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

0446340 - ÚOCHB 2016 RIV US eng J - Journal Article
Fajtová, Pavla - Štefanic, S. - Hradilek, Martin - Dvořák, Jan - Vondrášek, Jiří - Jílková, Adéla - Ulrychová, Lenka - McKerrow, J. H. - Caffrey, C. R. - Mareš, Michael - Horn, Martin
Prolyl Oligopeptidase from the Blood Fluke Schistosoma mansoni: From Functional Analysis to Anti-schistosomal Inhibitors.
PLoS Neglected Tropical Diseases. Roč. 9, č. 6 (2015), e0003827/1-e0003827/24. ISSN 1935-2735. E-ISSN 1935-2735
R&D Projects: GA ČR(CZ) GAP302/11/1481; GA MŠMT LO1302
Institutional support: RVO:61388963 ; RVO:68378050
Keywords : Schistosoma mansoni * schistosomiasis * prolyl oligopeptidase * blood fluke
Subject RIV: CE - Biochemistry; EB - Genetics ; Molecular Biology (UMG-J)
Impact factor: 3.948, year: 2015
http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0003827

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.
Permanent Link: http://hdl.handle.net/11104/0248346