Crystal structure of S-adenosyl-L-homocysteine hydrolase from the human malaria parasite Plasmodium falciparum
Crystal structure of S-adenosyl-L-homocysteine hydrolase from the human malaria parasite Plasmodium falciparum
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DOI：
10.1016/j.jmb.2004.08.104
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发表时间：
2004-10-29
影响因子：
5.6
通讯作者：
Nakamura, KT
中科院分区：
文献类型：
--
作者：
Tanaka, N;Nakanishi, M;Nakamura, KT
人类疟疾寄生虫恶性疟原虫每年造成100多万人死亡。对常规药物治疗产生抗药性的疟原虫菌株的出现刺激了对具有新作用模式的抗疟药的探索。S-腺苷-L-同型半胱氨酸水解酶（SAHH）是生物甲基化的调节剂。SAHH的抑制剂影响核酸、蛋白质和小分子的甲基化状态。恶性疟原虫SAHH（PfSAHH）抑制剂有望提供一种新型的抗疟疾化疗剂。尽管迫切需要开发选择性PfSAHH抑制剂作为治疗药物，但目前只有哺乳动物SAHH结构可用。在这里，我们报告的PfSAHH与反应产物腺苷（Ado）络合的晶体结构。Ado复合物结构的知识与智人SAHH（HsSAHH）的结构比较相结合，揭示了PfSAHH（Cys 59）和HsSAHH（Thr 60）之间的单一取代导致了与核苷抑制剂的差异相互作用。为了研究Cys 59在与核苷抑制剂相互作用中的作用，制备了突变体PfSAHH。Thr取代Cys 59导致突变PfSAHH，其显示HsSAHH样核苷抑制剂敏感性。目前的结构应该提供设计有效的和选择性PfSAHH抑制剂的机会。(C)2004爱思唯尔有限公司保留所有权利。
The human malaria parasite Plasmodium falciparum is responsible for the death of more than a million people each year. The emergence of strains of malarial parasite resistant to conventional drug therapy has stimulated searches for antimalarials with novel modes of action. S-Adenosyl-L-homocysteine hydrolase (SAHH) is a regulator of biological methylations. Inhibitors of SAHH affect the methylation status of nucleic acids, proteins, and small molecules. P. falciparum SAHH (PfSAHH) inhibitors are expected to provide a new type of chemotherapeutic agent against malaria. Despite the pressing need to develop selective PfSAHH inhibitors as therapeutic drugs, only the mammalian SAHH structures are currently available. Here, we report the crystal structure of PfSAHH complexed with the reaction product adenosine (Ado). Knowledge of the structure of the Ado complex in combination with a structural comparison with Homo sapiens SAHH (HsSAHH) revealed that a single substitution between the PfSAHH (Cys59) and HsSAHH (Thr60) accounts for the differential interactions with nucleoside inhibitors. To examine roles of the Cys59 in the interactions with nucleoside inhibitors, a mutant PfSAHH was prepared. A replacement of Cys59 by Thr results in mutant PfSAHH, which shows HsSAHH-like nucleoside inhibitor sensitivity. The present structure should provide opportunities to design potent and selective PfSAHH inhibitors. (C) 2004 Elsevier Ltd. All rights reserved.