Prolyl Oligopeptidase from the Blood Fluke Schistosoma mansoni: From Functional Analysis to Anti-schistosomal Inhibitors.
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...
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ftdoajarticles:oai:doaj.org/article:22076b38bc044fd5bb9ceba19797d471 2023-05-15T15:09:30+02:00 Prolyl Oligopeptidase from the Blood Fluke Schistosoma mansoni: From Functional Analysis to Anti-schistosomal Inhibitors. Pavla Fajtová Saša Štefanić Martin Hradilek Jan Dvořák Jiří Vondrášek Adéla Jílková Lenka Ulrychová James H McKerrow Conor R Caffrey Michael Mareš Martin Horn 2015-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0003827 https://doaj.org/article/22076b38bc044fd5bb9ceba19797d471 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC4454677?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0003827 https://doaj.org/article/22076b38bc044fd5bb9ceba19797d471 PLoS Neglected Tropical Diseases, Vol 9, Iss 6, p e0003827 (2015) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2015 ftdoajarticles https://doi.org/10.1371/journal.pntd.0003827 2022-12-31T03:36:47Z 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.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.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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 9 6 e0003827 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Pavla Fajtová Saša Štefanić Martin Hradilek Jan Dvořák Jiří Vondrášek Adéla Jílková Lenka Ulrychová James H McKerrow Conor R Caffrey Michael Mareš Martin Horn Prolyl Oligopeptidase from the Blood Fluke Schistosoma mansoni: From Functional Analysis to Anti-schistosomal Inhibitors. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
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.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.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. |
format |
Article in Journal/Newspaper |
author |
Pavla Fajtová Saša Štefanić Martin Hradilek Jan Dvořák Jiří Vondrášek Adéla Jílková Lenka Ulrychová James H McKerrow Conor R Caffrey Michael Mareš Martin Horn |
author_facet |
Pavla Fajtová Saša Štefanić Martin Hradilek Jan Dvořák Jiří Vondrášek Adéla Jílková Lenka Ulrychová James H McKerrow Conor R Caffrey Michael Mareš Martin Horn |
author_sort |
Pavla Fajtová |
title |
Prolyl Oligopeptidase from the Blood Fluke Schistosoma mansoni: From Functional Analysis to Anti-schistosomal Inhibitors. |
title_short |
Prolyl Oligopeptidase from the Blood Fluke Schistosoma mansoni: From Functional Analysis to Anti-schistosomal Inhibitors. |
title_full |
Prolyl Oligopeptidase from the Blood Fluke Schistosoma mansoni: From Functional Analysis to Anti-schistosomal Inhibitors. |
title_fullStr |
Prolyl Oligopeptidase from the Blood Fluke Schistosoma mansoni: From Functional Analysis to Anti-schistosomal Inhibitors. |
title_full_unstemmed |
Prolyl Oligopeptidase from the Blood Fluke Schistosoma mansoni: From Functional Analysis to Anti-schistosomal Inhibitors. |
title_sort |
prolyl oligopeptidase from the blood fluke schistosoma mansoni: from functional analysis to anti-schistosomal inhibitors. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2015 |
url |
https://doi.org/10.1371/journal.pntd.0003827 https://doaj.org/article/22076b38bc044fd5bb9ceba19797d471 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 9, Iss 6, p e0003827 (2015) |
op_relation |
http://europepmc.org/articles/PMC4454677?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0003827 https://doaj.org/article/22076b38bc044fd5bb9ceba19797d471 |
op_doi |
https://doi.org/10.1371/journal.pntd.0003827 |
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PLOS Neglected Tropical Diseases |
container_volume |
9 |
container_issue |
6 |
container_start_page |
e0003827 |
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1766340684407635968 |