The molecular structure of Schistosoma mansoni PNP isoform 2 provides insights into the nucleoside 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:10.1371/journal.pone.0203532

Cited by 9 publications

(8 citation statements)

References 51 publications

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“…In the structures presented here, 14 fragments were observed bound to the active site, a buried pocket delimited by the main chain of Leu118, Ala119 and Gly120, and the side chains of Tyr202, Glu203, Met221, Ala244, Asn245 and Ser247. The interactions of the fragments in this site is coherent with the pattern observed in the previously obtained co-crystals with adenine, cytidine, hypoxanthine, cytosine and tubercidin bound (20). For example, all fragments in this site position a ring moiety in the same region occupied by adenine and most of them are hydrogen bonded to Glu203 (Figure 6).…”

Section: Fragment Binding Sitessupporting

confidence: 87%

“…Several residues differ between PNP2 and PNP1 in this region, namely Q174K, K178Q and R283K, indicating that this fragment binding would likely not be conserved for PNP1. The active site of PNP2 has been described in the literature (20). Nitrogenous bases occupy a well-defined pocket, closer to helices α6 and α8, and are observed hydrogen bonding to residues Glu203, Asn245 and Ser247.…”

Section: Fragment Binding Sitesmentioning

confidence: 97%

“…Purine nucleoside phosphorylase 2 (PNP2) (PDB ID 5CXQ) is a new isoform of PNP, which was identified in the S. mansoni genome-wide Open Reading Frame search. The new isoform, which presents a high degree of conservation to PNP1, has three substitutions in the active site, making its catalytic site very different from the PNP1 (20). PNP2 is highly expressed in the cercariae, where PNP1 has its lowest expression level (6,7), which makes it a suitable drug target.…”

Section: Introductionmentioning

confidence: 99%

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Crystallographic approach to fragment-based hit discovery against Schistosoma mansoni purine nucleoside phosphorylase

Faheem

Valadares

Brandão-Neto

et al. 2021

Biochemical Journal

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Several Schistosoma species cause Schistosomiasis, an endemic disease in 78 countries that is ranked second amongst the parasitic diseases in terms of its socioeconomic impact and human health importance. The drug recommended for treatment by the WHO is praziquantel (PZQ), but there are concerns associated with PZQ, such as the lack of information about its exact mechanism of action, its high price, its effectiveness – which is limited to the parasite’s adult form – and reports of resistance. The parasites lack the de novo purine pathway, rendering them dependent on the purine salvage pathway or host purine bases for nucleotide synthesis. Thus, the Schistosoma purine salvage pathway is an attractive target for the development of necessary and selective new drugs. In this study, the purine nucleotide phosphorylase II (PNP2), a new isoform of PNP1, was submitted to a high-throughput fragment-based hit discovery using a crystallographic screening strategy. PNP2 was crystallized and crystals were soaked with 827 fragments, a subset of the Maybridge 1000 library. X-ray diffraction data was collected and structures were solved. Out of 827-screened fragments we have obtained a total of 19 fragments that show binding to PNP2. 14 of these fragments bind to the active site of PNP2, while five were observed in three other sites. Here we present the first fragment screening against PNP2.

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Section: Fragment Binding Sitessupporting

confidence: 87%

Section: Fragment Binding Sitesmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Crystallographic approach to fragment-based hit discovery against Schistosoma mansoni purine nucleoside phosphorylase

Faheem

Valadares

Brandão-Neto

et al. 2021

Biochemical Journal

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“…Additionally, several studies and molecular structures of the purine salvage pathway enzymes have been released [20][21][22][23][24][25][26][27][28]. The description of the structure and kinetics of these enzymes permits a better understanding of the context of the metabolism of nucleotides in S. mansoni and represents another layer of structural and kinetic knowledge for the purine salvage pathway, which could help in the design of novel antischistosomal drugs.…”

Section: Introductionmentioning

confidence: 99%

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

Romanello

Zeraik

Fernandes

et al. 2019

Molecular and Biochemical Parasitology

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“…As atividades reportadas, são variadas, como: purina nucleosídeo fosforilase (PNP) (EC 2.4.2.1), adenosina deaminase (ADEA) (EC 3.5.4.4) e metiltioadenosina fosforilase (MTAP) (EC 2.4.2.4). Desta forma, foram conduzidos experimentos para tentar verificar alguma dessas atividades enzimáticas, seguindo protocolo das reações conforme as metodologias reportadas (129,204).…”

Section: Ensaios Bioquímicos Ylmdunclassified

Estudo estrutural e funcional de hidrolases de glicosídeos de organismos termofílicos

Almeida¹

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Os meus agradecimentos a Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), pelo apoio financeiro, por meio da bolsa de estudos do Projeto 16/09152-6, o que permitiu minha dedicação para a realização dos trabalhos aqui apresentados além da minha formação profissional.Agradeço ao Prof. Dr. João R. C. Muniz, por aceitar ser meu orientador neste projeto, pelos ensinamentos, pela paciência quando estive perdido, pela compreensão e pelas oportunidades.Ao Prof. Dr. Wanius Garcia da UFABC, por me apoiar no projeto, e ser um grande parceiro do nosso grupo, principalmente pelas análises biofísicas de SAXS e espalhamentos de luz, discussões e enriquecedoras colaborações nos trabalhos. À Dra. Amanda Bernardes, por toda ajuda nas etapas iniciais do trabalho, pelas valiosas dicas no laboratório, pelos ensinamentos dos experimentos, e por todo apoio oferecido ao nosso grupo.À minha família, em especial minha mãe, Bertilha, meu pai, Luiz Carlos, minha avó, Joana D'arc e minha tia, Lilian, por todo apoio em momentos de dificuldade, pelo apoio emocional, pelo amor e carinho, tudo em prol da minha busca de realização desse sonho de fazer o doutorado aqui na USP de São Carlos.Agradeço imensamente aos amigos, de longa data, e também aos novos que essa fase trouxe para minha vida. Agradecerei pessoalmente, quando possível, um por um! Aos amigos e colegas de casa, da Rep onde vivi o início do doutorado, pela recepção, dicas, apoio, descontrações e aprendizados.Aos amigos e vizinhos da Vila, onde vivi a maioria da fase de doutorado, incluindo a sobrevivência em meio á terrível pandemia que atingiu todo o planeta. Sou profundamente grato por todo apoio, amizade, compreensão e aprendizado.Os meus agradecimentos a alguns dos professores que foram meus grandes incentivadores para perseverar nessa caminhada acadêmica, em especial aos professores do Ens. médio: Sebastião; do curso Técnico: Kenia, Marcos, Cleusa e Taciano; e da Graduação: Hamilton, Valter, Geórgia, José Rubens e Lauro.Aos colaboradores com quem pude trabalhar em conjunto neste período, e juntos produzirmos alguns dos trabalhos aqui apresentados, e outros que estão por vir.Aos companheiros de laboratório (Biofísica e Biologia Estrutural), e dos vários dias de lutas, que certamente cometerei o equívoco de esquecer algum nome neste momento, portanto, não me arriscarei em nomear todos.Os meus agradecimentos ao corpo de docentes do IFSC-USP em especial aos professores Drs,

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

Cited by 9 publications

References 51 publications

Crystallographic approach to fragment-based hit discovery against Schistosoma mansoni purine nucleoside phosphorylase

Crystallographic approach to fragment-based hit discovery against Schistosoma mansoni purine nucleoside phosphorylase

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

Estudo estrutural e funcional de hidrolases de glicosídeos de organismos termofílicos

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