Prolyl Oligopeptidase from the Blood Fluke Schistosoma mansoni : From Functional Analysis to Anti-schistosomal Inhibitors: e0003827
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 (...
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Veröffentlicht in: | PLoS neglected tropical diseases 2015-06, Vol.9 (6) |
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creator | Fajtová, Pavla Stefanic, Sasa Hradilek, Martin Dvorák, Jan Vondrásek, Jirí Jílková, Adéla Ulrychová, Lenka McKerrow, James H Caffrey, Conor R Mares, Michael Horn, Martin |
description | 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. |
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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.</description><identifier>ISSN: 1935-2727</identifier><identifier>EISSN: 1935-2735</identifier><identifier>DOI: 10.1371/journal.pntd.0003827</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Blood ; Drug resistance ; Enzymes ; Mass spectrometry ; Parasites ; Parasitic diseases ; Peptides ; Proteins ; Scientific imaging ; Tropical diseases</subject><ispartof>PLoS neglected tropical diseases, 2015-06, Vol.9 (6)</ispartof><rights>2015 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: : From Functional Analysis to Anti-schistosomal Inhibitors. PLoS Negl Trop Dis 9(6): e0003827. doi:10.1371/journal.pntd.0003827</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,864,27922,27923</link.rule.ids></links><search><creatorcontrib>Fajtová, Pavla</creatorcontrib><creatorcontrib>Stefanic, Sasa</creatorcontrib><creatorcontrib>Hradilek, Martin</creatorcontrib><creatorcontrib>Dvorák, Jan</creatorcontrib><creatorcontrib>Vondrásek, Jirí</creatorcontrib><creatorcontrib>Jílková, Adéla</creatorcontrib><creatorcontrib>Ulrychová, Lenka</creatorcontrib><creatorcontrib>McKerrow, James H</creatorcontrib><creatorcontrib>Caffrey, Conor R</creatorcontrib><creatorcontrib>Mares, Michael</creatorcontrib><creatorcontrib>Horn, Martin</creatorcontrib><title>Prolyl Oligopeptidase from the Blood Fluke Schistosoma mansoni : From Functional Analysis to Anti-schistosomal Inhibitors: e0003827</title><title>PLoS neglected tropical diseases</title><description>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.</description><subject>Blood</subject><subject>Drug resistance</subject><subject>Enzymes</subject><subject>Mass spectrometry</subject><subject>Parasites</subject><subject>Parasitic diseases</subject><subject>Peptides</subject><subject>Proteins</subject><subject>Scientific imaging</subject><subject>Tropical diseases</subject><issn>1935-2727</issn><issn>1935-2735</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><recordid>eNqNjz9PwzAUxC0EEuXPN2B4EnOCHeMmYQNEBBOVyl6ZxiUujl_wexny7QlSBSvL3Q2_k-6EuFIyV7pUN3scU7QhHyK3uZRSV0V5JBaq1iYrSm2Of3NRnoozor2UpjaVWohplTBMAV6D_8DBDexbSw52CXvgzsFDQGyhCeOng_W288RI2FvobSSMHu6g-UGbMW7Z4zwC7meZyBMwzpl9Rn-1AC-x8--eMdGFONnZQO7y4Ofiunl6e3zOhoRfoyPeHG7RRi3rZWWMqW71_6hvwZBYKA</recordid><startdate>20150601</startdate><enddate>20150601</enddate><creator>Fajtová, Pavla</creator><creator>Stefanic, Sasa</creator><creator>Hradilek, Martin</creator><creator>Dvorák, Jan</creator><creator>Vondrásek, Jirí</creator><creator>Jílková, Adéla</creator><creator>Ulrychová, Lenka</creator><creator>McKerrow, James H</creator><creator>Caffrey, Conor R</creator><creator>Mares, Michael</creator><creator>Horn, Martin</creator><general>Public Library of Science</general><scope>3V.</scope><scope>7QL</scope><scope>7SS</scope><scope>7T2</scope><scope>7T7</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8C1</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>F1W</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>H95</scope><scope>H97</scope><scope>K9.</scope><scope>L.G</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>20150601</creationdate><title>Prolyl Oligopeptidase from the Blood Fluke Schistosoma mansoni : From Functional Analysis to Anti-schistosomal Inhibitors</title><author>Fajtová, Pavla ; 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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.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><doi>10.1371/journal.pntd.0003827</doi><oa>free_for_read</oa></addata></record> |
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subjects | Blood Drug resistance Enzymes Mass spectrometry Parasites Parasitic diseases Peptides Proteins Scientific imaging Tropical diseases |
title | Prolyl Oligopeptidase from the Blood Fluke Schistosoma mansoni : From Functional Analysis to Anti-schistosomal Inhibitors: e0003827 |
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