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

Author(s)

Balasco Serrao, Vitor Hugo ^[1] ; Torini de Souza, Juliana Roberta ^[2] ; Romanello, Larissa ^[2] ; Pereira, Humberto D'Muniz ^[2]

Affiliation

^[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

• Document type: Review article
• Source: CURRENT PHARMACEUTICAL DESIGN; v. 23, n. 45, p. 6967-6983, 2017.
• Web of Science Citations: 2

Abstract

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)

• 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 Opportunities: 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 Opportunities: Regular Research Grants
• FAPESP's process: 12/10213-9 - Structural and functional studies of Purine nucleoside phosphorylase isoform 2, Methylthioadenosine phosphorylase and participants enzymes of GTP production from purine salvage pathway from Schistosoma mansoni.
• Grantee: Juliana Roberta Torini de Souza Oliveira
• Support Opportunities: Scholarships in Brazil - 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 Opportunities: Scholarships in Brazil - Doctorate