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J Biol Chem. 2017 Jul 7;292(27):11154-11164. doi: 10.1074/jbc.M116.766527. Epub 2017 May 23.

Structural and enzymatic insights into species-specific resistance to schistosome parasite drug therapy.

Author information

1
From the Departments of Biochemistry and Structural Biology and taylorab@uthscsa.edu.
2
the X-ray Crystallography Core Laboratory, University of Texas Health Science Center, San Antonio, Texas 78229.
3
Department of Chemistry and Physics, University of South Carolina, Aiken, South Carolina 29801.
4
From the Departments of Biochemistry and Structural Biology and.
5
Institute of Chemical Methodologies, Consiglio Nazionale delle Ricerche, Via Salaria Km 29.500, 00015 Monterotondo, Rome, Italy.
6
Institute of Cell Biology and Neurobiology, Consiglio Nazionale delle Ricerche, Via E. Ramarini 32, 00015 Monterotondo, Rome, Italy.
7
Center for Innovative Drug Discovery, Department of Chemistry, University of Texas, San Antonio, Texas 78249, and.
8
Pathology and.
9
From the Departments of Biochemistry and Structural Biology and fitzpatrickp@uthscsa.edu.
10
From the Departments of Biochemistry and Structural Biology and hartp@uthscsa.edu.
11
Department of Veterans Affairs, South Texas Veterans Health Care System, San Antonio, Texas 78229.

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.

KEYWORDS:

drug resistance; enzyme kinetics; enzyme structure; helminth; oxamniquine; parasite; schistosome; schistosomiasis; structural biology; sulfotransferase

PMID:
28536265
PMCID:
PMC5500785
DOI:
10.1074/jbc.M116.766527
[Indexed for MEDLINE]
Free PMC Article

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