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Research advances in biosynthesis of natural product drugs within the past decade FENG Jin, PAN Haixue, TANG Gongli Synthetic Biology Journal    2024, 5 (3): 408-446.   DOI: 10.12211/2096-8280.2023-092 Abstract （6861）   HTML （610）    PDF（pc） （9525KB）（4833）       Knowledge map    Save Natural products have long been considered as an important source for potential drugs. In history, natural products and their structural analogs have contributed substantially to the treatment of various diseases, especially cancers and infectious diseases. After a long history of applications, people have gradually begun to explore active ingredients in natural products that truly exert therapeutic effects, and discovered a series of functional compounds, such as morphine, quinine, ephedrine, etc. Over the past two hundred years, the discovery and research of natural products has undergone tremendous changes, from traditional identification and isolation methods to multidisciplinary approaches in the modern genomic era. Strategies for discovering natural products and tools for their prediction have been developed continuously. Although many novel and active natural products have been mined and discovered in the past two decades, considering the huge reserve of natural products in nature, a large number of genes or gene clusters encoding key enzymes for the biosynthesis of natural products have not yet been characterized, and both terrestrial and marine natural product resources are to be explored. Compared with traditional chemically synthesized molecules, natural products possess diverse skeletons for structural complexity, which have shown remarkable advantages in the discovery of new drugs. While there are still many challenges in discovering new drugs from natural products, such as the effective mining of molecules with new structural features, identification and isolation of functional natural products with trace abundance, derivatization of natural product analogs for exploring connections between their structures and activities, and the complete synthesis of complicated active natural products at large scales, etc., the emergence of novel analytical technologies and mining strategies is expected to substantially renovate natural product discovery. This review comments on the natural product drugs and semisynthetic drugs derived from natural products approved by the U.S. Food and Drug Administration within the past decade from January 2014 to October 2023, and provides an overview on the research progress on the biosynthesis of these natural products and their precursors. In addition, important progress in the biosynthesis of some drugs approved by FDA before is also briefly summarized. An in-depth understanding of the biosynthetic pathways and mechanisms underlying their efficacy is expected to provide valuable insights for the discovery and research of more new drugs in the future. Table and Figures | Reference | Related Articles | Metrics

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Biological degradation and utilization of lignin LIU Kuanqing, ZHANG Yi-Heng P.Job Synthetic Biology Journal    2024, 5 (6): 1264-1278.   DOI: 10.12211/2096-8280.2023-062 Abstract （4167）   HTML （296）    PDF（pc） （2325KB）（3215）       Knowledge map    Save Lignin is a major component of lignocellulose, accounting for 15%-30% on a dry weight basis, with an annual yield estimated to be 20 billion tonnes. Lignin is a heterogenous aromatic polymer of phenylpropanoids linked by various C—C and C—O bonds. It is an integral component of the secondary cell wall from terrestrial plants, providing plants with rigidness and fending off microbial pathogens. The abundance and renewability of lignin has recently attracted ample interest in valorizing this readily available polymer. However, the complex nature of lignin presents a significant challenge for lignin breakdown and utilization, and at present the majority of lignin is simply burned as a fuel. Among the different methods, biological utilization of lignin has emerged as a highly attractive approach, since it proceeds under mild conditions and is generally considered environmentally friendly, especially considering that environmental sustainability is trending worldwide. This review comprises three major sections. First, we will summarize key enzymes that nature has created to break down lignin, including laccase, manganese peroxidase, lignin peroxidase, dye-decolorizing peroxidase, and versatile peroxidase etc. Relevant enzymes and their catalytic mechanisms will also be briefly discussed. Second, we will review key reactions in priming and processing lignin