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

DOI: 10.1016/j.molbiopara.2019.02.005 DOI Help

Authors: Larissa Romanello (Instituto de Física de São Carlos, Universidade de São Paulo) , Ana Eliza Zeraik (Instituto de Física de São Carlos, Universidade de São Paulo) , Adriano De Freitas Fernandes (Instituto de Física de São Carlos, Universidade de São Paulo) , Juliana Roberta Torini (Instituto de Física de São Carlos, Universidade de São) , Louise E. Bird (OPPF-UK, Research Complex at Harwell; Wellcome Trust Centre for Human Genetics, University of Oxford) , Joanne E. Nettleship (OPPF-UK, Research Complex at Harwell; Wellcome Trust Centre for Human Genetics, University of Oxford) , Heather Rada (OPPF-UK, Research Complex at Harwell; Wellcome Trust Centre for Human Genetics, University of Oxford) , Yamini Reddivari (OPPF-UK, Research Complex at Harwell; Wellcome Trust Centre for Human Genetics, University of Oxford) , Ray J. Owens (OPPF-UK, Research Complex at Harwell; Wellcome Trust Centre for Human Genetics, University of Oxford) , Vitor Hugo Balasco Serrão (OPPF-UK, Research Complex at Harwell; Wellcome Trust Centre for Human Genetics, University of Oxford) , Ricardo Demarco (Instituto de Física de São Carlos, Universidade de São) , Jose Brandao-neto (Diamond Light Source) , Humberto D'muniz Pereira (Universidade de São Paulo)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular And Biochemical Parasitology

State: Published (Approved)
Published: February 2019
Diamond Proposal Number(s): 5073

Abstract: 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 2.8Ǻ. 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.

Journal Keywords: Schistosoma mansoni; purine salvage pathway; Hypoxanthine-guanine phosphoribosyltransferase; HGPRT

Subject Areas: Biology and Bio-materials


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography