The molecular structure of <i>Schistosoma mansoni</i> PNP isoform 2 provides insights into the nucleotide selectivity of PNPs

Torini, J.R.; Romanello, Larissa; Batista, Fernanda Aparecida Heleno; Serrão, Vitor Hugo Balasco; Faheem, Muhammad; Zeraik, Ana Eliza; Bird, Louise E.; Nettleship, Joanne E.; Reddivari, Yamini; Owens, Ray; DeMarco, Ricardo; Borges, Júlio César; Brandão-Neto, J.; Pereira, H.M.

doi:10.1101/300533

Cited by 3 publications

(2 citation statements)

References 51 publications

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“…The SmNDPK structure and kinetic activity presented here represent our latest effort to fully characterize the S. mansoni purine salvage pathway [50][51][52][53][54][55][56][57][58][59][60][61][62][63]. The association of SmNDPK with processes related to host-parasite interaction and sexual biology of the parasite makes it an interesting target for possible therapies, with further studies warranted to verify its potential.…”

Section: -Discussionmentioning

confidence: 99%

Characterization of a Schistosoma mansoni NDPK expressed in sexual and digestive organs

Torini

Fernandes

Serrão

et al. 2019

Molecular and Biochemical Parasitology

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Section: -Discussionmentioning

confidence: 99%

Characterization of a Schistosoma mansoni NDPK expressed in sexual and digestive organs

Torini

Fernandes

Serrão

et al. 2019

Molecular and Biochemical Parasitology

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“… 20 One crucial component of the salvage pathway is the catalysis of the reversible phosphorolysis of the N-ribosidic bond of 6-oxopurine deoxynucleosides and nucleosides delivering their correspondent base and ribose-1-phosphate. 21 PNP facilitates the metabolism of inosine into hypoxanthine, adenosine into adenine and guanosine into guanine, and in each case, a ribose phosphate is created. Mutations in the PNP enzyme lead to severe combined immunodeficiency (SCID).…”

Section: Introductionmentioning

confidence: 99%

In Silico Study of Cucurbita maxima Compounds as Potential Therapeutics Against Schistosomiasis

Mtemeli

Shoko

Ndlovu

et al. 2022

Bioinform Biol Insights

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Schistosomiasis, a disease usually related to poverty and poor sanitation, affects more than 200 million people worldwide. Since the 1970s, the medical sector has depended on a single drug, praziquantel, for the treatment of the disease. The emerging evidence of resistance of the Schistosoma parasite to praziquantel and the drug’s inefficacy against juvenile stages of the parasite makes the need to find alternative drugs an urgent matter. In this study, we explored the inhibition potential of compounds from Cucurbita maxima using molecular docking studies on Schistosoma mansoni purine nucleoside phosphorylase ( SmPNP) and Schistosoma haematobium 28-kDa glutathione S-transferase ( Sh28kDaGST). Following molecular docking studies and analysis of the active sites, the primary amino acids that were observed and shown to be involved in the SmPNP-ligand interaction are CYS 33, ARG 86, HIS 88, TYR 90, ALA 118, ALA 119, PRO 200, TYR 202, GLU 203, VAL 219, MET 221, THR 244, ASN 245, PRO 257 and HIS 259. For the Sh28dKa-ligand interaction, the primary amino acids were PHE 11, ARG 16, TRP 41, LEU 53, GLU 70 and SER 71. Momordicoside I aglycone binds to SmPNP with the lowest binding affinity of -7.9 kcal/mol by pi sigma bond interactions with HIS 88. Balsaminoside B binds to Sh28kDaGST with a binding affinity of −7.6 kcal/mol by hydrogen bond interaction with TRP 41, LEU 53 and SER 71. Pharmacokinetic studies showed favourable drug-like properties for the 10 compounds that exhibited the lowest binding energies. Therefore, we propose that bioactive compounds from C. maxima be considered as potential novel drug hits in the treatment of schistosomiasis.

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HGPRT and PNP: Recombinant Enzymes from Schistosoma mansoni and Their Role in Immunotherapy during Experimental Murine Schistosomiasis

et al. 2023

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Schistosomiasis is a parasitic infection caused by trematode worms (also called blood flukes) of the genus Schistosoma sp., which affects over 230 million people worldwide, causing 200,000 deaths annually. There is no vaccine or new drugs available, which represents a worrying aspect, since there is loss of sensitivity of the parasite to the medication recommended by the World Health Organization, Praziquantel. The present study evaluated the effects of the recombinant enzymes of S. mansoni Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT), Purine Nucleoside Phosphorylase (PNP) and the MIX of both enzymes in the immunotherapy of schistosomiasis in murine model. These enzymes are part of the purine salvage pathway, the only metabolic pathway present in the parasite for this purpose, being essential for the synthesis of DNA and RNA. Female mice of Swiss and BALB/c strains were infected with cercariae and treated, intraperitoneally, with three doses of 100 µg of enzymes. After the immunotherapy, the eggs and adult worms were counted in the feces; the number of eosinophils from the fluid in the peritoneal cavity and peripheral blood was observed; and the quantification of the cytokine IL-4 and the production of antibodies IgE was analyzed. The evaluation of the number of granulomas and collagen deposition via histological slides of the liver was performed. The results demonstrate that immunotherapy with the enzyme HGPRT seems to stimulate the production of IL-4 and promoted a significant reduction of granulomas in the liver in treated animals. The treatment with the enzyme PNP and the MIX was able to reduce the number of worms in the liver and in the mesenteric vessels of the intestine, to reduce the number of eggs in the feces and to negatively modulate the number of eosinophils. Therefore, immunotherapy with the recombinant enzymes of S. mansoni HGPRT and PNP might contribute to the control and reduction of the pathophysiological aspects of schistosomiasis, helping to decrease the morbidity associated with the infection in murine model.

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The molecular structure of Schistosoma mansoni PNP isoform 2 provides insights into the nucleotide selectivity of PNPs

Abstract: Purine nucleoside phosphorylases (PNPs) play an important role in the blood fluke parasite Schistosoma mansoni as a key enzyme of the purine salvage pathway. Here we present the structural and kinetic characterization of a new PNP isoform from S. mansoni, named as

Cited by 3 publications

References 51 publications

Characterization of a Schistosoma mansoni NDPK expressed in sexual and digestive organs

Characterization of a Schistosoma mansoni NDPK expressed in sexual and digestive organs

In Silico Study of Cucurbita maxima Compounds as Potential Therapeutics Against Schistosomiasis

HGPRT and PNP: Recombinant Enzymes from Schistosoma mansoni and Their Role in Immunotherapy during Experimental Murine Schistosomiasis

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