derived aromatics before they enter microbial metabolic pathways: O-demethylation, hydroxylation, decarboxylation, and ring opening, as well as representative enzymes involved and their catalytic mechanisms. Finally, we will present engineering efforts toward biological valorization of lignin and lignin derived aromatics, which is largely driven by synthetic biology approaches. Biological valorization of lignin is undoubtedly a field full of potential, however its realization still faces several major hurdles, such as low conversion efficiency and long processing time. Nevertheless, as synthetic biology is developing rapidly, harnessing the power of genetic and metabolic engineering to improve the efficiency of lignin breakdown and utilization, microbial tolerance to toxic aromatics, and redox balance will certainly be a promising path forward, paving the way for industrial application in the near future. Table and Figures | Reference | Related Articles | Metrics

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Research advances on paclitaxel biosynthesis LIU Xiaonan, LI Jing, ZHU Xiaoxi, XU Zishuo, QI Jian, JIANG Huifeng Synthetic Biology Journal    2024, 5 (3): 527-547.   DOI: 10.12211/2096-8280.2023-085 Abstract （3983）   HTML （398）    PDF（pc） （2052KB）（2688）       Knowledge map    Save Paclitaxel (Taxol) is a natural broad-spectrum anticancer drug, which is well-known for its potent anticancer activity. Its production mainly relies on the extraction and purification from the rare Taxus plant, followed by chemical semi-synthesis. The limited natural resource for paclitaxel imposes a significant constraint on its production capacity. In recent years, with the complete decoding of the Taxus genome and the rapid development of synthetic biology, constructing recombinant cells through synthetic biology techniques has emerged as an effective method to address this challenge. Since paclitaxel biosynthesis involves more than 20 steps of complicated enzymatic reactions and about half of them are P450 enzyme-mediated hydroxylation reactions, the complete elucidation of its biosynthetic pathway remains elusive. Meanwhile, the production of paclitaxel by engineered microbes is still at the initial stage, and there are numerous by-products, which seriously compromise the efficient synthesis of paclitaxel. Therefore, this article reviews research progress related to paclitaxel synthesis pathways, Taxus omics analyses, construction of chassis cells, synthesis of key precursors, modifications of crucial enzymes, and catalytic mechanisms underlying paclitaxel biosynthesis. Special attention is given to the recent breakthrough in elucidating the formation of oxetane ring and the discovery of Taxane 1-β- and 9-α-hydroxylases. Recent advances in the study of the catalytic mechanism of Taxadiene-5-α-hydroxylase and significant progress in engineering tobacco and yeast chassis will also be commented. Furthermore, challenges and future prospects involved in the paclitaxel synthetic biology research are discussed, such as the issues of low enzyme catalytic efficiency, significant product promiscuity, unknown specific reaction sequences, and the biosynthesis of critical paclitaxel intermediates, aiming to enhance the understandings of paclitaxel biosynthetic pathways and catalytic mechanisms for greener and more efficient production of paclitaxel. Table and Figures | Reference | Related Articles | Metrics

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Recent research progress in non-canonical biosynthesis of terpenoids CHENG Xiaolei, LIU Tiangang, TAO Hui Synthetic Biology Journal    2024, 5 (5): 1050-1071.   DOI: 10.12211/2096-8280.2024-006 Abstract （3613）   HTML （230）    PDF（pc） （4063KB）（2046）       Knowledge map    Save Terpenoids are a class of natural products with important physiological functions and significant biological activities that are widely found in nature and have a wide range of applications in the food, medical, and daily chemical industries. In the biosynthetic pathway of terpenoids, terpene synthases often determine the type and novelty of the terpene carbon skeleton, and tailoring enzymes, such as cytochrome P450 enzymes, can carry out a variety of post-modifications, ultimately resulting in terpenoids with a rich diversity of structures and functions. In recent years, with the development of genome-sequencing technology and synthetic biology, a large number of terpene biosynthetic enzymes of plant and microbial origin have been characterized, which, excitingly, include non-canonical terpene synthases that can also catalyze the generation of unique cyclized skeletons. Meanwhile, the use of combinatorial biosynthetic strategies