title: Deciphering the transcriptional regulation of cholesterol catabolic pathway in mycobacteria: identification of the inducer of KstR repressor.
abstract: Cholesterol degradation plays a prominent role in Mycobacterium tuberculosis infection; therefore, to develop new tools to combat this disease, we need to decipher the components comprising and regulating the corresponding pathway. A TetR-like repressor (KstR) regulates the upper part of this complex catabolic pathway, but the induction mechanism remains unknown. Using a biophysical approach, we have discovered that the inducer molecule of KstR in M. smegmatis mc(2)155 is not cholesterol but 3-oxo-4-cholestenoic acid, one of the first metabolic intermediates. Binding this compound induces dramatic conformational changes in KstR that promote the KstR-DNA interaction to be released from the operator, retaining its dimeric state. Our findings suggest a regulatory model common to all cholesterol degrading bacteria in which the first steps of the pathway are critical to its mineralization and explain the high redundancy of the enzymes involved in these initial steps.
authors.affiliation: From the Departments of Environmental Biology and.
authors.forename: Esther
authors.initials: E
authors.lastname: García-Fernández
authors.affiliation: Chemical and Physical Biology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid 28040, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Medrano
authors.affiliation: From the Departments of Environmental Biology and.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Galán
authors.affiliation: From the Departments of Environmental Biology and jlgarcia@cib.csic.es.
authors.forename: José Luis
authors.initials: JL
authors.lastname: García
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology; D008954:Models, Biological; D020102:Mycobacterium smegmatis / Q000235:genetics / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*; D014376:Tuberculosis / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D012097:Repressor Proteins; D002784:Cholesterol
keywords: Actinobacteria; Cholesterol Metabolism; Cholesterol Regulation; Mycobacterium; Transcription Regulation