Reconstruction of the saframycin core scaffold defines dual Pictet-Spengler mechanisms
Reconstruction of the saframycin core scaffold defines dual Pictet-Spengler mechanisms
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DOI：
10.1038/nchembio.365
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发表时间：
2010-06-01
影响因子：
14.8
通讯作者：
Oikawa, Hideaki
中科院分区：
文献类型：
--
作者：
Koketsu, Kento;Watanabe, Kenji;Oikawa, Hideaki
Saframycin A是一种具有独特五环四氢异喹啉骨架的强效抗肿瘤抗生素。我们发现，非核糖体肽合成酶SfmC催化一个七步转化容易合成的二肽基底物与长的酰基链到一个复杂的沙夫霉素支架。基于一系列的酶促反应，我们提出了一个详细的机制，涉及减少各种肽基硫酯由一个单一的R结构域，然后由迭代的C结构域介导的Pictet-Spengler反应。
Saframycin A is a potent antitumor antibiotic with a unique pentacyclic tetrahydroisoquinoline scaffold. We found that the nonribosomal peptide synthetase SfmC catalyzes a seven-step transformation of readily synthesized dipeptidyl substrates with long acyl chains into a complex saframycin scaffold. Based on a series of enzymatic reactions, we propose a detailed mechanism involving the reduction of various peptidyl thioesters by a single R domain followed by iterative C domain-mediated Pictet-Spengler reactions.