Modification of glycopeptidolipids by an O-methyltransferase of Mycobacterium smegmatis

Dharshini Jeevarajah1, John H Patterson1, Malcolm J McConville1

  • 1Departments of Microbiology and Immunology1, and Biochemistry and Molecular Biology2, University of Melbourne, Victoria 3010, Australia.

Insights

Mycobacterium smegmatis glycopeptidolipids (GPLs) have a unique fatty acid modification. A specific methyltransferase, Mtf2, was identified as essential for this crucial GPL fatty acid methylation process.

Area of Science:

  • Microbiology and Molecular Biology
  • Cell Wall Biosynthesis
  • Mycobacterial Pathogenesis

Background:

  • Glycopeptidolipids (GPLs) are key structural components in the cell walls of non-tuberculous mycobacteria.
  • Mycobacterium smegmatis GPLs feature a diglycosylated lipopeptide core with variable methylation and acetylation.
  • Understanding GPL biosynthesis is critical for targeting mycobacterial infections.

Purpose of the Study:

  • To investigate the genes involved in Mycobacterium smegmatis GPL biosynthesis.
  • To identify and characterize methyltransferases responsible for GPL modification.
  • To elucidate the specific role of the methyltransferase Mtf2 in GPL structure.

Main Methods:

  • Bioinformatic analysis of the M. smegmatis chromosomal region upstream of the mps gene.
  • Construction and analysis of an mtf2 mutant in M. smegmatis.
  • Biochemical characterization of Mtf2's methyltransferase activity.

Main Results:

  • A novel GPL biosynthetic locus was identified, containing genes for glycosylation, methylation, acetylation, and transport.
  • Four methyltransferases were encoded within the locus; Mtf2 showed unique characteristics.
  • An mtf2 mutant demonstrated a complete inability to methylate GPL fatty acids, confirming Mtf2's function.

Conclusions:

  • Mtf2 is a novel methyltransferase specifically responsible for the methylation of GPL fatty acids in M. smegmatis.
  • This finding expands our understanding of GPL structural diversity and biosynthesis in mycobacteria.
  • Mtf2 represents a potential target for future therapeutic strategies against non-tuberculous mycobacteria.

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