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首页> 外文期刊>Proteins: Structure, Function, and Genetics >Structure, evolution, and inhibitor interaction of S-adenosyl-L-homocysteine hydrolase from Plasmodium falciparum.
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Structure, evolution, and inhibitor interaction of S-adenosyl-L-homocysteine hydrolase from Plasmodium falciparum.

机译：恶性疟原虫的S-腺苷-L-高半胱氨酸水解酶的结构，进化和抑制剂相互作用。

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摘要

S-adenosylhomocysteine hydrolase (SAHH) is a key regulator of S-adenosylmethionine-dependent methylation reactions and an interesting pharmacologic target. We cloned the SAHH gene from Plasmodium falciparum (PfSAHH), with an amino acid sequence agreeing with that of the PlasmoDB genomic database. Even though the expressed recombinant enzyme, PfSAHH, could use 3-deaza-adenosine (DZA) as an alternative substrate in contrast to the human SAHH, it has a unique inability to substitute 3-deaza-(+/-)aristeromycin (DZAri) for adenosine. Among the analogs of DZA, including neplanocin A, DZAri was the most potent inhibitor of the PfSAHH enzyme activity, with a K(i) of about 150 nM, whether Ado or DZA was used as a substrate. When the same DZA analogs were tested for their antimalarial activity, they also inhibited the in vitro growth of P. falciparum parasites potently. Homology-modeling analysis revealed that a single substitution (Thr60-Cys59) between the human and malarial PfSAHH, in an otherwise similar SAH-binding pocket, might account for the differential interactions with the nucleoside analogs. This subtle difference in the active site may be exploited in the development of novel drugs that selectively inhibit PfSAHH. We performed a comprehensive phylogenetic analysis of the SAHH superfamily and inferred that SAHH evolved in the common ancestor of Archaea and Eukaryota, and was subsequently horizontally transferred to Bacteria. Additionally, an analysis of the unusual and uncharacterized AHCYL1 family of the SAHH paralogs extant only in animals reveals striking divergence of its SAH-binding pocket and the loss of key conserved residues, thus suggesting an evolution of novel function(s).
机译：S-腺苷同型半胱氨酸水解酶（SAHH）是S-腺苷甲硫氨酸依赖性甲基化反应的关键调节剂，是一个有趣的药理靶标。我们从恶性疟原虫（PfSAHH）克隆了SAHH基因，其氨基酸序列与PlasmoDB基因组数据库的氨基酸序列一致。尽管表达的重组酶PfSAHH可以使用3-deaza-腺苷（DZA）作为替代底物，而不是人SAHH，但它具有独特的无法替代3-deaza-（+/-）aristeromycin（DZAri）的能力。用于腺苷。在DZA的类似物（包括neplanocin A）中，DZAri是PfSAHH酶活性的最有效抑制剂，无论使用Ado还是DZA作为底物，其K（i）约为150 nM。当测试相同的DZA类似物的抗疟活性时，它们还有效抑制了恶性疟原虫的体外生长。同源性模型分析表明，人和疟疾PfSAHH之间的单个取代（Thr60-Cys59），在其他类似的SAH结合口袋中，可能解释了与核苷类似物的差异相互作用。在选择性抑制PfSAHH的新药的开发中，可以利用活性位点的这种细微差别。我们对SAHH超家族进行了全面的系统发育分析，并推断SAHH在古细菌和真核生物的共同祖先中进化，随后被水平转移到细菌中。此外，对仅存在于动物中的SAHH旁系同源物的异常且未表征的AHCYL1家族的分析显示，其SAH结合口袋的显着差异以及关键保守残基的丢失，从而暗示了新功能的进化。

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