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首页> 外文期刊>Bioorganic and Medicinal Chemistry >Structural and mechanistic insights into the action of Plasmodium falciparum spermidine synthase.
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Structural and mechanistic insights into the action of Plasmodium falciparum spermidine synthase.

机译：恶性疟原虫亚精胺合酶作用的结构和机理见解。

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摘要

Spermidine synthase is currently considered as a promising drug target in the malaria parasite, Plasmodium falciparum, due to the vital role of spermidine in the activation of the eukaryotic translation initiation factor (eIF5A) and cell proliferation. However, very limited information was available regarding the structure and mechanism of action of the protein at the start of this study. Structural and mechanistic insights of the P. falciparum spermidine synthase (PfSpdSyn) were obtained utilizing molecular dynamics simulations of a homology model based on the crystal structures of the Arabidopsis thaliana and Thermotoga maritima homologues. Our data are supported by in vitro site-directed mutagenesis of essential residues as well as by a crystal structure of the protein that became available recently. We provide, for the first time, dynamic evidence for the mechanism of the aminopropyltransferase action of PfSpdSyn. This characterization of the structural and mechanistic properties of the PfSpdSyn aswell as the elucidation of the active site residues involved in substrate, product, and inhibitor interactions paves the way toward inhibitor selection or design of parasite-specific inhibitors.
机译：由于亚精胺在真核翻译起始因子（eIF5A）的激活和细胞增殖中的重要作用，目前认为亚精胺合酶是疟原虫恶性疟原虫中有希望的药物靶标。然而，在这项研究开始时，关于蛋白质的结构和作用机理的信息非常有限。恶性疟原虫亚精氨酸合酶（PfSpdSyn）的结构和机制的见解是利用基于拟南芥和拟南芥的同源晶体结构的同源模型的分子动力学模拟获得的。我们的数据得到了必需残基的体外定点诱变以及最近可用的蛋白质晶体结构的支持。我们首次为PfSpdSyn的氨丙基转移酶作用机理提供了动态证据。 PfSpdSyn的结构和力学特性的这种表征以及底物，产物和抑制剂相互作用中涉及的活性位点残基的阐明为抑制剂选择或寄生虫特异性抑制剂的设计铺平了道路。

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