Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan.
Curr Opin Chem Biol. 2012 Apr;16(1-2):142-9. doi: 10.1016/j.cbpa.2012.02.021. Epub 2012 Mar 10.
Nonribosomal peptide synthetase (NRPS) is a programmable modular machinery that produces a number of biologically active small-molecule peptides. 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 proposed a detailed mechanism involving the reduction of various peptidyl thioesters by a single R domain followed by iterative C domain-mediated Pictet-Spengler reactions. This shows that NRPSs possess a remarkable capability to acquire novel function for diversifying structures of peptide natural products.
非核糖体肽合成酶（NRPS）是一种可编程的模块化机器，能够产生许多具有生物活性的小分子肽。沙福霉素 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 催化易于合成的二肽酰基底物与长酰基链的七步转化，形成复杂的沙福霉素骨架。基于一系列酶促反应，我们提出了一个详细的机制，涉及单个 R 结构域还原各种肽基硫酯，然后通过迭代 C 结构域介导的 Pictet-Spengler 反应。这表明 NRPS 具有显著的能力，可以获得新的功能，从而使肽类天然产物的结构多样化。
