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X-Ray Crystallography to Study the Oligomeric State Transition of the Thermotoga maritima M42 Aminopeptidase TmPep1050
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Structure of a microsporidian methionine aminopeptidase type 2 complexed with fumagillin and TNP-470

John Jeff Alvarado1, Anjana Nemkal, J Michael Sauder

  • 1Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Molecular and Biochemical Parasitology
|August 8, 2009
PubMed

Insights

Microsporidia cause infections, especially in immunocompromised individuals. Fumagillin and analogues show promise against Enterocytozoon bieneusi by inhibiting methionine aminopeptidase type 2 (MetAP2).

Area of Science:

  • Parasitology
  • Structural Biology
  • Drug Discovery

Background:

  • Microsporidia are opportunistic pathogens causing various infections, particularly in immunocompromised patients.
  • Existing treatments like benzimidazoles are ineffective against Enterocytozoon bieneusi.
  • Fumagillin and its analogues exhibit in vitro and in vivo activity against microsporidiosis, specifically targeting E. bieneusi.

Purpose of the Study:

  • To investigate the structural basis for fumagillin and analogue inhibition of microsporidian methionine aminopeptidase type 2 (MetAP2).
  • To explore the potential for developing specific inhibitors against microsporidian MetAP2, particularly for E. bieneusi.

Main Methods:

  • Cloning and expression of Encephalitozoon cuniculi MetAP2 (EcMetAP2) using a baculovirus system.
  • Determination of the crystal structure of EcMetAP2 with and without inhibitors (fumagillin, TNP-470).
  • Generation of a homology model for E. bieneusi MetAP2 based on the EcMetAP2 structure.

Main Results:

  • The crystal structure revealed EcMetAP2 belongs to the MetAP2c family.
  • Structural comparison of microsporidian MetAP2 with human MetAP2 was achieved.
  • Insights into inhibitor design for specific targeting of microsporidian MetAP2 were gained.

Conclusions:

  • The structural characterization of EcMetAP2 provides a foundation for understanding MetAP2 inhibition in microsporidia.
  • Comparative structural analysis highlights potential for developing selective inhibitors against microsporidian MetAP2.
  • This research offers a strategy for designing novel therapeutics against E. bieneusi and other microsporidian infections.

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