In vitro and in vivo characterization of the multiple isoforms of Schistosoma mansoni hypoxanthine-guanine phosphoribosyltransferases

摘要

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 o praziquantel resistance have been described, as well as stimulated efforts to develop new drugs against schis tosomiasis. 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 witl IMP at a resolution of 2.8 angstrom. 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 HGPR1 might be involved in the process related to sexual maturation and reproduction in worms; furthermore, it: 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 antischistosoma chemotherapy target, the kinetics parameters reveal the impossibility to use SmHGPRT as an efficient the motherapeutic target.