Structural studies of vacuolar plasmepsins.
Structural studies of vacuolar plasmepsins.
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DOI：
10.1016/j.bbapap.2011.04.008
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发表时间：
2012-01
影响因子：
3.2
通讯作者：
Wlodawer, Alexander
中科院分区：
文献类型：
--
作者：
Bhaumik, Prasenjit;Gustchina, Alla;Wlodawer, Alexander
疟原虫蛋白酶（Plasmepsins，PMs）是存在于不同种类疟原虫中的胃蛋白酶样天冬氨酸蛋白酶。四种疟原虫（间日疟原虫、卵形疟原虫、三日疟原虫和最致命的恶性疟原虫）是导致影响全球数百万人的人类疟疾的主要原因。由于寄生虫突变的复杂性和速率加上区域变化，以及出现对抗疟疾剂如氯喹和磺胺嘧啶/乙胺嘧啶有抗性的恶性疟原虫菌株，因此存在寻找新的和持久的化疗药物疗法的持续压力。由于许多蛋白酶代表治疗靶标，并且PM已被证明在寄生虫的存活中起重要作用，因此这些酶最近被鉴定为用于开发新型抗疟药物的有希望的靶标。恶性疟原虫的基因组编码10种PM（PMI、PMII、PMIV-X和组织天冬氨酸蛋白酶（HAP）），其中4种（PMI、PMII、PMIV和HAP）位于食物液泡内，直接参与人类血红蛋白的降解，并且具有50-79%的氨基酸序列同一性。这篇评论的重点是结构研究，只有这四种酶，包括它们的直系同源物在其他疟原虫物种。几乎所有的原始晶体学研究进行了PMII，但最近的工作PMIV，PMI和HAP导致了一个更完整的图片的结构功能关系的空泡PM。在过去的15年中，已经报道了许多液泡型纤溶酶抑制剂复合物的结构以及它们的酶原。此类研究获得的信息将有助于开发更好的抑制剂，这些抑制剂可能成为一类新的强效抗疟药物。
Plasmepsins (PMs) are pepsin-like aspartic proteases present in different species of parasite Plasmodium. Four Plasmodium species (P. vivax, P. ovale, P. malariae, and the most lethal P. falciparum) are mainly responsible for causing human malaria that affects millions worldwide. Due to the complexity and rate of parasite mutation coupled with regional variations, and the emergence of P. falciparum strains which are resistant to antimalarial agents such as chloroquine and sulfadoxine/pyrimethamine, there is constant pressure to find new and lasting chemotherapeutic drug therapies. Since many proteases represent therapeutic targets and PMs have been shown to play an important role in the survival of parasite, these enzymes have recently been identified as promising targets for the development of novel antimalarial drugs. The genome of P. falciparum encodes ten PMs (PMI, PMII, PMIV-X and histo-aspartic protease (HAP)), four of which (PMI, PMII, PMIV and HAP) reside within the food vacuole, are directly involved in degradation of human hemoglobin, and share 50-79% amino acid sequence identity. This review focuses on structural studies of only these four enzymes, including their orthologs in other Plasmodium species. Almost all original crystallographic studies were performed with PMII, but more recent work on PMIV, PMI, and HAP resulted in a more complete picture of the structure-function relationship of vacuolar PMs. Many structures of inhibitor complexes of vacuolar plasmepsins, as well as their zymogens, have been reported in the last 15 years. Information gained by such studies will be helpful for the development of better inhibitors that could become a new class of potent antimalarial drugs.
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1107/s0907444902014695
发表时间：
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影响因子：
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发表时间：
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影响因子：
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