5tiy

Publication Abstract from PubMed

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.

Structural and enzymatic insights into species-specific resistance to schistosome parasite drug therapy.,Taylor AB, Roberts KM, Cao X, Clark NE, Holloway SP, Donati E, Polcaro CM, Pica-Mattoccia L, Tarpley RS, McHardy SF, Cioli D, LoVerde PT, Fitzpatrick PF, Hart PJ J Biol Chem. 2017 Jul 7;292(27):11154-11164. doi: 10.1074/jbc.M116.766527. Epub, 2017 May 23. PMID:28536265^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.