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PLoS Negl Trop Dis. 2015 Jun 3;9(6):e0003827. doi: 10.1371/journal.pntd.0003827. eCollection 2015.

Prolyl Oligopeptidase from the Blood Fluke Schistosoma mansoni: From Functional Analysis to Anti-schistosomal Inhibitors.

Author information

1
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic; First Faculty of Medicine, Charles University, Prague, Czech Republic.
2
Institute of Parasitology, University of Zurich, Zurich, Switzerland.
3
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
4
Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic; Institute of Parasitology, Biology Centre, Academy of Sciences of the Czech Republic, Ceske Budejovice, Czech Republic.
5
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic; Faculty of Science, Charles University, Prague, Czech Republic.
6
Center for Innovation and Discovery in Parasitic Diseases, Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America.

Abstract

BACKGROUND:

Blood flukes of the genus Schistosoma cause schistosomiasis, a parasitic disease that infects over 240 million people worldwide, and for which there is a need to identify new targets for chemotherapeutic interventions. Our research is focused on Schistosoma mansoni prolyl oligopeptidase (SmPOP) from the serine peptidase family S9, which has not been investigated in detail in trematodes.

METHODOLOGY/PRINCIPAL FINDINGS:

We demonstrate that SmPOP is expressed in adult worms and schistosomula in an enzymatically active form. By immunofluorescence microscopy, SmPOP is localized in the tegument and parenchyma of both developmental stages. Recombinant SmPOP was produced in Escherichia coli and its active site specificity investigated using synthetic substrate and inhibitor libraries, and by homology modeling. SmPOP is a true oligopeptidase that hydrolyzes peptide (but not protein) substrates with a strict specificity for Pro at P1. The inhibition profile is analogous to those for mammalian POPs. Both the recombinant enzyme and live worms cleave host vasoregulatory, proline-containing hormones such as angiotensin I and bradykinin. Finally, we designed nanomolar inhibitors of SmPOP that induce deleterious phenotypes in cultured schistosomes.

CONCLUSIONS/SIGNIFICANCE:

We provide the first localization and functional analysis of SmPOP together with chemical tools for measuring its activity. We briefly discuss the notion that SmPOP, operating at the host-parasite interface to cleave host bioactive peptides, may contribute to the survival of the parasite. If substantiated, SmPOP could be a new target for the development of anti-schistosomal drugs.

PMID:
26039195
PMCID:
PMC4454677
DOI:
10.1371/journal.pntd.0003827
[Indexed for MEDLINE]
Free PMC Article

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