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首页> 外文期刊>Journal of the American Chemical Society >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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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

机译：大肠杆菌允许将新分离的Quinomycin生物合成酶有效地模块化整合到Echinomycin生物合成途径中，以有效设计和合成有效的抗生素非天然天然产物

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摘要

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, triostin A, and SW-163s, are important secondary metabolites imparting antibiotic antitumor activity via DNA bisintercalation. Previously we have shown the production of echinomycin and triostin 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.
机译：天然产品针对多种目标（包括病毒，微生物和肿瘤）表现出令人印象深刻的活动。然而，它们的缺乏和不希望的毒性经常阻碍了它们的临床使用。为基于质粒的药效团生物合成而进行工程改造的大肠杆菌不仅可以提供简便且可扩展地生产有价值但难以获得的化合物的替代方法，而且还具有提供直接而有效的方法来制备天然产物类似物的潜力。非核糖体肽的奎诺霉素家族，包括棘霉素，曲霉菌素A和SW-163s，是重要的次级代谢产物，可通过DNA双嵌入作用赋予抗生素抗肿瘤活性。以前，我们已经显示了使用我们方便的模块化质粒系统将这些异源生物合成途径引入到大肠杆菌中，在大肠杆菌中生产棘霉素和曲霉素A的情况。但是，我们尚未开发出能够在大肠杆菌中产生具有生物活性的非天然天然产物的新型生物合成途径。在这里，我们报告鉴定一个新的基因簇，负责SW-163s的生物合成，其中涉及以前未知的（+）-（1S，2S）-降糖醛酸的生物合成，以及通过对甲基纤维素的反复甲基化生成各种尺寸的脂肪族侧链未激活的碳中心。用新鉴定的SW-163生物合成基因簇中的基因替代棘霉素生物合成基因，我们能够合理地改造基于质粒的棘霉素生物合成途径，以在大肠杆菌中生产新型生物活性化合物。

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  • 来源
    《Journal of the American Chemical Society》 |2009年第26期|9347-9353|共7页
  • 作者

    Kenji Watanabe; Kinya Hotta; Mino Nakaya; Alex P. Praseuth; Clay C. C. Wang; Daiki lnada; Kosaku Takahashi; Eri Fukushi; Hiroki Oguri; Hideaki Oikawa;

  • 作者单位

    Research Core for Interdisciplinary Sciences, Okayama University, Okayama 700-8530, Japan;

    Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore;

    Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan;

    BioPharmaceuticals Formulation Development, Allergan, Inc., 2525 Dupont Drive, Irvine, California 92612;

    Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, California 90033;

    Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan;

    Division of Applied Bioscience, Graduate School of Agriculture, Hokkaido University, Sapporo 060-8589, Japan;

    The Analytical Core facility of NMR and Mass spectrometry, School of Agriculture, Hokkaido University, Sapporo 060-8589, Japan;

    Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore Creative Research Initiative 'Sousei' (CRIS), Hokkaido University, Sapporo 001-0021, Japan;

    Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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