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Monitoring the Assembly of a Secreted Bacterial Virulence Factor Using Site-specific Crosslinking
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Interaction between polyketide synthase and transporter suggests coupled synthesis and export of virulence lipid in

Madhulika Jain1, Jeffery S Cox

  • 1Department of Microbiology and Immunology, University of California, San Francisco, California, United States of America.

Plos Pathogens
|October 5, 2005
PubMed

Insights

Mycobacterium tuberculosis uses MmpL7 transporter to export phthiocerol dimycocerosate (PDIM) lipids. This study reveals MmpL7 interacts with the PpsE enzyme, coordinating PDIM synthesis and transport for virulence.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Biochemistry

Background:

  • Virulent mycobacteria rely on surface polyketides for host cell interaction.
  • The transport mechanism of these hydrophobic molecules across the bacterial cell envelope remains unclear.
  • Phthiocerol dimycocerosate (PDIM) is a crucial polyketide lipid for Mycobacterium tuberculosis virulence.

Purpose of the Study:

  • To elucidate the mechanism of PDIM transport across the cell envelope in Mycobacterium tuberculosis.
  • To identify the interaction between the PDIM biosynthetic enzyme PpsE and its transporter MmpL7.
  • To investigate the functional significance of the PpsE-MmpL7 interaction in PDIM export.

Main Methods:

  • Biochemical assays to detect interactions between MmpL7 domains and PpsE.
  • Genetic manipulation, including overexpression of MmpL7 interaction domain.
  • Dominant-negative assays to assess the impact on PDIM synthesis.

Main Results:

  • A specific domain of the MmpL7 transporter biochemically interacts with the PpsE polyketide synthase.
  • This is the first reported interaction between a biosynthetic enzyme and its cognate transporter.
  • Overexpression of the MmpL7 interaction domain inhibited PDIM synthesis, indicating disruption of the synthase-transporter complex.

Conclusions:

  • MmpL7 likely functions in a complex with the PDIM synthesis machinery for efficient transport.
  • Coordination between polyketide synthesis and transport may be a general mechanism for lipid export in microorganisms.
  • Understanding this process offers potential targets for novel anti-mycobacterial therapies.

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