Iterative Catalysis in the Biosynthesis of Mitochondrial Complex II Inhibitors Harzianopyridone and Atpenin B
Iterative Catalysis in the Biosynthesis of Mitochondrial Complex II Inhibitors Harzianopyridone and Atpenin B
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DOI：
10.1021/jacs.0c03438
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发表时间：
2020-05-13
影响因子：
15
通讯作者：
Tang, Yi
中科院分区：
文献类型：
--
作者：
Bat-Erdene, Undramaa;Kanayama, Daiki;Tang, Yi
五取代吡啶天然产物harzianopyridone和atpenins是线粒体复合物II的有效抑制剂。我们确定了这些化合物从其真菌生产者的途径，并发现生物合成步骤需要多种迭代酶。特别地，甲基转移酶和黄素依赖性单加氧酶反复用于引入C5和C6甲氧基。该途径出人意料地需要安装和去除N-甲氧基，该基团被认为是调节吡啶酮环反应性的导向基团，可能通过α效应。
The pentasubstituted pyridine natural products harzianopyridone and atpenins are potent inhibitors of mitochondrial complex II. We identified the pathways of these compounds from their fungal producers and uncovered that the biosynthetic steps require multiple iterative enzymes. In particular, a methyltransferase and a flavin-dependent monooxygenase are used iteratively to introduce C5 and C6 methoxy groups. The pathway unexpectedly requires the installation and removal of an N-methoxy group, which is proposed to be a directing group that tunes the reactivity of the pyridone ring, possibly through the alpha effect.