Taylor Alexander B, Roberts Kenneth M, Cao Xiaohang, Clark Nathaniel E, Holloway Stephen P, Donati Enrica, Polcaro Chiara M, Pica-Mattoccia Livia, Tarpley Reid S, McHardy Stanton F, Cioli Donato, LoVerde Philip T, Fitzpatrick Paul F, Hart P John
From the Departments of Biochemistry and Structural Biology and
the X-ray Crystallography Core Laboratory, University of Texas Health Science Center, San Antonio, Texas 78229.
J Biol Chem. 2017 Jul 7;292(27):11154-11164. doi: 10.1074/jbc.M116.766527. Epub 2017 May 23.
The antischistosomal prodrug oxamniquine is activated by a sulfotransferase (SULT) in the parasitic flatworm Of the three main human schistosome species, only is sensitive to oxamniquine therapy despite the presence of SULT orthologs in and The reason for this species-specific drug action has remained a mystery for decades. Here we present the crystal structures of and SULTs, including SULT in complex with oxamniquine. We also examined the activity of the three enzymes ; 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.
抗血吸虫前体药物奥沙尼喹由寄生扁虫中的一种磺基转移酶（SULT）激活。在三种主要的人体血吸虫物种中，尽管曼氏血吸虫和埃及血吸虫中存在SULT直系同源物，但只有日本血吸虫对奥沙尼喹治疗敏感。几十年来，这种物种特异性药物作用的原因一直是个谜。在此，我们展示了曼氏血吸虫和埃及血吸虫SULT的晶体结构，包括与奥沙尼喹结合的日本血吸虫SULT。我们还检测了这三种酶的活性；令人惊讶的是，所有三种酶对奥沙尼喹均有活性，但我们观察到催化效率的差异，这表明动力学是物种特异性毒性的决定因素。这些结果为设计奥沙尼喹衍生物以治疗由所有血吸虫物种引起的感染提供了指导，从而对抗目前治疗中出现的耐药性。
