期刊
METABOLIC ENGINEERING
卷 42, 期 -, 页码 185-193出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymben.2017.06.012
关键词
Transient plant expression technology; Synthetic biology; Terpenes; Triterpenoids; Combinatorial biosynthesis; Drug discovery
资金
- Norwich Research Park Studentship
- joint Engineering and Physical Sciences Research Council/ Biotechnological and Biological Sciences Research Council (BBSRC) [BB/ L014130/1]
- European Union [KBBE-2013-7]
- John Innes Centre Knowledge Exchange and Commercialization grant [BB/KEC1740/1]
- BBSRC Institute Strategic Programme Grant 'Understanding and Exploiting Plant and Microbial Metabolism' [BB/J004561/1]
- John Innes Foundation
- European Research Council under European Union (ERC) [614779]
- Biotechnology and Biological Sciences Research Council [BBS/E/J/000PR9790, BBS/E/J/00000614, BBS/E/J/000PR9794, BB/M028860/1, BBS/E/J/000CA533, BB/M028712/1, BB/L014130/1] Funding Source: researchfish
- BBSRC [BB/M028860/1, BBS/E/J/000CA533, BBS/E/J/000PR9794, BB/M028712/1, BB/L014130/1, BBS/E/J/000PR9790] Funding Source: UKRI
- European Research Council (ERC) [614779] Funding Source: European Research Council (ERC)
Plants are an excellent source of drug leads. However availability is limited by access to source species, low abundance and recalcitrance to chemical synthesis. Although plant genomics is yielding a wealth of genes for natural product biosynthesis, the translation of this genetic information into small molecules for evaluation as drug leads represents a major bottleneck. For example, the yeast platform for artemisinic acid production is estimated to have taken>150 person years to develop. Here we demonstrate the power of plant transient transfection technology for rapid, scalable biosynthesis and isolation of triterpenes, one of the largest and most structurally diverse families of plant natural products. Using pathway engineering and improved agro-infiltration methodology we are able to generate gram-scale quantities of purified triterpene in just a few weeks. In contrast to heterologous expression in microbes, this system does not depend on re-engineering of the host. We next exploit agro-infection for quick and easy combinatorial biosynthesis without the need for generation of multi-gene constructs, so affording an easy entree to suites of molecules, some new-to-nature, that are recalcitrant to chemical synthesis. We use this platform to purify a suite of bespoke triterpene analogs and demonstrate differences in anti-proliferative and anti-inflammatory activity in bioassays, providing proof of concept of this system for accessing and evaluating medicinally important bioactives. Together with new genome mining algorithms for plant pathway discovery and advances in plant synthetic biology, this advance provides new routes to synthesize and access previously inaccessible natural products and analogs and has the potential to reinvigorate drug discovery pipelines.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据