has led to the creation of many novel and unnatural terpenoids, further enriching the kingdom of terpenoids. Here, we review the recent advances in non-canonical terpene cyclases and combinatorial biosynthetic pathways over the past five years, with a view to shedding light on the discovery and biosynthesis of novel terpenes in the future. Firstly, the newly discovered novel enzymes with terpene cyclization functions are reviewed, containing a new subclass of type Ⅰ terpene synthases, non-squalene triterpene synthases, UbiA-type terpene cyclases, cytochrome P450 oxygenases, methyltransferases, vanadium-dependent haloperoxidases, and haloacid dehalogenase, along with their sequences, functions, and possible cyclization mechanisms, which can contribute to our understanding of terpenoid biosynthetic enzymes and the discovery of novel terpenoids. This review then describes the combinatorial biosynthesis of non-canonical terpenoids. By combining terpene synthases with methyltransferases or natural/artificial cytochrome P450 oxygenases, a series of unnatural terpenoids containing non-canonical C11 and C16 backbones, or with unusual structural modifications, were produced. This could inspire the structural innovation studies of terpenoids in the future. The discovery of novel enzymes and the construction of novel combinatorial biosynthetic pathways will further broaden the structural diversity and chemical space of terpenoids, which is expected to provide more potential novel terpenoids for clinical drug development. Table and Figures | Reference | Related Articles | Metrics

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Research progress in synthesis of astaxanthin by microbial fermentation ZHOU Qiang, ZHOU Dawei, SUN Jingxiang, WANG Jingnan, JIANG Wankui, ZHANG Wenming, JIANG Yujia, XIN Fengxue, JIANG Min Synthetic Biology Journal    2024, 5 (1): 126-143.   DOI: 10.12211/2096-8280.2023-065 Abstract （3522）   HTML （329）    PDF（pc） （2271KB）（4616）       Knowledge map    Save Astaxanthin is a value-added terpene with strong antioxidant activity as well as other physiological functions, such as anti-cancer, enhancing immunity, eye protection, and cardio-cerebrovascular protection. Natural astaxanthin mainly comes from algae and aquatic crustaceans such as lobster shell. Astaxanthin presents with stereoisomerism and geometric isomerism, which have different biological activities and applications. Currently, astaxanthin in the market is obtained primarily through natural extraction from Haematococcus pluvialis or Xanthophyllomyces dendrorhous and chemical synthesis as well. While H. pluvialis has a long growth cycle and high light demand, leading to low biomass productivity and extraction rate for high production cost of astaxanthin, X. dendrorhous has a low astaxanthin yield and is easy to degenerate, making them challenging for the large-scale commercial production. The chemical synthesis of astaxanthin involves multiple reactions with complicated processes, producing mixed isomers and various byproducts, which consequently compromises its antioxidant capacity. Moreover, the assimilation and utilization of chemically synthesized astaxanthin in vivo is poor compared to its natural product, making it not suitable for being used by human being. With the continuous development of synthetic biology, microbial fermentation has been developed as an effective way for the commercial production of astaxanthin to better meet consumer demand. At present, astaxanthin-producing microorganisms include bacteria, fungi, and algae. This review introduces astaxanthin's structure, properties, production methods, and processes for its extraction and purification, with an emphasis on natural and engineered biosynthetic pathways. The latest progress in the production of astaxanthin by different microorganisms such as H. pluvialis, Yarrowia lipolytica and Escherichia coli is summarized, along with strategies for increasing astaxanthin production through genetic engineering and fermentation process optimization. Future metabolic engineering strategies are proposed, such as over-expression of astaxanthin synthesis genes, promoters with higher substitution intensity, subcellular localization, metabolic pathway optimization, etc, to increase astaxanthin yield for wide usage in food, medical, cosmetic and feed industries. Table and Figures | Reference | Related Articles | Metrics

