Structural and functional attributes of malaria parasite diadenosine tetraphosphate hydrolase

Scientific Reports
Arvind SharmaAmit Sharma

Abstract

Malaria symptoms are driven by periodic multiplication cycles of Plasmodium parasites in human red blood corpuscles (RBCs). Malaria infection still accounts for ~600,000 annual deaths, and hence discovery of both new drug targets and drugs remains vital. In the present study, we have investigated the malaria parasite enzyme diadenosine tetraphosphate (Ap4A) hydrolase that regulates levels of signalling molecules like Ap4A by hydrolyzing them to ATP and AMP. We have tracked the spatial distribution of parasitic Ap4A hydrolase in infected RBCs, and reveal its unusual localization on the infected RBC membrane in subpopulation of infected cells. Interestingly, enzyme activity assays reveal an interaction between Ap4A hydrolase and the parasite growth inhibitor suramin. We also present a high resolution crystal structure of Ap4A hydrolase in apo- and sulphate- bound state, where the sulphate resides in the enzyme active site by mimicking the phosphate of substrates like Ap4A. The unexpected infected erythrocyte localization of the parasitic Ap4A hydrolase hints at a possible role of this enzyme in purinerigic signaling. In addition, atomic structure of Ap4A hydrolase provides insights for selective drug targeting.

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Citations

Dec 18, 2019·Antimicrobial Agents and Chemotherapy·Natalie WiedemarPascal Mäser
Aug 1, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Diana FontinhaMiguel Prudêncio
Feb 8, 2019·Malaria Journal·Dorothy Wavinya Nyamai, Özlem Tastan Bishop
Jun 30, 2021·Protein Science : a Publication of the Protein Society·Jyoti Chhibber-GoelAmit Sharma

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Methods Mentioned

BETA
confocal microscopy
Assay
PCR
Thermal shift
X-ray

Software Mentioned

MolProbity
HKL2000
COOT
PHASER
StepOnePlus
Origin
SHELXD
HKL2MAP
Microcal origin
phenix

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