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首页> 外文期刊>Applied Microbiology >Characterization of the Biosynthetic Genes for 10,11-Dehydrocurvularin, a Heat Shock Response-Modulating Anticancer Fungal Polyketide from Aspergillus terreus
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Characterization of the Biosynthetic Genes for 10,11-Dehydrocurvularin, a Heat Shock Response-Modulating Anticancer Fungal Polyketide from Aspergillus terreus

机译：10，11-Dehydrocurvularin，一种热休克反应调节抗癌真菌真菌聚酮化合物的生物合成基因的表征。

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10,11-Dehydrocurvularin is a prevalent fungal phytotoxin with heat shock response and immune-modulatory activities. It features a dihydroxyphenylacetic acid lactone polyketide framework with structural similarities to resorcylic acid lactones like radicicol or zearalenone. A genomic locus was identified from the dehydrocurvularin producer strain Aspergillus terreus AH-02-30-F7 to reveal genes encoding a pair of iterative polyketide synthases ( A. terreus CURS1 [AtCURS1] and AtCURS2) that are predicted to collaborate in the biosynthesis of 10,11-dehydrocurvularin. Additional genes in this locus encode putative proteins that may be involved in the export of the compound from the cell and in the transcriptional regulation of the cluster. 10,11-Dehydrocurvularin biosynthesis was reconstituted in Saccharomyces cerevisiae by heterologous expression of the polyketide synthases. Bioinformatic analysis of the highly reducing polyketide synthase AtCURS1 and the nonreducing polyketide synthase AtCURS2 highlights crucial biosynthetic programming differences compared to similar synthases involved in resorcylic acid lactone biosynthesis. These differences lead to the synthesis of a predicted tetraketide starter unit that forms part of the 12-membered lactone ring of dehydrocurvularin, as opposed to the penta- or hexaketide starters in the 14-membered rings of resorcylic acid lactones. Tetraketide N -acetylcysteamine thioester analogues of the starter unit were shown to support the biosynthesis of dehydrocurvularin and its analogues, with yeast expressing AtCURS2 alone. Differential programming of the product template domain of the nonreducing polyketide synthase AtCURS2 results in an aldol condensation with a different regiospecificity than that of resorcylic acid lactones, yielding the dihydroxyphenylacetic acid scaffold characterized by an S-type cyclization pattern atypical for fungal polyketides.
机译：10,11-去氢曲霉素是一种常见的真菌植物毒素，具有热休克反应和免疫调节活性。它具有二羟基苯基乙酸内酯聚酮化合物骨架，其结构与间苯二酸内酯如紫杉醇或玉米赤霉烯酮相似。从脱氢曲伏霉素生产菌株曲霉曲霉AH-02-30-F7中鉴定出一个基因组位点，以揭示编码一对重复的聚酮化合物合酶（曲霉曲霉CURS1 [AtCURS1]和AtCURS2）的基因，这些基因预计将在10的生物合成中协同作用。 ，11-去氢曲维林。该基因座中的其他基因编码推测的蛋白质，这些蛋白质可能与化合物从细胞的输出以及簇的转录调控有关。通过聚酮化合物合酶的异源表达，在酿酒酵母中重建了10,11-脱氢曲维林的生物合成。高还原性聚酮化合物合酶AtCURS1和非还原性聚酮化合物合酶AtCURS2的生物信息学分析突出显示了与间苯二酸内酯生物合成中涉及的类似合成酶相比，关键的生物合成程序设计差异。与间苯二酸内酯的14元环中的五酮或六酮起始物相反，这些差异导致形成了预测的四酮起始物单元的合成，该起始单元形成了脱氢curvularin的12元内酯环的一部分。已显示起始单元的四酮N-乙酰半胱胺硫酯类似物可支持脱氢曲霉素及其类似物的生物合成，而酵母仅表达AtCURS2。非还原性聚酮化合物合酶AtCURS2的产物模板结构域的差异编程导致醛醇缩合具有与间苯二酸内酯不同的区域特异性，从而产生了以S型环化模式为特征的真菌聚酮化合物为特征的二羟基苯基乙酸支架。

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