Enzymatic Synthesis of Molecular Skeletons of Complex Antitumor Antibiotics with Non-ribosomal Peptide Synthetases
Enzymatic Synthesis of Molecular Skeletons of Complex Antitumor Antibiotics with Non-ribosomal Peptide Synthetases
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DOI：
10.5059/yukigoseikyokaishi.67.1152
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发表时间：
2009-11
影响因子：
0.2
通讯作者：
Kenji Watanabe;H. Oguri;H. Oikawa
中科院分区：
文献类型：
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作者：
Kenji Watanabe;H. Oguri;H. Oikawa
非核糖体肽合成酶 (NRPS) 是一种可编程模块化机器，可产生许多具有生物活性的小分子肽。最近在了解 NRPS 催化机制方面取得的进展使我们能够设计这种复杂的催化系统。我们证明了复杂的天然抗肿瘤肽棘霉素和红霉素的体内和体外酶促合成。基于大肠杆菌的表达系统作为一个灵活而强大的平台，通过删除、突变和交换特定亚基来生产复杂的天然产物及其类似物。切除的棘霉素硫酯酶结构域表现出显着的底物耐受性并创建了环肽库。另一方面，saframycin NRPS 催化了非常不寻常的七步转化，构建了五环四氢异喹啉骨架。
Nonribosomal peptide synthetase (NRPS) is a programmable modular machinery which produces a number of biologically active small–molecule peptides. Recent progress on understanding the catalytic mechanism of NRPS enabled us to engineer this complex catalytic system. We demonstrated both in vivo and in vitro enzymatic synthesis of complex natural antitumor peptides echinomycin and saframycin. An Escherichia coli–based expression system served as a flexible yet robust platform for producing complex natural products and their analogs by deletion, mutation and swapping of a specific subunit. The excised thioesterase domain of echinomycin exhibited remarkable substrate tolerance and created a cyclic peptide library. On the other hand, saframycin NRPS catalyzed highly unusual seven–step transformations to construct a pentacyclic tetrahydro–isoquinoline skeleton.