Structure and substrate fingerprint of aminopeptidase P from Plasmodium falciparum

Nyssa Drinkwater, Komagal Kannan Sivaraman, Rebecca S. Bamert, Wioletta Rut, Khadija Mohamed, Natalie B. Vinh, Peter J. Scammells, Marcin Drag, Sheena McGowan

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)3189-3204
Number of pages16
JournalBiochemical Journal
Volume473
Issue number19
DOIs
Publication statusPublished - 27 Sep 2016

Keywords

  • aminopeptidase
  • crystallography
  • malaria
  • plasmodium falciparum
  • protease inhibitor
  • substrate specificity

Cite this

Drinkwater, N., Kannan Sivaraman, K., Bamert, R. S., Rut, W., Mohamed, K., Vinh, N. B., ... McGowan, S. (2016). Structure and substrate fingerprint of aminopeptidase P from Plasmodium falciparum. Biochemical Journal, 473(19), 3189-3204. https://doi.org/10.1042/BCJ20160550
Drinkwater, Nyssa ; Kannan Sivaraman, Komagal ; Bamert, Rebecca S. ; Rut, Wioletta ; Mohamed, Khadija ; Vinh, Natalie B. ; Scammells, Peter J. ; Drag, Marcin ; McGowan, Sheena. / Structure and substrate fingerprint of aminopeptidase P from Plasmodium falciparum. In: Biochemical Journal. 2016 ; Vol. 473, No. 19. pp. 3189-3204.
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Drinkwater, N, Kannan Sivaraman, K, Bamert, RS, Rut, W, Mohamed, K, Vinh, NB, Scammells, PJ, Drag, M & McGowan, S 2016, 'Structure and substrate fingerprint of aminopeptidase P from Plasmodium falciparum' Biochemical Journal, vol. 473, no. 19, pp. 3189-3204. https://doi.org/10.1042/BCJ20160550

Structure and substrate fingerprint of aminopeptidase P from Plasmodium falciparum. / Drinkwater, Nyssa; Kannan Sivaraman, Komagal; Bamert, Rebecca S.; Rut, Wioletta; Mohamed, Khadija; Vinh, Natalie B.; Scammells, Peter J.; Drag, Marcin; McGowan, Sheena.

In: Biochemical Journal, Vol. 473, No. 19, 27.09.2016, p. 3189-3204.

Research output: Contribution to journalArticleResearchpeer-review

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Drinkwater N, Kannan Sivaraman K, Bamert RS, Rut W, Mohamed K, Vinh NB et al. Structure and substrate fingerprint of aminopeptidase P from Plasmodium falciparum. Biochemical Journal. 2016 Sep 27;473(19):3189-3204. https://doi.org/10.1042/BCJ20160550