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.

• Authors: Alexander B Taylor, Kenneth M Roberts, Xiaohang Cao, Nathaniel E Clark, Stephen P Holloway, Enrica Donati, Chiara M Polcaro, Livia Pica-Mattoccia, Reid S Tarpley, Stanton F McHardy, Donato Cioli, Philip T LoVerde, Paul F Fitzpatrick, P John Hart
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 292 Issue 27 Pg. 11154-11164 (07 07 2017) ISSN: 1083-351X [Electronic] United States
• PMID: 28536265 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Helminth Proteins
• Oxamniquine
• Sulfotransferases

Topics

• Animals
• Crystallography, X-Ray
• Drug Resistance
• Helminth Proteins (chemistry, genetics, metabolism)
• Oxamniquine
• Schistosoma haematobium (enzymology, genetics)
• Schistosoma japonicum (enzymology, genetics)
• Sulfotransferases (chemistry, genetics)