Plasmodium falciparum pyruvate kinase as a novel target for antimalarial drug-screening.
Plasmodium falciparum pyruvate kinase as a novel target for antimalarial drug-screening.
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DOI：
10.1016/j.tmaid.2006.01.015
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发表时间：
2007-03-01
影响因子：
12
通讯作者：
Sim, T S
中科院分区：
文献类型：
--
作者：
Chan, Maurice;Tan, Doreen S H;Sim, T S
背景：全球旅行者感染疟疾的风险越来越大。在许多疟疾流行地区，抗药性的出现日益增加，这突出表明需要寻找新的抗疟药物筛选靶点。在这项研究中，使用丙酮酸激酶作为药物靶点进行评估。编码丙酮酸激酶（命名为PK 1）的基因的功能验证先前已被报道。然而，恶性疟原虫编码的这种酶的替代拷贝也可以绕过PK 1的作用。方法：采用RT-PCR方法检测PK 1和PK 2在体外培养条件下的表达情况。生物计算分析进行了鉴定之间的结构差异的恶性疟原虫丙酮酸激酶和相应的酶从其人类host.RESULTS：PK 1和PK 2确实是积极转录期间的红细胞内阶段，这表明在感染过程中的两种酶的参与。的PK 1和PK 2的效应器结合位点的氨基酸残基的比较，那些人的丙酮酸激酶揭示了一些显着的差异，可以作为目标的选择性抑制剂设计对寄生虫pyruvate kinases.CONCLUSION：在疟疾感染的血液阶段的PK 1和PK 2的表达的实验证据。有趣的是，系统发育分析显示，“PK 2”型酶似乎仅限于顶复门，这是关于PK 2作为药物靶标的评估的重要观察结果。
BACKGROUND: Global travellers are increasingly at risk of contracting malaria. The increasing occurrence of drug-resistance in many endemic areas emphasizes the need for novel drug targets for antimalarial-screening. In this study, the use of pyruvate kinase as a drug-target is evaluated. The functional validation of a gene encoding pyruvate kinase (designated PK1) has previously been reported. However, alternative copies of this enzyme encoded by Plasmodium falciparum could also circumvent the role of PK1. A survey of genome data revealed a putative ORF seemingly coding for another pyruvate kinase (designated PK2).METHODS: The expression of PK1 and PK2 in in vitro cultures were investigated by RT-PCR. Biocomputational analysis was carried out to identify structural differences between the P. falciparum pyruvate kinases and the corresponding enzymes from its human host.RESULTS: Both PK1 and PK2 were indeed actively transcribed during the intraerythrocytic stages, suggesting the involvement of both enzymes during infection. A comparison of amino acid residues at the effector binding sites of PK1 and PK2, to those of the human pyruvate kinases revealed some significant differences that could serve as targets for selective inhibitors to be designed against parasitic pyruvate kinases.CONCLUSION: Experimental evidence for the expression of both PK1 and PK2 during the blood stages of malaria infection was provided. Interestingly, phylogenetic analysis revealed that the "PK2" type of enzyme appears to be confined to Apicomplexans, an important observation with respect to the assessment of PK2 as a drug-target.