Characterization of a glutathione metabolic mutant of Mycobacterium tuberculosis and its resistance to glutathione and nitrosoglutathione.
Glutathione is a tripeptide and antioxidant, synthesized at high levels by cells during the production of reactive oxygen and nitrogen intermediates. Glutathione also serves as a carrier molecule for nitric oxide in the form of S-nitrosoglutathione. Previous studies from this laboratory have shown that glutathione and S-nitrosoglutathione are directly toxic to mycobacteria. Glutathione is not transported into the cells as a tripeptide. Extracellular glutathione is converted to a dipeptide due to the action of transpeptidase, and the dipeptide is then transported into the bacterial cells. The processing of glutathione and S-nitrosoglutathione is brought about by the action of the enzyme gamma-glutamyl transpeptidase. The function of gamma-glutamyl transpeptidase is to cleave glutathione and S-nitrosoglutathione to the dipeptide (Cys-Gly), which is then transported into the bacterium by the multicomponent ABC transporter dipeptide permease. We have created a mutant strain of Mycobacterium tuberculosis lacking this metabolic enzyme. We investigated the sensitivity of this strain to glutathione and S-nitrosoglutathione compared to that of the wild-type bacteria. In addition, we examined the role of glutathione and/or S-nitrosoglutathione in controlling the growth of intracellular M. tuberculosis inside mouse macrophages.
Dayaram
Yaswant K
YK
Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, 225 Warren Street, Newark, New Jersey 07103, USA.
Talaue
Meliza T
MT
Connell
Nancy D
ND
Venketaraman
Vishwanath
V
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D026422:S-Nitrosoglutathione / Q000378:metabolism / Q000494:pharmacology; D005723:gamma-Glutamyltransferase / Q000235:genetics*
D000890:Anti-Infective Agents; D026422:S-Nitrosoglutathione; D005723:gamma-Glutamyltransferase; D005978:Glutathione