Deciphering The Transcriptional Regulation of Cholesterol Catabolic Pathway in Mycobacteria: Identification of the Inducer of KstR Repressor [Microbiology]

May 6th, 2014 by Garcia–Fernandez, E., Medrano, F. J., Galan, B., Garcia, J. L.

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 mc2155 is not cholesterol but 3-oxo-4-cholestenoic acid, one of the first metabolic intermediates. Binding of 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.
  • Posted in Journal of Biological Chemistry, Publications
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