Molecular Characterization and Mutational Analysis of Recombinant Diadenosine 5′,5″-P1,P4-Tetraphosphate Hydrolase from Plasmodium falciparum
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概要
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Asymmetrical diadenosine 5′,5″-P1,P4-tetraphosphate hydrolase (EC 3.6.1.17) from human malaria parasite Plasmodium falciparum was expressed in Escherichia coli, purified to homogeneity, and characterized for the first time as a biological target for chemotherapeutic agents against malaria. Plasmodium falciparum Ap4A (PfAp4A) hydrolase not only catalyzes diadenosine 5′,5″-P1,P4-tetraphosphate (Ap4A) to ATP and AMP, but also diadenosine 5′,5″-P1,P5-pentaphosphate (Ap5A) to ATP and ADP. Marked enzyme heat stability corresponding to the highest level of activity was observed at 60°C. The recombinant enzyme showed maximal activity in the presence of 5 mM Mg2+ ions. Kinetic analysis revealed the values of Km and Kcat as 0.6 µM and 2.5 min−1, respectively. Comparative protein modeling indicated an additional space in the substrate binding site of the parasitic enzyme compared with that of humans. Mutagenic analysis of the amino acid residue (Pro133) forming the additional space revealed a 5-fold increase in the wild-type Km value when replaced by a smaller (Ala) residue. Furthermore, catalytic activity was markedly affected by introducing a larger residue (Phe), thus creating the potential to develop a specific inhibitor of PfAp4A hydrolase.
著者
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ENDO Satoshi
Laboratory of Biochemistry, Gifu Pharmaceutical University
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Kitade Yukio
United Graduate School Of Drug Discovery And Medical Information Sciences Gifu Univ.
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Oh-hashi Kentaro
Department Of Biological Chemistry Faculty Of Pharmaceutical Sciences Nagoya City University
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Oh-hashi Kentaro
Department of Biomolecular Science, Faculty of Engineering, Gifu University
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Kitamura Yoshiaki
Center for Advanced Drug Research, Gifu University
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Osman Waleed
United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University
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