Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kemitorvet, Building 220, 2800 Kgs. Lyngby, Denmark.
Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kemitorvet, Building 220, 2800 Kgs. Lyngby, Denmark; Metabolic and Biomolecular Engineering National Research Laboratory, Department of Chemical and Biomolecular Engineering (BK21 Plus Program), Institute for the BioCentury, Korea Advanced Institute of Science and Technology, 34141 Daejeon, Republic of Korea.
Biotechnol Adv. 2019 Nov 1;37(6):107366. doi: 10.1016/j.biotechadv.2019.03.005. Epub 2019 Mar 7.
Actinomycetes are one of the most valuable sources of natural products with industrial and medicinal importance. After more than half a century of exploitation, it has become increasingly challenging to find novel natural products with useful properties as the same known compounds are often repeatedly re-discovered when using traditional approaches. Modern genome mining approaches have led to the discovery of new biosynthetic gene clusters, thus indicating that actinomycetes still harbor a huge unexploited potential to produce novel natural products. In recent years, innovative synthetic biology and metabolic engineering tools have greatly accelerated the discovery of new natural products and the engineering of actinomycetes. In the first part of this review, we outline the successful application of metabolic engineering to optimize natural product production, focusing on the use of multi-omics data, genome-scale metabolic models, rational approaches to balance precursor pools, and the engineering of regulatory genes and regulatory elements. In the second part, we summarize the recent advances of synthetic biology for actinomycetal metabolic engineering including cluster assembly, cloning and expression, CRISPR/Cas9 technologies, and chassis strain development for natural product overproduction and discovery. Finally, we describe new advances in reprogramming biosynthetic pathways through polyketide synthase and non-ribosomal peptide synthetase engineering. These new developments are expected to revitalize discovery and development of new natural products with medicinal and other industrial applications.
放线菌是具有工业和药用重要性的天然产物最有价值的来源之一。经过半个多世纪的开发，使用传统方法常常会反复发现相同的已知化合物，因此寻找具有有用特性的新型天然产物变得越来越具有挑战性。现代基因组挖掘方法已经发现了新的生物合成基因簇，这表明放线菌仍然具有巨大的未开发潜力，可以产生新型天然产物。近年来，创新的合成生物学和代谢工程工具极大地加速了新型天然产物的发现和放线菌的工程化。在这篇综述的第一部分，我们概述了代谢工程在优化天然产物生产方面的成功应用，重点介绍了多组学数据、基因组规模代谢模型、平衡前体池的合理方法以及调控基因和调控元件的工程化。在第二部分，我们总结了合成生物学在放线菌代谢工程中的最新进展，包括簇组装、克隆和表达、CRISPR/Cas9 技术以及底盘菌株的开发，用于天然产物的过量生产和发现。最后，我们描述了通过聚酮合酶和非核糖体肽合成酶工程重新编程生物合成途径的新进展。这些新的发展有望重振具有药用和其他工业应用的新型天然产物的发现和开发。
