合成生物学在医药及能源领域的应用

合成生物学是以工程学思想为指导,对天然生物系统进行重新设计与改造,同时设计并合成新的生物元件、模块和系统的崭新学科。合成生物学是自然科学发展到现阶段的产物,并已经在医药、能源等领域取得了一些显著成果。本文综述了在工程细胞中利用合成生物学方法构建抗疟疾药物青蒿素的前体物青蒿二烯,抗癌药物紫杉醇的前体物紫杉二烯,以及脂肪酸酯、脂肪醇、高级醇的合成途径等研究进展。此外,一些重要的合成生物学相关技术,大大加速工程细胞的重构与进化,为构建应用于生产领域的新功能细胞提供方便实用的工具。     

酶法合成精细化学品与药物

酶促催化合成精细化学品及药物是有机合成在化学领域的一个重大进展,酶法合成在手性化合物、药物、功能生物分子、非天然化合物、精细化学品及其中间体等方面具有明显的优势和应用前景。     

合成生物学在生物基塑料制造中的应用

合成生物学是以工程学思想为指导,对天然生物基因组进行改造和重构,合成新的生物元件,构建新的代谢途径,生产新产品或获得新表型的新兴学科。生物基塑料是以天然物质为原料在微生物作用或化学反应下生成的塑料。利用合成生物学改造工程菌株的方法制备合成生物基塑料已经成为学术界和产业界关注的热点。本文综述了合成生物学的发展和重要的合成生物学技术,重点综述了利用合成生物学技术构建聚羟基烷酸酯、尼龙、聚乳酸和丁二酸丁二醇酯等生物基塑料聚合物单体及其衍生物的代谢途径和工程优化领域的研究进展。     

酿酒酵母细胞表达异源萜类化合物的研究进展

萜类化合物具有可观的经济价值,但是目前的生产过程复杂、产量低。酿酒酵母甲羟戊酸途径为萜类化合物的合成提供直接前体,因此酿酒酵母细胞具有合成异源萜类化合物的天然优势。对酿酒酵母甲羟戊酸途径的清晰认识是对其进行有效利用的基础,本文从代谢途径、关键酶的特点和全局调控机制3个方面对该途径进行了介绍。从代谢途径的构建和优化、模块与底盘细胞的适配、模块构建及组装方式的角度概述了酿酒酵母细胞异源合成单萜、倍半烯萜、二萜、三萜类化合物的研究进展。指出实现酿酒酵母高效合成萜类化合物所需要解决的基础问题是对酿酒酵母甲羟戊酸途径进行更为全面了解和对萜类化合物的天然代谢途径进行明确解析;另外,合成生物学的进一步发展也将为此提供应用基础。     

放线菌聚酮类化合物的合成生物学研究及生物制造

聚酮化合物具有广泛的药用活性和极高的经济价值,但如何高效、经济、绿色、环保地合成聚酮化合物是目前急需解决的问题。随着合成生物学的发展及分子生物学技术的进步,不断有新的技术和策略被用于聚酮化合物的生物制造。本文介绍了聚酮化合物生物制造中的关键酶、前体物质及代谢途径等,分析了通过CRISPR技术及翻译后修饰代谢工程优化代谢调控网络;通过替换及优化启动子等手段改造与优化代谢途径;通过构建简单、高效的异源表达系统等策略提高聚酮化合物的生物制造效率等。在此基础上对红霉素、阿维菌素、多杀菌素的合成生物学研究的最新进展进行了总结,进而对当前聚酮化合物生物制造面临的产量及效率低下等问题和可能的解决途径,如平衡初级代谢与次级代谢,构建新型、优势底盘细胞及代谢网络的重新设计与改造等进行了展望。     

化学品绿色制造核心技术——合成生物学

合成生物学即生物学的工程化,因其打破了非生命化学物质和生命物质之间的界线,推动了生命科学由理解生命到创造生命的革新,因此对科学发展和技术创新起到了颠覆性作用,引发了化学品绿色制造的巨大变革。合成生物学作为化学品绿色制造的核心技术,主要从原料到菌种再到过程进行全链条设计和优化。本文首先从原料多样化、产品的合成与底盘细胞的选择这三个方面,综述了化学品绿色制造过程中合成生物学所起到的关键核心作用。在此基础上系统阐述了人工体系的设计与构建,并对今后如何通过发展合成生物学来促进化学品绿色制造,从“原料、底盘细胞、反应过程”这三个方面提出了相应的展望。     

工程化酿酒酵母合成植物三萜类化合物

三萜类化合物如甘草次酸、皂苷等是许多药物在细胞内发挥药理活性的主要存在形式,可作为药物的主要活性成分,有些还可作为甜味剂等。但是萜类化合物在天然植株中含量很低,不能很好地对其开发和利用。随着萜类物质代谢中关键酶的发现,整个萜类代谢途径变得清晰。近年来合成生物学快速发展,为利用微生物发酵生产三萜化合物奠定了基础。综述了酿酒酵母中三萜化合物的合成途径及在此途径中起重要作用的细胞色素单氧化酶的研究进展。     

