Sharma Arvind, Yogavel Manickam, Sharma Amit
Structural and Computational Biology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Road, New Delhi, 110067, India.
Sci Rep. 2016 Feb 1;6:19981. doi: 10.1038/srep19981.
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.
疟疾症状是由疟原虫在人体红细胞（RBC）中的周期性增殖循环所驱动的。疟疾感染每年仍导致约60万人死亡，因此发现新的药物靶点和药物仍然至关重要。在本研究中，我们研究了疟原虫酶二腺苷四磷酸（Ap4A）水解酶，该酶通过将信号分子如Ap4A水解为ATP和AMP来调节其水平。我们追踪了寄生性Ap4A水解酶在受感染红细胞中的空间分布，并揭示了其在受感染细胞亚群的受感染红细胞膜上的异常定位。有趣的是，酶活性测定揭示了Ap4A水解酶与寄生虫生长抑制剂苏拉明之间的相互作用。我们还展示了apo-和硫酸盐结合状态下Ap4A水解酶的高分辨率晶体结构，其中硫酸盐通过模拟Ap4A等底物的磷酸盐而位于酶活性位点。寄生性Ap4A水解酶在受感染红细胞中的意外定位暗示了该酶在嘌呤能信号传导中的可能作用。此外，Ap4A水解酶的原子结构为选择性药物靶向提供了见解。
