Schistosoma mansoni, the parasite responsible for schistosomiasis, lacks the “de novo” purine biosynthetic pathway and depends entirely on the purine salvage pathway for the supply of purines. Numerous reports of praziquantel resistance have been described, as well as stimulated efforts to develop new drugs against schistosomiasis. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is a key enzyme of the purine salvage pathway. Here, we describe a crystallographic structure of the S. mansoni HPGRT-1 (SmHGPRT), complexed with IMP at a resolution of 2.8 Ǻ. Four substitutions were identified in the region of the active site between SmHGPRT-1 and human HGPRT. We also present data from RNA-Seq and WISH, suggesting that some isoforms of HGPRT might be involved in the process related to sexual maturation and reproduction in worms; furthermore, its enzymatic assays show that the isoform SmHGPRT-3 does not present the same catalytic efficiency as other isoforms. Finally, although other studies have previously suggested this enzyme as a potential antischistosomal chemotherapy target, the kinetics parameters reveal the impossibility to use SmHGPRT as an efficient chemotherapeutic target.

曼氏血吸虫（Schistosoma mansoni）是负责血吸虫病的寄生虫，缺乏“从头”嘌呤的生物合成途径，完全依赖于嘌呤的挽救途径来提供嘌呤。已经描述了对吡喹酮抗药性的大量报道，并刺激了开发抗血吸虫病新药的努力。次黄嘌呤-鸟嘌呤磷酸核糖基转移酶（HGPRT）是嘌呤挽救途径的关键酶。在这里，我们描述了曼氏葡萄球菌HPGRT-1（Sm HGPRT）的晶体结构，与IMP复合后的分辨率为2.8。在Sm之间的活性位点区域中鉴定出四个取代HGPRT-1和人类HGPRT。我们还提供了来自RNA-Seq和WISH的数据，表明HGPRT的某些亚型可能与蠕虫的性成熟和繁殖有关。此外，其酶促测定显示同工型Sm HGPRT-3与其他同工型没有相同的催化效率。最后，尽管以前有其他研究表明该酶可作为潜在的抗血吸虫化学疗法的靶标，但动力学参数显示不可能将Sm HGPRT用作有效的化学治疗靶标。