Metabolic Fate of Human Immunoactive Sterols in Mycobacterium tuberculosis

J Mol Biol. 2021 Feb 19;433(4):166763. doi: 10.1016/j.jmb.2020.166763. Epub 2020 Dec 24.


Mycobacterium tuberculosis (Mtb) infection is among top ten causes of death worldwide, and the number of drug-resistant strains is increasing. The direct interception of human immune signaling molecules by Mtb remains elusive, limiting drug discovery. Oxysterols and secosteroids regulate both innate and adaptive immune responses. Here we report a functional, structural, and bioinformatics study of Mtb enzymes initiating cholesterol catabolism and demonstrated their interrelation with human immunity. We show that these enzymes metabolize human immune oxysterol messengers. Rv2266 - the most potent among them - can also metabolize vitamin D3 (VD3) derivatives. High-resolution structures show common patterns of sterols binding and reveal a site for oxidative attack during catalysis. Finally, we designed a compound that binds and inhibits three studied proteins. The compound shows activity against Mtb H37Rv residing in macrophages. Our findings contribute to molecular understanding of suppression of immunity and suggest that Mtb has its own transformation system resembling the human phase I drug-metabolizing system.

Keywords: 25-hydroxy-cholesterol; CYP crystal structure; Mycobacterium tuberculosis; host-pathogen interactions; immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxysteroid Dehydrogenases / chemistry
  • 3-Hydroxysteroid Dehydrogenases / metabolism
  • Catalysis
  • Cytochrome P-450 Enzyme System / chemistry
  • Cytochrome P-450 Enzyme System / metabolism
  • Energy Metabolism*
  • Enzyme Activation
  • Host-Pathogen Interactions* / immunology
  • Humans
  • Immunity
  • Isoenzymes
  • Models, Molecular
  • Mycobacterium tuberculosis / immunology*
  • Oxysterols / chemistry
  • Oxysterols / metabolism
  • Recombinant Proteins
  • Structure-Activity Relationship
  • Tuberculosis / immunology*
  • Tuberculosis / metabolism*
  • Tuberculosis / microbiology


  • Isoenzymes
  • Oxysterols
  • Recombinant Proteins
  • Cytochrome P-450 Enzyme System
  • 3-Hydroxysteroid Dehydrogenases