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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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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]
Total Authors: 13
[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
Total Affiliations: 5
Document type: Journal article
Source: Molecular and Biochemical Parasitology; v. 229, p. 24-34, APR 2019.
Web of Science Citations: 0

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