甲基营养型大肠杆菌构建策略的研究进展

利用微生物细胞工厂实现原料转化和产品合成是绿色生物制造的核心。然而,当前生物制造仍以富含糖类的谷物粮食为主要原料,存在“与民争粮”的争议,亟需开发非粮原料。甲醇作为煤化工产业中的重要产品,具有来源广、价格低、还原性强等优势,有替代粮食原料的潜力。天然甲基营养菌可利用甲醇生产单细胞蛋白和各种氨基酸,但存在理论收率低、遗传改造工具不足等缺点。随着合成生物学的发展,以大肠杆菌等模式生物作为底盘细胞构建人工甲基营养菌,实现甲醇到各种化学品的生产已成为研究热点。本文总结了多种甲基营养型大肠杆菌的构建策略,明确了影响天然路径代谢的关键因素与代谢过程中的重要中间产物,概括了各种天然路径在大肠杆菌中的优化策略与人工新路径的构建方法,并对工程菌株的优化提出了展望。     

左旋薄荷醇合成技术的进展

薄荷醇是一种用途很广的环状单萜烯醇 ,其合成原料有天然旋光性化合物和非旋光的石油化学品。讨论了薄荷醇的几种合成方法 ,提出了利用异戊二烯为原料合成薄荷醇是今后生产薄荷醇的主要路线     

酿酒酵母高效合成萜类化合物的组合调控策略

萜类化合物具有广泛的生理活性与重要的经济价值,利用酿酒酵母进行萜类合成具有低价、高效等优势。然而部分植物源合成萜类的关键酶在酿酒酵母中难表达、产量低,难以工业应用,因此有效的调控策略显得至关重要。本文从萜类化合物在酿酒酵母中的合成途径入手,介绍了关键酶、代谢途径、CRISPR基因编辑系统和人工合成染色体技术4个方面的调控策略在酿酒酵母合成萜类化合物中的应用。阐述了关键酶的筛选、改造,理性与非理性设计,MVA途径、乙酰辅酶A合成途径与亚细胞结构的代谢途径改造的优势。指出了多重调控策略组合调控的方式是实现酿酒酵母高效合成萜类化合物的有效方法。此外,CRISPR基因编辑系统与人工合成染色体技术的快速发展将为酿酒酵母细胞工厂的深入开发与利用提供有力工具。     

如何工程化生物学

随着化学学科的发展和应用需求,化学工程应运而生;随着生物学的发展和工程化需求,代表着“生物学第三次革命”的合成生物学也随之诞生。合成生物学,即生物学的工程化,它从工程学角度设计创建元件、器件或模块,以及通过这些元器件改造和优化现有自然生物体系,但是如何对复杂生命进行工程化一直是合成生物学工作者不断探索的重大科学问题。本文系统地阐释了迄今为止工程化生物学的4个特点:①模块化和标准化;②正交性;③鲁棒性;④适配性及其对应研究进展。最后从“设计-构建-测试”循环的研究模式入手提出了今后如何进一步有效地工程化生物学。     

人工合成微生物混菌体系的研究进展

合成生物学正在从设计构建基本功能元件和模块,逐步向着从头设计人工细胞及构建人工生物群落的方向发展,人工合成微生物混菌体系已经成为未来合成生物学研究的重要方向。本文综述了人工构建微生物群落生态关系、群落时空动态和分布式计算等基础研究的进展。同时,微生物混菌体系在医药、环境、能源等领域发挥着不可替代的作用,人工合成混菌体系在相关领域也表现出巨大的应用潜力。     

Application of synthetic biology in manufacture of bio-based plastics

Synthetic biology is a new discipline that uses engineering ideas as a guide to transform and reconstruct natural biological genomes, synthesize new biological components, construct new metabolic routes, and produce novel products or obtain new phenotypes. Bio-based plastics are plastics produced under the action of microorganisms or the chemical reactions using natural materials as raw materials. The usage of synthetic biology to construct engineered strains to produce bio-based plastics has become a hot topic in academia and industry. This paper reviews the development of synthetic biology and important techniques in the field of synthetic biology, focusing on the research progress in the field of metabolic pathways and engineering optimization for the construction of bio-based plastic polymer monomers and derivatives such as polyhydroxyalkanoate, nylon, polylactic acid, and butylene glycol succinate using synthetic biological techniques.     

