Tandem prenyltransferases catalyze isoprenoid elongation and complexity generation in biosynthesis of quinolone alkaloids.
Tandem prenyltransferases catalyze isoprenoid elongation and complexity generation in biosynthesis of quinolone alkaloids.
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DOI：
10.1021/jacs.5b03022
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发表时间：
2015-04-22
影响因子：
15
通讯作者：
Tang Y
中科院分区：
文献类型：
--
作者：
Zou Y;Zhan Z;Li D;Tang M;Cacho RA;Watanabe K;Tang Y
异戊二烯基修饰天然产物及其氧化转化对于引入结构复杂性和生物活性是重要的。了解自然界执行异戊二烯化的不同机制可以导致新的酶工具。青霉喹诺酮（1）是一种有效的杀虫生物碱，含有高度修饰的十碳异戊二烯基。在这里，我们揭示了一个迭代的异戊二烯化机制，安装使用两个芳香族异戊二烯基转移酶（PenI和PenG）的基因簇1从胸腺青霉菌的10个碳单元。最初的Friedel-Crafts烷基化反应由PenI催化，得到二甲基烯丙基喹诺酮6。然后，五碳侧链通过黄素依赖性单加氧酶脱氢成芳基二烯9，其用作用二甲基烯丙基二磷酸进行第二次烷基化的富电子底物，以产生苯乙烯基产物10。完成的氧化的十碳异戊二烯基然后显示经历进一步的结构变形以产生1的直接前体yaequinolone C12。因此，我们的研究揭示了天然产物生物合成中前所未有的异戊二烯基链延伸机制。
Modification of natural products with prenyl groups and the ensuing oxidative transformations are important for introducing structural complexity and biological activities. Understanding the different mechanisms Nature performs prenylation can lead to new enzymatic tools. Penigequinolones (1) are potent insecticidal alkaloids that contain a highly modified ten-carbon prenyl group. Here we reveal an iterative prenylation mechanism for installing the ten-carbon unit using two aromatic prenyltransferases (PenI and PenG) present in the gene cluster of 1 from Penicillium thymicola. The initial Friedel-Crafts alkylation is catalyzed by PenI to yield the dimethylallyl quinolone 6. The five-carbon side chain is then dehydrogenated by a Flavin-dependent monooxygenase to an aryldiene 9, which serves as the electron-rich substrate for a second alkylation with dimethylallyl diphosphate to yield a stryrenyl product 10. The completed, oxidized ten-carbon prenyl group is then shown to undergo further structural morphing to yield yaequinolone C 12, the immediate precursor of 1. Our studies therefore uncover an unprecedented prenyl chain extension mechanism in natural product biosynthesis.