title: Cholesterol catabolism by Mycobacterium tuberculosis requires transcriptional and metabolic adaptations.
abstract: To understand the adaptation of Mycobacterium tuberculosis to the intracellular environment, we used comprehensive metabolite profiling to identify the biochemical pathways utilized during growth on cholesterol, a critical carbon source during chronic infection. Metabolic alterations observed during cholesterol catabolism centered on propionyl-CoA and pyruvate pools. Consequently, growth on this substrate required the transcriptional induction of the propionyl-CoA-assimilating methylcitrate cycle (MCC) enzymes, via the Rv1129c regulatory protein. We show that both Rv1129c and the MCC enzymes are required for intracellular growth in macrophages and that the growth defect of MCC mutants is largely attributable to the degradation of host-derived cholesterol. Together, these observations define a coordinated transcriptional and metabolic adaptation that is required for scavenging carbon during intracellular growth.
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Griffin
authors.forename: Amit K
authors.initials: AK
authors.lastname: Pandey
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Gilmore
authors.forename: Valerie
authors.initials: V
authors.lastname: Mizrahi
authors.forename: John D
authors.initials: JD
authors.lastname: McKinney
authors.forename: Carolyn R
authors.initials: CR
authors.lastname: Bertozzi
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Sassetti
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D004798:Enzymes / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000382:microbiology; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000214:Acyl Coenzyme A; D001426:Bacterial Proteins; D004798:Enzymes; C009061:propionyl-coenzyme A; D019289:Pyruvic Acid; D002784:Cholesterol