban, South Africa 4001.
authors.forename: John
authors.initials: J
authors.lastname: Adamson
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada.
authors.forename: Sandra
authors.initials: S
authors.lastname: Peña-Diaz
authors.affiliation: Institute of Modern Biopharmaceuticals, School of Life Sciences, Southwest University, Chongqing 400715, China, and.
authors.forename: Wu
authors.initials: W
authors.lastname: Li
authors.affiliation: Kwazulu-Natal Research Institute for Tuberculosis and HIV, Durban, South Africa 4001, Department of Microbiology and Centers for AIDS Research and Free Radical Biology, University of Alabama, Birmingham, Alabama 35233.
authors.forename: Adrie J C
authors.initials: AJ
authors.lastname: Steyn
authors.affiliation: From the Division of Infectious Diseases, Department of Medicine and yossi@mail.ubc.ca.
authors.forename: Yossef
authors.initials: Y
authors.lastname: Av-Gay
mesh_terms: D000818:Animals; D002460:Cell Line; D004880:Ergothioneine / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D014376:Tuberculosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D004880:Ergothioneine; D011494:Protein Kinases; C112455:PknD protein, Nostoc sp. PCC 7120
keywords: Mycobacterium tuberculosis; bacterial protein kinase; bacterial signal transduction; ergothioneine; histidine methylation; microbiology; thiol