@article{148dc44242a34cfa93f006ed7a115ce6,
title = "Structural and enzymatic insights into species-specific resistance to schistosome parasite drug therapy",
abstract = "The antischistosomal prodrug oxamniquine is activated by a sulfotransferase (SULT) in the parasitic flatworm Schistosoma mansoni. Of the three main human schistosome species, only S. mansoni is sensitive to oxamniquine therapy despite the presence of SULT orthologs in Schistosoma hematobium and Schistosoma japonicum. The reason for this species-specific drug action has remained a mystery for decades. Here we present the crystal structures of S. hematobium and S. japonicum SULTs, including S. hematobium SULT in complex with oxamniquine. We also examined the activity of the three enzymes in vitro; surprisingly, all three are active toward oxamniquine, yet we observed differences in catalytic efficiency that implicate kinetics as the determinant for species-specific toxicity. These results provide guidance for designing oxamniquine derivatives to treat infection caused by all species of schistosome to combat emerging resistance to current therapy.",
author = "Taylor, {Alexander B.} and Roberts, {Kenneth M.} and Xiaohang Cao and Clark, {Nathaniel E.} and Holloway, {Stephen P.} and Enrica Donati and Polcaro, {Chiara M.} and Livia Pica-Mattoccia and Tarpley, {Reid S.} and McHardy, {Stanton F.} and Donato Cioli and LoVerde, {Philip T.} and Fitzpatrick, {Paul F} and Hart, {Peter J}",
note = "Funding Information: This work was supported by National Institutes of Health Grant R01AI115691 (to P. J. H. and P. T. L.) and Welch Foundation Grants AQ-1245 (to P. F. F.) and AQ-1399 (to P. J. H.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Support for the X-ray Crystallography Core Laboratory by the University of Texas Health Science Center at San Antonio Office of the Vice President for Research and the Cancer Therapy and Research Center (National Institutes of Health Grant P30 CA054174) is gratefully acknowledged. This work is based upon research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by National Institute of General Medical Sciences, National Institutes of Health Grant P41 GM103403. The Pilatus 6M detector on 24-ID-C beam line is funded by National Institutes of Health Office of Research Infrastructure Programs High-End Instrumentation Grant S10 RR029205. This research used resources of the Advanced Photon Source, a United States Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract DE-AC02-06CH11357. Publisher Copyright: {\textcopyright} 2017, American Society for Biochemistry and Molecular Biology Inc. All rights reserved",
year = "2017",
month = jul,
day = "7",
doi = "10.1074/jbc.M116.766527",
language = "English (US)",
volume = "292",
pages = "11154--11164",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "27",
}