Nature Inspired Small Molecules for Chemical Biology

Chemical biology and drug discovery are instrumental sciences to address unmet medical needs and to gain a deeper understanding of normal and disease state biology in mammalian systems. Unlike most genetic tools, the small molecule modulation of biology is reversible, controllable in space, time and quantity, avoids the removal of gene products from cellular systems and thus enables perturbation of biology in its native state. Natural products, their derivatives as well as small molecules based on the core‐scaffolds of natural products including natural product fragments allow targeting unique, biologically relevant fractions of chemical space that may deliver quality tool compounds. In this essay, we discuss various synthesis approaches inspired by natural products to deliver biologically active small molecules. We argue and provide evidence that inspiration by natural product structure remains a powerful guiding principle for the development of novel approaches to the study biology by means of novel bioactive small molecules.     

Bioorthogonal chemistry: applications in activity-based protein profiling

The close interaction between organic chemistry and biology goes back to the late 18th century, when the modern natural sciences began to take shape. After synthetic organic chemistry arose as a discipline, organic chemists almost immediately began to pursue the synthesis of naturally occurring compounds, thereby contributing to the understanding of their functions in biological processes. Research in those days was often remarkably interdisciplinary; in fact, it constituted chemical biology research before the phrase even existed. For example, histological dyes, both of an organic and inorganic nature, were developed and applied by independent researchers (Gram and Golgi) with the aim of visualizing cellular substructures (the bacterial cell wall and the Golgi apparatus). Over the years, as knowledge within the various fields of the natural sciences deepened, research disciplines drifted apart, becoming rather monodisciplinary. In these years, broadly ranging from the end of World War II to about the 1980s, organic chemistry continued to impact life sciences research, but contributions were of a more indirect nature. As an example, the development of the polymerase chain reaction, from which molecular biology and genetics research have greatly profited, was partly predicated on the availability of synthetic oligonucleotides. These molecules first became available in the late 1960s, the result of organic chemists pursuing the synthesis of DNA oligomers primarily because of the synthetic challenges involved. Today, academic natural sciences research is again becoming more interdisciplinary, and sometimes even multidisciplinary. What was termed "chemical biology" by Stuart Schreiber at the end of the last century can be roughly described as the use of intellectually chemical approaches to shed light on processes that are fundamentally rooted in biology. Chemical tools and techniques that are developed for biological studies in the exciting and rapidly evolving field of chemical biology research include contributions from many areas of the multifaceted discipline of chemistry, and particularly from organic chemistry. Researchers apply knowledge inherent to organic chemistry, such as reactivity and selectivity, to the manipulation of specific biomolecules in biological samples (cell extracts, living cells, and sometimes even animal models) to gain insight into the biological phenomena in which these molecules participate. In this Account, we highlight some of the recent developments in chemical biology research driven by organic chemistry, with a focus on bioorthogonal chemistry in relation to activity-based protein profiling. The rigorous demands of bioorthogonality have not yet been realized in a truly bioorthogonal reagent pair, but remarkable progress has afforded a range of tangible contributions to chemical biology research. Activity-based protein profiling, which aims to obtain information on the workings of a protein (or protein family) within the larger context of the full biological system, has in particular benefited from these advances. Both activity-based protein profiling and bioorthogonal chemistry have been around for approximately 15 years, and about 8 years ago the two fields very profitably intersected. We expect that each discipline, both separately and in concert, will continue to make important contributions to chemical biology research.     

Smart Design of Small-Molecule Libraries: When Organic Synthesis Meets Cheminformatics

Synthetic chemists are always looking for new methods to maximize the diversity and complexity of small-molecule libraries. Diversity-oriented synthesis can give access to new chemotypes with high chemical diversity, exploiting complexity-generating reactions and divergent approaches. However, there is a need for new tools to drive synthetic efforts towards unexplored and biologically relevant regions of chemical space. Because the number of publicly accessible biological data will increase in the years to come, cheminformatics can represent a real opportunity to develop better chemical libraries. This minireview focuses on novel cheminformatics approaches used to design molecular scaffolds, as well as to analyze their quality, giving a perspective of them in the field of chemical biology and drug discovery through some selected case studies.     

Current State-of-the-Art Toward Chemoenzymatic Synthesis of Polyketide Natural Products

Polyketide natural products have significant promise as pharmaceutical targets for human health and as molecular tools to probe disease and complex biological systems. While the biosynthetic logic of polyketide synthases (PKS) is well-understood, biosynthesis of designer polyketides remains challenging due to several bottlenecks, including substrate specificity constraints, disrupted protein-protein interactions, and protein solubility and folding issues. Focusing on substrate specificity, PKSs are typically interrogated using synthetic thioesters. PKS assembly lines and their products offer a wealth of information when studied in a chemoenzymatic fashion. This review provides an overview of the past two decades of polyketide chemoenzymatic synthesis and their contributions to the field of chemical biology. These synthetic strategies have successfully yielded natural product derivatives while providing critical insights into enzymatic promiscuity and mechanistic activity.