Comparison of 10,11-Dehydrocurvularin Polyketide Synthases from Alternaria cinerariae and Aspergillus terreus Highlights Key Structural Motifs.
Comparison of 10,11-Dehydrocurvularin Polyketide Synthases from Alternaria cinerariae and Aspergillus terreus Highlights Key Structural Motifs.
复制标题
从酸氨酸和曲曲霉的10,11-脱水聚尿布蛋白聚酮化合物合成酶的比较突出了关键的结构基序。
DOI：
10.1002/cbic.201500428
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发表时间：
2015-11
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;Gao Z;Lambkin GR;Xu W;Winter JM;Marcus SL;Tang Y;Vederas JC
来自真菌的迭代I型聚酮合酶（PKSs）是多功能酶，它们以高度有序的序列重复使用其活性位点来组装复杂的天然产物。具有抗癌特性的植物毒性大环内酯10，11-脱氢弯孢菌素（DHC）是通过高度还原（HR）迭代PKS和非还原（NR）迭代PKS的协同作用产生的。我们已经确定了在Alternaria cinerariae中的DHC基因簇，在酵母中异源表达活性HR PKS（Dhc 3）和NR PKS（Dhc 5），并将它们与在土曲霉中产生DHC的相应蛋白质进行比较。这些酶的系统发育分析和同源建模已经确定了与产物形成有关的可变表面和保守基序。我们已经确定并异源表达了两个迭代I型PKSs生产的植物毒性抗癌剂10，11-脱氢弯孢菌素（DHC）在链格孢cinerariae。这提供了与土曲霉中类似代谢物基因簇进行生物信息学比较的独特机会，其突出了代谢物产生所需的关键结构特征。
Iterative type I polyketide synthases (PKSs) from fungi are multifunctional enzymes that use their active sites repeatedly in a highly ordered sequence to assemble complex natural products. A phytotoxic macrolide with anticancer properties, 10,11-dehydrocurvularin (DHC), is produced by cooperation of a highly reducing (HR) iterative PKS and a non-reducing (NR) iterative PKS. We have identified the DHC gene cluster in Alternaria cinerariae, heterologously expressed the active HR PKS (Dhc3) and NR PKS (Dhc5) in yeast and compared them to corresponding proteins that make DHC in Aspergillus terreus. Phylogenetic analysis, and homology modeling of these enzymes has identified variable surfaces and conserved motifs that are implicated in product formation. We have identified and heterologous expressed two iterative type I PKSs necessary for production of the phytotoxic anticancer agent 10,11-dehydrocurvularin (DHC) in Alternaria cinerariae. This afforded the unique opportunity for bioinformatic comparison to the analogous metabolite gene cluster in Aspergillus terreus, which highlighted key structural features necessary for metabolite production.