Structure of the <i>Plasmodium falciparum</i> M17 aminopeptidase and significance for the design of drugs targeting the neutral exopeptidases

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  • Sheena McGowan
    Department of Biochemistry and Molecular Biology, Monash University, Clayton Campus, Melbourne, Victoria, 3800, Australia;
  • Christine A. Oellig
    Department of Biochemistry and Molecular Biology, Monash University, Clayton Campus, Melbourne, Victoria, 3800, Australia;
  • Woldeamanuel A. Birru
    Department of Biochemistry and Molecular Biology, Monash University, Clayton Campus, Melbourne, Victoria, 3800, Australia;
  • Tom T. Caradoc-Davies
    Australian Synchrotron, 800 Blackburn Rd, Clayton, Melbourne, Victoria, 3800, Australia;
  • Colin M. Stack
    School of Biomedical and Health Sciences, University of Western Sydney (UWS), Narellan Road, Campbelltown, New South Wales 2560, Australia;
  • Jonathan Lowther
    School of Chemistry, University of Edinburgh, Joseph Black Building, West Mains Road, Edinburgh Eh9 3JJ, United Kingdom;
  • Tina Skinner-Adams
    Malaria Biology Laboratory, The Queensland Institute of Medical Research, 300 Herston Road Herston, Brisbane, Queensland 4006, Australia;
  • Artur Mucha
    Department of Bioorganic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, Wybrzeze, Wyspianskiego 27, 50-370 Wroclaw, Poland;
  • Pawel Kafarski
    Department of Bioorganic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, Wybrzeze, Wyspianskiego 27, 50-370 Wroclaw, Poland;
  • Jolanta Grembecka
    Department of Molecular Physiology and Biological Physics, University of Virginia, 1300 Jefferson Park Avenue, Jordan Hall, Charlottesville, VA;
  • Katharine R. Trenholme
    Malaria Biology Laboratory, The Queensland Institute of Medical Research, 300 Herston Road Herston, Brisbane, Queensland 4006, Australia;
  • Ashley M. Buckle
    Department of Biochemistry and Molecular Biology, Monash University, Clayton Campus, Melbourne, Victoria, 3800, Australia;
  • Donald L. Gardiner
    Malaria Biology Laboratory, The Queensland Institute of Medical Research, 300 Herston Road Herston, Brisbane, Queensland 4006, Australia;
  • John P. Dalton
    Institute for the Biotechnology of Infectious Diseases (IBID), University of Technology Sydney, Level 6, Building 4, Corner of Thomas and Harris Street, Ultimo, Sydney, New South Wales 2007, Australia; and
  • James C. Whisstock
    Department of Biochemistry and Molecular Biology, Monash University, Clayton Campus, Melbourne, Victoria, 3800, Australia;

Abstract

<jats:p> Current therapeutics and prophylactics for malaria are under severe challenge as a result of the rapid emergence of drug-resistant parasites. The human malaria parasite <jats:italic>Plasmodium falciparum</jats:italic> expresses two neutral aminopeptidases, <jats:italic>Pf</jats:italic> A-M1 and <jats:italic>Pf</jats:italic> A-M17, which function in regulating the intracellular pool of amino acids required for growth and development inside the red blood cell. These enzymes are essential for parasite viability and are validated therapeutic targets. We previously reported the x-ray crystal structure of the monomeric <jats:italic>Pf</jats:italic> A-M1 and proposed a mechanism for substrate entry and free amino acid release from the active site. Here, we present the x-ray crystal structure of the hexameric leucine aminopeptidase, <jats:italic>Pf</jats:italic> A-M17, alone and in complex with two inhibitors with antimalarial activity. The six active sites of the <jats:italic>Pf</jats:italic> A-M17 hexamer are arranged in a disc-like fashion so that they are orientated inwards to form a central catalytic cavity; flexible loops that sit at each of the six entrances to the catalytic cavern function to regulate substrate access. In stark contrast to <jats:italic>Pf</jats:italic> A-M1, <jats:italic>Pf</jats:italic> A-M17 has a narrow and hydrophobic primary specificity pocket which accounts for its highly restricted substrate specificity. We also explicate the essential roles for the metal-binding centers in these enzymes (two in <jats:italic>Pf</jats:italic> A-M17 and one in <jats:italic>Pf</jats:italic> A-M1) in both substrate and drug binding. Our detailed understanding of the <jats:italic>Pf</jats:italic> A-M1 and <jats:italic>Pf</jats:italic> A-M17 active sites now permits a rational approach in the development of a unique class of two-target and/or combination antimalarial therapy. </jats:p>

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