合成生物学与天然产物开发

天然产物依然是临床用药的重要来源。合成生物学的诞生为天然产物的开发提供了全新的机遇,传统的微生物药物、植物天然产物等研究领域都因合成生物学而获得新生。重点介绍了合成生物学在天然产物开发中的应用,包括新化合物及其生物合成元件的筛选,基于理性设计的天然产物异源生物合成,人工底盘细胞的系统优化等。     

天然产物类药物的合成生物学研究

结构复杂多样的天然产物是现代药物的重要组成部分和新药发现的重要源泉。建立在基因工程及代谢工程、合成化学、基因组学、系统生物学等学科基础上的合成生物学研究对于结构复杂的天然产物类药物研究有特殊的意义。核心是通过在发酵友好、高效的微生物中设计、构建目标化合物的生物合成途径,经系统地调控和优化由重组微生物发酵生产来源稀缺的天然产物类药物或前体。该方法是不远的将来解决来源、成本与环境、资源协调问题最好的途径之一,也是解决海洋天然产物或特殊生境微生物药物面临的如何持续供应化合物这一个瓶颈问题的最佳选择。该文将对天然产物类药物合成生物学研究涉及的主要策略和重要进展进行阐述。     

植物来源药用天然产物的合成生物学研究进展

大多数药用天然产物在植物中含量低微,提取分离困难;而且这些化合物一般结构复杂,化学合成难度大,还容易造成环境污染.基于合成生物学技术获得药用天然产物具有绿色环保和可持续发展等优点.文中以药用萜类化合物人参皂苷、紫杉醇、青蒿素、丹参酮,生物碱类化合物长春新碱、吗啡以及黄酮类化合物灯盏花素为例,总结了植物来源药用萜类、生物...     

芳香类天然产物的合成生物学研究进展

植物芳香类天然产物具有重要的药用价值,可制成具有抗菌、抗炎、镇痛、抗氧化、杀虫驱虫、祛痰止咳、安神镇静和抗肿瘤等药效的医药保健用品.然而,由于植物中芳香类天然产物含量较低并且难以提取和纯化,严重限制了其工业化生产及应用.合成生物学和代谢工程技术的发展为天然产物的生产提供了新的思路,可以利用人工微生物细胞工厂来实现多种芳...     

Synthetic biology: lessons from engineering yeast MAPK signalling pathways

All living cells respond to external stimuli and execute specific physiological responses through signal transduction pathways. Understanding the mechanisms controlling signalling pathways is important for diagnosing and treating diseases and for reprogramming cells with desired functions. Although many of the signalling components in the budding yeast Saccharomyces cerevisiae have been identified by genetic studies, many features concerning the dynamic control of pathway activity, cross‐talk, cell‐to‐cell variability or robustness against perturbation are still incompletely understood. Comparing the behaviour of engineered and natural signalling pathways offers insight complementary to that achievable with standard genetic and molecular studies. Here, we review studies that aim at a deeper understanding of signalling design principles and generation of novel signalling properties by engineering the yeast mitogen‐activated protein kinase (MAPK) pathways. The underlying approaches can be applied to other organisms including mammalian cells and offer opportunities for building synthetic pathways and functionalities useful in medicine and biotechnology.     

Synthetic biology for natural product drug production and engineering

Natural products continue to provide privileged scaffolds for drug discovery. However, challenges in supply and structure diversification can limit development. Here, we discuss recent (2017–2020) examples of synthetic biology approaches used to address challenges in supply and contribute to structure diversification of selected plant and bacterial natural products. Our examples include plant terpenoids, alkaloids, and lignans and bacterial polyketides, nonribosomal peptides, and ribosomally synthesized and posttranslationally modified peptides.     

Synthetic medicinal chemistry of selected antimalarial natural products

Natural products remain a rich source of novel molecular scaffolds for novel antimalarial agents in the fight against malaria. This has been well demonstrated in the case of quinine and artemisinin both of which have served as templates for the development of structurally simpler analogues that either served or continue to serve as effective antimalarials. This review will expound on these two natural products as well as other selected natural products that have served either as antimalarial agents or as potential lead compounds in the development of antimalarial drugs.     

