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Deciphering the Molecular Mechanism and Function of Pore-Forming Toxins Using Leishmania major
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Structure of Leishmania mexicana phosphomannomutase highlights similarities with human isoforms

Lukasz Kedzierski1, Robyn L Malby, Brian J Smith

  • 1Infection and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.

Journal of Molecular Biology
|September 12, 2006
PubMed

Insights

Phosphomannomutase (PMM) is crucial for parasite survival. Structural similarities between Leishmania and human PMM complicate the development of selective anti-leishmanial drugs.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Parasitology

Background:

  • Phosphomannomutase (PMM) is essential for glycoconjugate biosynthesis in eukaryotes.
  • Leishmania PMM is a potential drug target due to its role in parasite virulence.

Purpose of the Study:

  • To determine the crystal structure of Leishmania mexicana PMM.
  • To investigate the structural basis for PMM function and potential drug development.

Main Methods:

  • X-ray crystallography was used to determine the structure of L. mexicana PMM.
  • Generation of Leishmania major PMM knockouts and expression of human PMM.

Main Results:

  • The crystal structure of L. mexicana PMM was determined to 2.1 Å resolution.
  • L. mexicana PMM exhibits a novel dimeric structure within the haloacid dehalogenase family.
  • Leishmania PMM knockouts were avirulent, and human PMM expression did not restore virulence.

Conclusions:

  • Despite structural similarities, developing parasite-selective PMM inhibitors presents a challenge.
  • PMM remains a target, but structural conservation necessitates careful inhibitor design.

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