Michael S. Glickman: Biosynthesis and Pathogenic Role of the M. tuberculosis Cell Envelope

The Mtb cell envelope differs substantially from the cell walls of gram-positive and gram-negative bacteria and contains many unique lipid and glycolipid molecules, including mycolic acids, lipoarabinomannan, trehalose dimycolate, and phthiocerol dimycocerosate. While the structures of many of these molecules have been defined in exquisite chemical detail, their role in pathogenesis has only recently become clear with genetic studies in M. tuberculosis. To understand the role of these unique chemical entities in pathogenesis, we and others have generated defined mutants of M. tuberculosis that lack specific components of the cell envelope. We have focused on the cyclopropane modification of mycolic acids, a lipid modification that is present in diverse bacteria, but is especially elaborate in M. tuberculosis (and absent from saprophytic mycobacteria). We have focused on a family of S-adenosyl methionine-dependent methyltransferases of M. tuberculosis that modify mycolic acids with cyclopropyl groups and methyl branches. By studying null mutants in each methyltransferase and combinations of methyltransferase, we have:

  • Defined the biosynthetic role of each methyltransferase in mycolic acid modification
  • Demonstrated that site- and stereochemically specific mycolic acid cyclopropanation has an important role in Mtb pathogenesis
  • Demonstrated that cyclopropanation of mycolic acids on trehalose dimycolate acts directly to activate (cis cyclopropanation) or repress (trans-cyclopropanation) host innate immune activation
  • Validated the mycolic acid methyltransferases as a drug target through a chemical inhibitor (1) and creation of an M. tuberculosis strain lacking all cyclopropanation(2)

Mycolic acid modification in M. tuberculosis The structure of the three major mycolic acid classes (alpha, methoxy, and keto) are shown. Each cyclopropane ring or methyl branch is annotated with the name of the gene encoding the methyltransferase required for the synthesis of that modification. For details, see references below.

  1. Glickman M.S., Cox J.S., and Jacobs W.R. Jr., A novel mycolic acid cyclopropane synthetase is required for cording, persistence, and virulence of Mycobacterium tuberculosis. Mol Cell, 2000. 5(4): p. 717-27.
  2. Glickman M.S., Cahill S.M., and Jacobs W.R. Jr., The Mycobacterium tuberculosis cmaA2 gene encodes a mycolic acid trans-cyclopropane synthetase. J Biol Chem, 2001. 276(3): p. 2228-33.
  3. Huang C.C., et al., Crystal structures of mycolic acid cyclopropane synthases from Mycobacterium tuberculosis. J Biol Chem, 2002. 277(13): p. 11559-69.
  4. Glickman M.S., The mmaA2 gene of Mycobacterium tuberculosis encodes the distal cyclopropane synthase of the alpha-mycolic acid. J Biol Chem, 2003. 278(10): p. 7844-9.
  5. Rao V., et al., Mycobacterium tuberculosis controls host innate immune activation through cyclopropane modification of a glycolipid effector molecule. J Exp Med, 2005. 201(4): p. 535-43.
  6. Rao V., et al., Trans-cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis–induced inflammation and virulence. J Clin Invest, 2006. 116(6): p. 1660-7.
  7. Barkan D., et al., Mycolic acid cyclopropanation is essential for viability, drug resistance, and cell wall integrity of Mycobacterium tuberculosis. Chem Biol, 2009. 16(5): p. 499-509.
  8. Barkan D., et al., Redundant function of cmaA2 and mmaA2 in Mycobacterium tuberculosis cis cyclopropanation of oxygenated mycolates. J Bacteriol, 2010. 192(14): p. 3661-8.
  9. Barkan D., et al., Mycobacterium tuberculosis lacking all mycolic acid cyclopropanation is viable but highly attenuated and hyperinflammatory in mice. Infect Immun, 2012. 80(6): p. 1958-68.