Romanello Larissa, Zeraik Ana Eliza, de Freitas Fernandes Adriano, Torini Juliana Roberta, Bird Louise E, Nettleship Joanne E, Rada Heather, Reddivari Yamini, Owens Ray J, Serrão Vitor Hugo Balasco, DeMarco Ricardo, Brandão-Neto José, Pereira Humberto D'Muniz
Instituto de Física de São Carlos, Universidade de São Paulo, 13563-120, São Carlos, SP, Brazil.
OPPF-UK, Research Complex at Harwell, Rutherford Appleton Laboratory, Oxford, OX11 0FA, UK; Division of Structural Biology, University of Oxford, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Headington, Oxon, OX2 7BN, UK.
Mol Biochem Parasitol. 2019 Apr;229:24-34. doi: 10.1016/j.molbiopara.2019.02.005. Epub 2019 Feb 14.
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.
曼氏血吸虫是导致血吸虫病的寄生虫，它缺乏“从头合成”嘌呤的生物合成途径，完全依赖嘌呤补救途径来供应嘌呤。已有许多关于吡喹酮耐药性的报道，同时也激发了开发抗血吸虫病新药的努力。次黄嘌呤 - 鸟嘌呤磷酸核糖转移酶（HGPRT）是嘌呤补救途径的关键酶。在此，我们描述了曼氏血吸虫HPGRT - 1（SmHGPRT）与IMP复合的晶体结构，分辨率为2.8埃。在SmHGPRT - 1和人HGPRT活性位点区域鉴定出四个取代。我们还展示了RNA测序和原位杂交的数据，表明HGPRT的一些同工型可能参与蠕虫的性成熟和繁殖相关过程；此外，其酶活性测定表明同工型SmHGPRT - 3的催化效率与其他同工型不同。最后，尽管此前其他研究曾提出该酶是潜在的抗血吸虫化疗靶点，但动力学参数表明无法将SmHGPRT用作有效的化疗靶点。
