Production of New Cladosporin Analogues by Reconstitution of the Polyketide Synthases Responsible for the Biosynthesis of this Antimalarial Agent.
Production of New Cladosporin Analogues by Reconstitution of the Polyketide Synthases Responsible for the Biosynthesis of this Antimalarial Agent.
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DOI：
10.1002/anie.201509345
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发表时间：
2016-01-11
期刊：
影响因子：
--
通讯作者：
Vederas JC
中科院分区：
文献类型：
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作者：
Cochrane RV;Sanichar R;Lambkin GR;Reiz B;Xu W;Tang Y;Vederas JC
抗疟药cladosporin是一种纳米摩尔恶性疟原虫赖氨酸- trna合成酶抑制剂，对血液期和肝脏期感染均有抑制作用。Cladosporin可以从真菌Cladosporium cladosporioides中分离得到，它被认为是由高还原（HR）和非还原（NR）迭代的I型聚酮合成酶（PKS）对生物合成的。宿主生物的基因组测序，以及随后这些酶在酿酒酵母中的异源表达产生了cladosporin，证实了假定的基因簇的身份。在cladosporin生物合成过程中，五肽中间类似物的加入表明HR PKS cl2和NR PKS cl3进行了5+3组装。在cladosporin基因簇中也发现了一个推测的赖氨酸- trna合成酶抗性基因。活性位点的分析强调了关键的结构特征，被认为是对克拉多菌素耐药的重要因素。
The anti-malarial agent cladosporin is a nanomolar inhibitor of Plasmodium falciparum lysyl-tRNA synthetase, and exhibits activity against both blood and liver stage infection. Cladosporin can be isolated from the fungus Cladosporium cladosporioides, where it was believed to be biosynthesized by a highly reducing (HR) and non-reducing (NR) iterative type I polyketide synthase (PKS) pair. Genome sequencing of the host organism, and subsequent heterologous expression of these enzymes in Saccharomyces cerevisiae produced cladosporin, confirming the identity of the putative gene cluster. Incorporation of a pentaketide intermediate analog indicated a 5+3 assembly by the HR PKS Cla2 and the NR PKS Cla3 during cladosporin biosynthesis. A putative lysyl-tRNA synthetase resistance gene was also identified in the cladosporin gene cluster. Analysis of the active site emphasizes key structural features thought to be important in resistance to cladosporin.