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

Juliana Torini, Larissa Romanello, Fernanda Batista, Vitor Hugo Serrao, Muhammad Faheem, Ana Eliza Zeraik, Louise Bird, Joanne Nettleship, Yamini Reddivari, Ray Owens, Ricardo DeMarco, Julio Cesar Borges, Jose Brandao-Neto, Humberto Pereira
doi: https://doi.org/10.1101/300533
Juliana Torini
University of Sao Paulo;
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Larissa Romanello
University of Sao Paulo;
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Fernanda Batista
LNBio;
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Vitor Hugo Serrao
University of Sao Paulo;
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Muhammad Faheem
Universidade Catolica de Brasilia;
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Ana Eliza Zeraik
University of Sao Paulo;
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Louise Bird
OPPF-UK;
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Joanne Nettleship
OPPF-UK;
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Yamini Reddivari
OPPF-UK;
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Ray Owens
OPPF-UK;
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Ricardo DeMarco
University of Sao Paulo;
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Julio Cesar Borges
University of Sao Paulo;
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Jose Brandao-Neto
Diamond Light Source
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Humberto Pereira
University of Sao Paulo;
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  • For correspondence: hmuniz.pereira@gmail.com
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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 SmPNP2. Screening of different ligands using a thermofluorescence approach indicated cytidine and cytosine as potential ligands. The binding of cytosine was confirmed by isothermal titration calorimetry, with a KD of 27 μM, and kinetic parameters for cytidine catalysis were obtained by ITC resulting in a KM of 76.3 μM. SmPNP2 also displays catalytic activity against inosine and adenosine, making it the first described PNP with robust catalytic activity towards both pyrimidines and purines. Crystallographic structures of SmPNP2 with different ligands were obtained and comparison of these structures with the previously described S. mansoni PNP (SmPNP1) provided clues for the unique capability of SmPNP2 to bind pyrimidines. When compared with the structure of SmPNP1, substitutions in the vicinity of SmPNP2 active site alter the architecture of the nucleoside base binding site allowing an alternative binding mode for nucleosides, with a 180° rotation from the canonical binding mode. The remarkable plasticity of this binding site deepens the understanding of the correlation between structure and nucleotide selectivity, offering new ways to analyses PNP activity.

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The copyright holder for this preprint is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
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  • Posted April 13, 2018.

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The molecular structure of Schistosoma mansoni PNP isoform 2 provides insights into the nucleotide selectivity of PNPs
Juliana Torini, Larissa Romanello, Fernanda Batista, Vitor Hugo Serrao, Muhammad Faheem, Ana Eliza Zeraik, Louise Bird, Joanne Nettleship, Yamini Reddivari, Ray Owens, Ricardo DeMarco, Julio Cesar Borges, Jose Brandao-Neto, Humberto Pereira
bioRxiv 300533; doi: https://doi.org/10.1101/300533
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The molecular structure of Schistosoma mansoni PNP isoform 2 provides insights into the nucleotide selectivity of PNPs
Juliana Torini, Larissa Romanello, Fernanda Batista, Vitor Hugo Serrao, Muhammad Faheem, Ana Eliza Zeraik, Louise Bird, Joanne Nettleship, Yamini Reddivari, Ray Owens, Ricardo DeMarco, Julio Cesar Borges, Jose Brandao-Neto, Humberto Pereira
bioRxiv 300533; doi: https://doi.org/10.1101/300533

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