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

Author(s):Show less -

Romanello, Larissa ^[1] ; Zeraik, Ana Eliza ^[1] ; Fernandes, Adriano de Freitas ^[1] ; Torini, Juliana Roberta ^[1] ; Bird, Louise E. ^{[2, 3]} ; Nettleship, Joanne E. ^{[2, 3]} ; Rada, Heather ^{[2, 3]} ; Reddivari, Yamini ^{[2, 3]} ; Owens, Ray J. ^{[2, 3]} ; Serrao, Vitor Hugo Balasco ^[4] ; DeMarco, Ricardo ^[1] ; Brandao-Neto, Jose ^[5] ; Pereira, Humberto D'Muniz ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Fis Sao Carlos, BR-13563120 Sao Carlos, SP - Brazil

^[2] Rutherford Appleton Lab, OPPF UK, Res Complex Harwell, Oxford OX11 0FA - England

^[3] Univ Oxford, Div Struct Biol, Wellcome Trust Ctr Human Genet, Roosevelt Dr, Headington OX2 7BN, Oxon - England

^[4] Univ Toronto, Lab Med & Pathobiol, Toronto, ON M5S 1A8 - Canada

^[5] Diamond Light Source, Harwell Sci & Innovat Campus, Didcot OX11 0DE, Oxon - England

• Document type: Journal article
• Source: Molecular and Biochemical Parasitology; v. 229, p. 24-34, APR 2019.
• Web of Science Citations: 0

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 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. (AU)

• FAPESP's process: 12/05532-8 - Structural and kinetic studies of adenosine kinase, hypoxanthine-guanine phosphoribosyltransferase, Adenilsuccinate synthetase and Adenilsuccinato lyase enzymes from Schistosoma mansoni
• Grantee: Larissa Romanello
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 12/14223-9 - Structural and kinetical studies of the enzymes involved in the purine metabolism in Schistosoma mansoni
• Grantee: Humberto D'Muniz Pereira
• Support type: Regular Research Grants
• FAPESP's process: 13/20715-4 - Studies of the correlation between septin dynamics and Ca2+ homeostasis in muscular cells from Schistosoma mansoni
• Grantee: Ana Eliza Zeraik
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 12/23730-1 - Characterization of macromolecular interactions of proteins involved in the selenocysteine synthesis from Escherichia coli
• Grantee: Vitor Hugo Balasco Serrão
• Support type: Scholarships in Brazil - Doctorate