Structural and Enzymatic Insights into Species-specific Resistance to Schistosome Parasite Drug Therapy [Enzymology]

The antischistosomal pro-drug oxamniquine is activated by a sulfotransferase (SULT) in the human parasite Schistosoma mansoni. Of the three main human blood fluke species, only S. mansoni is sensitive to oxamniquine therapy despite the presence of SULT orthologs in S. haematobium and S. japonicum. The reason for this species-specific drug action has remained a mystery for decades. Here we present the crystal structures of S. haematobium and S. japonicum SULTs, including S. haematobium SULT in complex with oxamniquine. Our finding that all three enzymes show activity toward oxamniquine in vitro reveals differences in catalytic efficiency that implicate kinetics as the determinant for species-specific toxicity. These results support the initiative for designing oxamniquine derivatives to treat infection caused by all species of blood fluke to combat emerging resistance to current therapy.

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