Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526 (Japan).
Angew Chem Int Ed Engl. 2014 Nov 17;53(47):12880-4. doi: 10.1002/anie.201407920. Epub 2014 Sep 22.
The 6,6-quinolone scaffold of the viridicatin-type of fungal alkaloids are found in various quinolone alkaloids which often exhibit useful biological activities. Thus, it is of interest to identify viridicatin-forming enzymes and understand how such alkaloids are biosynthesized. Here an Aspergillal gene cluster responsible for the biosynthesis of 4'-methoxyviridicatin was identified. Detailed in vitro studies led to the discovery of the dioxygenase AsqJ which performs two distinct oxidations: first desaturation to form a double bond and then monooxygenation of the double bond to install an epoxide. Interestingly, the epoxidation promotes non-enzymatic rearrangement of the 6,7-bicyclic core of 4'-methoxycyclopenin into the 6,6-quinolone viridicatin scaffold to yield 4'-methoxyviridicatin. The finding provides new insight into the biosynthesis of the viridicatin scaffold and suggests dioxygenase as a potential tool for 6,6-quinolone synthesis by epoxidation of benzodiazepinediones.
真菌生物碱的绿麦角新碱型的 6,6-喹诺酮骨架存在于各种喹诺酮生物碱中，这些生物碱通常具有有用的生物活性。因此，确定绿麦角新碱形成酶并了解这些生物碱如何生物合成是很有意义的。在这里，鉴定了一个负责 4'-甲氧基绿麦角新碱生物合成的曲霉基因簇。详细的体外研究发现了双加氧酶 AsqJ，它进行了两次不同的氧化反应：首先是去饱和形成双键，然后是双键的单加氧酶化以安装环氧化物。有趣的是，环氧化促进了 4'-甲氧基环麦角新碱的 6,7-双环核心的非酶促重排，形成 6,6-喹诺酮绿麦角新碱支架，生成 4'-甲氧基绿麦角新碱。这一发现为绿麦角新碱支架的生物合成提供了新的见解，并表明双加氧酶可以通过苯并二氮杂卓二酮的环氧化作用作为 6,6-喹诺酮合成的潜在工具。
