skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Studies of Toxoplasma gondii and Plasmodium falciparum enoyl acyl carrier protein reductase and implications for the development of antiparasitic agents

Abstract

The crystal structures of T. gondii and P. falciparum ENR in complex with NAD{sup +} and triclosan and of T. gondii ENR in an apo form have been solved to 2.6, 2.2 and 2.8 Å, respectively. Recent studies have demonstrated that submicromolar concentrations of the biocide triclosan arrest the growth of the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii and inhibit the activity of the apicomplexan enoyl acyl carrier protein reductase (ENR). The crystal structures of T. gondii and P. falciparum ENR in complex with NAD{sup +} and triclosan and of T. gondii ENR in an apo form have been solved to 2.6, 2.2 and 2.8 Å, respectively. The structures of T. gondii ENR have revealed that, as in its bacterial and plant homologues, a loop region which flanks the active site becomes ordered upon inhibitor binding, resulting in the slow tight binding of triclosan. In addition, the T. gondii ENR–triclosan complex reveals the folding of a hydrophilic insert common to the apicomplexan family that flanks the substrate-binding domain and is disordered in all other reported apicomplexan ENR structures. Structural comparison of the apicomplexan ENR structures with their bacterial and plant counterparts has revealed that although the active sites ofmore » the parasite enzymes are broadly similar to those of their bacterial counterparts, there are a number of important differences within the drug-binding pocket that reduce the packing interactions formed with several inhibitors in the apicomplexan ENR enzymes. Together with other significant structural differences, this provides a possible explanation of the lower affinity of the parasite ENR enzyme family for aminopyridine-based inhibitors, suggesting that an effective antiparasitic agent may well be distinct from equivalent antimicrobials.« less

Authors:
 [1];  [2];  [3];  [1];  [3];  [4];  [3];  [1]
  1. The Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN (United Kingdom)
  2. Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205 (United States)
  3. Department of Ophthalmology and Visual Sciences, Paediatrics (Infectious Diseases) and Pathology and the Committees on Molecular Medicine, Genetics, Immunology and The College, The University of Chicago, Chicago, IL 60637 (United States)
  4. Department of Immunology, University of Strathclyde, Glasgow G4 0NR, Scotland (United Kingdom)
Publication Date:
OSTI Identifier:
22348014
Resource Type:
Journal Article
Resource Relation:
Journal Name: Acta Crystallographica. Section D: Biological Crystallography; Journal Volume: 63; Journal Issue: Pt 3; Other Information: PMCID: PMC2483495; PMID: 17327670; PUBLISHER-ID: en5210; OAI: oai:pubmedcentral.nih.gov:2483495; Copyright (c) International Union of Crystallography 2007; This is an open-access article distributed under the terms described at http://journals.iucr.org/services/termsofuse.html.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
Denmark
Language:
English
Subject:
75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY; AFFINITY; CARRIERS; CRYSTAL STRUCTURE; CRYSTALS; INTERACTIONS; PLASMA; STOWING; SUBSTRATES

Citation Formats

Muench, Stephen P., Prigge, Sean T., McLeod, Rima, Rafferty, John B., Kirisits, Michael J., Roberts, Craig W., Mui, Ernest J., and Rice, David W., E-mail: d.rice@sheffield.ac.uk. Studies of Toxoplasma gondii and Plasmodium falciparum enoyl acyl carrier protein reductase and implications for the development of antiparasitic agents. Denmark: N. p., 2007. Web. doi:10.1107/S0907444906053625.
Muench, Stephen P., Prigge, Sean T., McLeod, Rima, Rafferty, John B., Kirisits, Michael J., Roberts, Craig W., Mui, Ernest J., & Rice, David W., E-mail: d.rice@sheffield.ac.uk. Studies of Toxoplasma gondii and Plasmodium falciparum enoyl acyl carrier protein reductase and implications for the development of antiparasitic agents. Denmark. doi:10.1107/S0907444906053625.
Muench, Stephen P., Prigge, Sean T., McLeod, Rima, Rafferty, John B., Kirisits, Michael J., Roberts, Craig W., Mui, Ernest J., and Rice, David W., E-mail: d.rice@sheffield.ac.uk. Thu . "Studies of Toxoplasma gondii and Plasmodium falciparum enoyl acyl carrier protein reductase and implications for the development of antiparasitic agents". Denmark. doi:10.1107/S0907444906053625.
@article{osti_22348014,
title = {Studies of Toxoplasma gondii and Plasmodium falciparum enoyl acyl carrier protein reductase and implications for the development of antiparasitic agents},
author = {Muench, Stephen P. and Prigge, Sean T. and McLeod, Rima and Rafferty, John B. and Kirisits, Michael J. and Roberts, Craig W. and Mui, Ernest J. and Rice, David W., E-mail: d.rice@sheffield.ac.uk},
abstractNote = {The crystal structures of T. gondii and P. falciparum ENR in complex with NAD{sup +} and triclosan and of T. gondii ENR in an apo form have been solved to 2.6, 2.2 and 2.8 Å, respectively. Recent studies have demonstrated that submicromolar concentrations of the biocide triclosan arrest the growth of the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii and inhibit the activity of the apicomplexan enoyl acyl carrier protein reductase (ENR). The crystal structures of T. gondii and P. falciparum ENR in complex with NAD{sup +} and triclosan and of T. gondii ENR in an apo form have been solved to 2.6, 2.2 and 2.8 Å, respectively. The structures of T. gondii ENR have revealed that, as in its bacterial and plant homologues, a loop region which flanks the active site becomes ordered upon inhibitor binding, resulting in the slow tight binding of triclosan. In addition, the T. gondii ENR–triclosan complex reveals the folding of a hydrophilic insert common to the apicomplexan family that flanks the substrate-binding domain and is disordered in all other reported apicomplexan ENR structures. Structural comparison of the apicomplexan ENR structures with their bacterial and plant counterparts has revealed that although the active sites of the parasite enzymes are broadly similar to those of their bacterial counterparts, there are a number of important differences within the drug-binding pocket that reduce the packing interactions formed with several inhibitors in the apicomplexan ENR enzymes. Together with other significant structural differences, this provides a possible explanation of the lower affinity of the parasite ENR enzyme family for aminopyridine-based inhibitors, suggesting that an effective antiparasitic agent may well be distinct from equivalent antimicrobials.},
doi = {10.1107/S0907444906053625},
journal = {Acta Crystallographica. Section D: Biological Crystallography},
number = Pt 3,
volume = 63,
place = {Denmark},
year = {Thu Mar 01 00:00:00 EST 2007},
month = {Thu Mar 01 00:00:00 EST 2007}
}