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Schistosoma mansoni Purine and Pyrimidine Biosynthesis: Structures and Kinetic Experiments in the Search for the Best Therapeutic Target

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Balasco Serrao, Vitor Hugo [1] ; Torini de Souza, Juliana Roberta [2] ; Romanello, Larissa [2] ; Pereira, Humberto D'Muniz [2]
Número total de Autores: 4
Afiliação do(s) autor(es):
[1] Harvard Univ, Harvard Med Sch, Dept Neurobiol, Boston, MA 02115 - USA
[2] Univ Sao Paulo, Phys Inst Sao Carlos, Phys & Interdisciplinary Dept, Sao Carlos, SP - Brazil
Número total de Afiliações: 2
Tipo de documento: Artigo de Revisão
Fonte: CURRENT PHARMACEUTICAL DESIGN; v. 23, n. 45, p. 6967-6983, 2017.
Citações Web of Science: 2

Background: Schistosoma mansoni is the etiological agent of schistosomiasis, a debilitating treatment neglected tropical disease that affects approximately 218 million people worldwide. Despite its importance, the treatment of schistosomiasis relies on a single drug, praziquantel. Some reports on the resistance of S. mansoni to this drug have stimulated efforts to develop new drugs to treat this disease. S. mansoni possesses all the same pyrimidine pathways (de novo, salvage and thymidylate cycles) as those of its host. The opposite scenario is true for purine metabolism, in which only the salvage pathway is present. These pathways have previously been proposed as potential drug targets. Results: Using modern molecular biology techniques, large-scale study of these pathways has become possible; 24 genes have been studied, and several protein structures and kinetic parameters have been determined. Unique characteristics of schistosomal enzymes have been obtained, which show that this organism possesses two isoforms of uridine phosphorylase (UP), which share 92% of identity. However, only one isoform has a canonical function, whereas the second isoform is expressed through all life stages and does not have a known function. In addition, the methylthioadenosine phosphorylase (MTAP) is one of the enzymes responsible for the previously described adenosine phosphorylase activity, thus representing one main difference between S. mansoni and its host. The study of adenine phosphoribosyltransferase has revealed possible differential expression of the APRT gene in females. This result is consistent with those obtained for the experimental treatment of schistosomiasis in monkeys with the adenosine analog tubercidin, which eliminates the disease mainly in females. Conclusion: These important conclusions may aid in the development of new alternative drugs to treat schistosomiasis. (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: 12/10213-9 - Determinação estrutural e funcional das enzimas Metiltioadenosina fosforilase, purina nucleosídeo fosforilase isoforma 2 e das enzimas participantes da produção de GTP da via de salvação de purinas em Schistosoma mansoni
Beneficiário:Juliana Roberta Torini de Souza
Linha de fomento: Bolsas no Brasil - 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