Malaria is one of the world's most prevalent parasitic diseases, with over 200 million cases annually. Alarmingly, the spread of drug-resistant parasites threatens the effectiveness of current antimalarials and has made the development of novel therapeutic strategies a global health priority. Malaria parasites have a complicated lifecycle, involving an asymptomatic ‘liver stage’ and a symptomatic ‘blood stage’. During the blood stage, the parasites utilise a proteolytic cascade to digest host hemoglobin, which produces free amino acids absolutely necessary for parasite growth and reproduction. The enzymes required for hemoglobin digestion are therefore attractive therapeutic targets. The final step of the cascade is catalyzed by several metalloaminopeptidases, including aminopeptidase P (APP). We developed a novel platform to examine the substrate fingerprint of APP from Plasmodium falciparum (PfAPP) and to show that it can catalyze the removal of any residue immediately prior to a proline. Further, we have determined the crystal structure of PfAPP and present the first examination of the 3D structure of this essential malarial enzyme. Together, these analyses provide insights into potential mechanisms of inhibition that could be used to develop novel antimalarial therapeutics.
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October 2016
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Cover Image
Cover Image
Crystal structure of human hemoglobin β subunit (PDB ID: 1A3N) with an in silico mutation of phenylalanine 41 to tyrosine (green) to enhance function as a blood substitute; image kindly provide by Brandon Reeder and Chris Cooper (University of Essex). For details see Silkstone et al. in this issue (pages 3371–3383).
Research Article|
September 27 2016
Structure and substrate fingerprint of aminopeptidase P from Plasmodium falciparum
Nyssa Drinkwater;
Nyssa Drinkwater
*
1Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton Campus, Melbourne, VIC 3800, Australia
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Komagal Kannan Sivaraman;
Komagal Kannan Sivaraman
1Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton Campus, Melbourne, VIC 3800, Australia
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Rebecca S. Bamert;
Rebecca S. Bamert
1Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton Campus, Melbourne, VIC 3800, Australia
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Wioletta Rut;
Wioletta Rut
2Department of Bioorganic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, Wroclaw, Poland
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Khadija Mohamed;
Khadija Mohamed
2Department of Bioorganic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, Wroclaw, Poland
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Natalie B. Vinh;
Natalie B. Vinh
3Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, Parkville, VIC 3052, Australia
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Peter J. Scammells;
Peter J. Scammells
3Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, Parkville, VIC 3052, Australia
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Marcin Drag;
Marcin Drag
2Department of Bioorganic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, Wroclaw, Poland
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Sheena McGowan
Sheena McGowan
*
1Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton Campus, Melbourne, VIC 3800, Australia
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Publisher: Portland Press Ltd
Received:
June 05 2016
Revision Received:
July 24 2016
Accepted:
July 26 2016
Accepted Manuscript online:
July 26 2016
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2016 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society
2016
Biochem J (2016) 473 (19): 3189–3204.
Article history
Received:
June 05 2016
Revision Received:
July 24 2016
Accepted:
July 26 2016
Accepted Manuscript online:
July 26 2016
Citation
Nyssa Drinkwater, Komagal Kannan Sivaraman, Rebecca S. Bamert, Wioletta Rut, Khadija Mohamed, Natalie B. Vinh, Peter J. Scammells, Marcin Drag, Sheena McGowan; Structure and substrate fingerprint of aminopeptidase P from Plasmodium falciparum. Biochem J 1 October 2016; 473 (19): 3189–3204. doi: https://doi.org/10.1042/BCJ20160550
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