Escherichia coli allows efficient modular incorporation of newly isolated quinomycin biosynthetic enzyme into echinomycin biosynthetic pathway for rational design and synthesis of potent antibiotic unnatural natural product.
Escherichia coli allows efficient modular incorporation of newly isolated quinomycin biosynthetic enzyme into echinomycin biosynthetic pathway for rational design and synthesis of potent antibiotic unnatural natural product.
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大肠杆菌允许将新分离的奎诺霉素生物合成酶有效地融合到棘霉素的生物合成途径中，以合理设计和合成有效的抗生素非自然天然产品。
DOI：
10.1021/ja902261a
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发表时间：
2009-07-08
影响因子：
15
通讯作者：
Oikawa H
中科院分区：
文献类型：
--
作者：
Watanabe K;Hotta K;Nakaya M;Praseuth AP;Wang CC;Inada D;Takahashi K;Fukushi E;Oguri H;Oikawa H
天然产物显示出令人印象深刻的活性，对广泛的目标，包括病毒，微生物和肿瘤。然而，它们的临床应用经常受到其稀缺性和不良毒性的阻碍。不仅可以工程大肠杆菌质粒为基础的药效团生物合成提供了替代手段的简单和易于扩展的生产有价值的，但难以获得的化合物，但也进行了潜在的提供一个简单而有效的手段，制备天然产物类似物。非核糖体肽的喹霉素家族，包括棘霉素、trtiostin A和SW-163 s，是通过DNA二嵌作用赋予抗生素抗肿瘤活性的重要次级代谢物。以前我们已经证明棘霉素和trtiostin A在E.利用我们的方便和模块化的质粒系统将这些异源生物合成途径引入大肠杆菌中。杆菌然而，我们还没有开发出一种新的生物合成途径，能够产生生物活性的非天然天然产物在E。杆菌在这里，我们报告了一个新的基因簇负责SW-163的生物合成，涉及以前未知的生物合成的（+）-（1 S，2S）-norcoronamic酸和生成的脂肪族侧链的各种大小通过迭代甲基化的非活性碳中心的鉴定。用来自新鉴定的SW-163生物合成基因簇的基因替换棘霉素生物合成基因，我们能够合理地重新设计基于质粒的棘霉素生物合成途径，用于在E.杆菌
Natural products display impressive activities against a wide range of targets, including viruses, microbes and tumors. However, their clinical use is hampered frequently by their scarcity and undesirable toxicity. Not only can engineering Escherichia coli for plasmid-based pharmacophore biosynthesis offer alternative means of simple and easily-scalable production of valuable yet hard-to-obtain compounds, but also carries a potential for providing a straightforward and efficient means of preparing natural product analogs. The quinomycin family of nonribosomal peptides, including echinomycin, trtiostin A and SW-163s, are important secondary metabolites imparting antibiotic antitumor activity via DNA bisintercalation. Previously we have shown the production of echinomycin and trtiostin A in E. coli using our convenient and modular plasmid system to introduce these heterologous biosynthetic pathways into E. coli. However, we have yet to develop a novel biosynthetic pathway capable of producing bioactive unnatural natural products in E. coli. Here we report an identification of a new gene cluster responsible for the biosynthesis of SW-163s that involves previously unknown biosynthesis of (+)-(1S, 2S)-norcoronamic acid and generation of aliphatic side chains of various sizes via iterative methylation of an unactivated carbon center. Substituting an echinomycin biosynthetic gene with a gene from the newly identified SW-163 biosynthetic gene cluster, we were able to rationally re-engineer the plasmid-based echinomycin biosynthetic pathway for the production of a novel bioactive compound in E. coli.
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影响因子：
56.9
作者：
Nougayrede, Jean-Philippe;Homburg, Stefan;Oswald, Eric
通讯作者：
Oswald, Eric
影响因子：
4.9
作者：
Woodyer, Ryan D.;Li, Gongyong;van der Donk, Wilfred A.
通讯作者：
van der Donk, Wilfred A.
影响因子：
64.8
作者：
Trauger, JW;Kohli, RM;Walsh, CT
通讯作者：
Walsh, CT
影响因子：
3.2
作者：
Lomovskaya, N;Hong, SK;Hutchinson, R
通讯作者：
Hutchinson, R
影响因子：
14.8
作者：
Watanabe, Kenji;Hotta, Kinya;Oikawa, Hideaki
通讯作者：
Oikawa, Hideaki