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

Autor(es):Mostrar menos -

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: Molecular and Biochemical Parasitology; v. 229, p. 24-34, APR 2019.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 12/05532-8 - Estudos estruturais e cinéticos das enzimas adenosina kinase, Hipoxantina-guanina fosforibosiltransferase, Adenilsuccinato sintetase e Adenilsuccinato liase de Schistosoma mansoni
• Beneficiário: Larissa Romanello
• Linha de fomento: Bolsas no Brasil - Doutorado
• Processo FAPESP: 12/14223-9 - Estudos estruturais e cinéticos das enzimas da via de salvação de purina de Schistosoma mansoni
• Beneficiário: Humberto D'Muniz Pereira
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/20715-4 - Estudo da correlação entre a dinâmica de septinas e a homeostase de Ca2+ em células musculares de Schistosoma mansoni
• Beneficiário: Ana Eliza Zeraik
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 12/23730-1 - Caracterização das interações macromoleculares das proteínas envolvidas na síntese de selenocisteínas em escherichia coli
• Beneficiário: Vitor Hugo Balasco Serrão
• Linha de fomento: Bolsas no Brasil - Doutorado