Synthetic studies on breviones and structurally related natural products

Breviones, allelopathic agents that have been isolated from Penicillium sp., are structurally unique diterpenoid derivatives. Breviones have attracted attention due to their bioactivity, because their allelopathic activities may offer agricultural use as environmentally benign herbicides. On the other hand, their structural uniqueness is also remarkable, and construction of their unique structure is a challenge from the viewpoint of organic synthesis. This review summarizes synthetic studies on breviones and structurally related natural products.     

Synthetic biology

Synthetic biologists come in two broad classes. One uses unnatural molecules to reproduce emergent behaviours from natural biology, with the goal of creating artificial life. The other seeks interchangeable parts from natural biology to assemble into systems that function unnaturally. Either way, a synthetic goal forces scientists to cross uncharted ground to encounter and solve problems that are not easily encountered through analysis. This drives the emergence of new paradigms in ways that analysis cannot easily do. Synthetic biology has generated diagnostic tools that improve the care of patients with infectious diseases, as well as devices that oscillate, creep and play tic-tac-toe.     

合成生物学

近年来用化学合成的手段合成生物物质的研究进展很快。有感染活力的小儿麻痹症病毒RNA与φX-174噬菌体基因先后合成成功。估计2006年可能会有能合成1百万bp DNA的仪器问世。此外,目前已能向蛋白质中引入80种非常见氨基酸,从而使蛋白质获得新的性质。化学合成的进展使合成与改造生命成为现实,这对研究生物学基本规律有很大的意义,但这也是一把“双刃剑”,带来伦理与反恐的问题及对可能的潜在威胁的担忧。2004年6月在美国麻省理工学院举行了第一届合成生物学国际会议。2005年8月在美国旧金山举行的合成生物学会议,讨论了生物合成这个领域对药物发展、细胞重编程、生物机器人等方面的潜在意义。     

Synthetic biology and metabolic engineering of actinomycetes for natural product discovery

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.     

Synthetic cell biology

Synthesis of data into formal models of cellular function is rapidly becoming a necessary industry. The complexity of the interactions among cellular constituents and the quantity of data about these interactions hinders the ability to predict how cells will respond to perturbation and how they can be engineered for industrial or medical purposes. Models provide a systematic framework to describe and analyze these complex systems. In the past few years, models have begun to have an impact on mainstream biology by creating deeper insight into the design rules of cellular signal processing, providing a basis for rational engineering of cells, and for resolving debates about the root causes of certain cellular behaviors. This review covers some of the recent work and challenges in developing these "synthetic cell" models and their growing practical applications.     

Synthetic biology evolves

Synthetic biology is advancing rapidly as biologists, physicists and engineers are combining their efforts to understand and program cell function. By characterizing isolated genetic components or modules, experimentalists have paved the way for more quantitative analyses of genetic networks. A recent paper presents a method of computational, or in silico, evolution in which a set of components can evolve into networks that display desired behaviors. An integrated approach that includes a strategy of in silico design by evolution, together with efforts exploiting directed evolution in vivo, is likely to be the next step in the evolution of synthetic biology.     

Genomics-enabled discovery of phosphonate natural products and their biosynthetic pathways

Phosphonate natural products have proven to be a rich source of useful pharmaceutical, agricultural, and biotechnology products, whereas study of their biosynthetic pathways has revealed numerous intriguing enzymes that catalyze unprecedented biochemistry. Here we review the history of phosphonate natural product discovery, highlighting technological advances that have played a key role in the recent advances in their discovery. Central to these developments has been the application of genomics, which allowed discovery and development of a global phosphonate metabolic framework to guide research efforts. This framework suggests that the future of phosphonate natural products remains bright, with many new compounds and pathways yet to be discovered.     

Synthetic biology enabling access to designer polyketides

The full potential of polyketide discovery has yet to be reached owing to a lack of suitable technologies and knowledge required to advance engineering of polyketide biosynthesis. Recent investigations on the discovery, enhancement, and non-natural use of these biosynthetic gene clusters via computational biology, metabolic engineering, structural biology, and enzymology-guided approaches have facilitated improved access to designer polyketides. Here, we discuss recent successes in gene cluster discovery, host strain engineering, precursor-directed biosynthesis, combinatorial biosynthesis, polyketide tailoring, and high-throughput synthetic biology, as well as challenges and outlooks for rapidly generating useful target polyketides.