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Synthetic biology drives the sustainable production of terpenoid fragrances and flavors ZHANG Mengyao, CAI Peng, ZHOU Yongjin Synthetic Biology Journal    2025, 6 (2): 334-356.   DOI: 10.12211/2096-8280.2024-057 Abstract （2978）   HTML （204）    PDF（pc） （3063KB）（2084）       Knowledge map    Save The demand for personal care products has been increasing steadily. Consumers are now seeking for products that offer enhanced functionality, natural ingredients, and superior feeling experiences. Fragrances and flavors are key components in personal care formulations. Terpenes and their derivatives dominate natural fragrances due to their diverse structures and scents, widespread availability from plants and animals, stable function, and high safety profile. The terpene fragrance market is projected to grow at an annual growth rate of 6.4%, reaching $1.01 billion by 2028, indicating a high market revenue and promising future. Currently, the acquisition of natural terpene fragrances is constrained by the long growth cycle of plants, low terpene content, and high extraction cost. Thus, there is an urgent need for developing new technology, such as synthetic biology, to achieve large-scale production of diverse fragrance compounds at an environment-friendly manner. This review explores the application and development of synthetic biology in the sustainable production of terpene fragrances, highlighting how data-driven synthetic biology and biotechnological innovations empower terpene fragrance production. It also compares classical and alternative terpenoid biosynthesis pathways, elucidating their differences and advantages, which can offer comprehensive insights for chassis design toward terpenoid efficient biosynthesis. Additionally, this review explores recent advances in terpene synthase discovery and engineering as well as cell factory construction. Furthermore, we comprehensively summarizes challenges encountered in the construction of three major types of terpene fragrance cell factories: monoterpenes, sesquiterpenes, and nor-isoprenoids, and discusses metabolic engineering strategies that can be employed to address these issues, including enzyme optimization, pathway reconstruction, and cellular detoxification. At the end, we comment the current landscape of patents and industrial competition, offering insights into future challenges and opportunities, including the hurdles of biosynthesis technology, the discovery and design of new products, as well as the market regulation and safety concerns. Table and Figures | Reference | Related Articles | Metrics

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Chemoenzymatic synthesis of natural products: evolution of synthetic methodology and strategy ZHANG Shouqi, WANG Tao, KONG Yao, ZOU Jiasheng, LIU Yuanning, XU Zhengren Synthetic Biology Journal    2024, 5 (5): 913-940.   DOI: 10.12211/2096-8280.2024-028 Abstract （2723）   HTML （156）    PDF（pc） （5090KB）（2618）       Knowledge map    Save Natural product is an important source of small-molecule drugs and probes, but its synthesis is challenging and has attracted lasting attention in the field of organic chemistry. With the continuous advancement of chromatographic techniques for separation and spectroscopic methods for structural analysis, the pace of discovering tiny bioactive natural products is accelerating, concomitantly leading to an increase in the diversity and complexity of the newly identified structures. However, to meet the demand of the quantity for the study of their structure-activity relationships, target identification, in vivo activity evaluation, etc., growing challenges in the requirement for the synthetic efficiency, economy, and scalability of natural products are emerging. Synthetic practices in a chemoenzymatic way have provided multi-dimensional visions for natural product research, which emerged as a hot research topic in recent years. On the one hand, enzymatic catalysis has provided highly efficient and selective synthetic methodologies that would complement traditional synthetic methods. On the other hand, the introduction of enzyme-catalyzed reactions would bring a new mode of strategic design for synthesis, enabling the rapid and diverse synthesis of natural products with high efficiency. In this context, how to integrate the enzyme-catalyzed reactions into the synthesis of natural products is the key to a successful chemoenzymatic synthesis. We herein summarized three roles played by the applications of enzyme-catalyzed reactions in the current practices of chemoenzymatic synthesis of natural products. ①The involvement of biocatalysis would introduce a chiral center or a key functional group into the starting material, or supply complex synthetic precursors (e.g., polysubstituted (hetero)aromatics, chiral pools, etc.) via in vitro enzyme-catalyzed reactions or fermentation, hence advancing the starting line of synthesis; ②Late-stage enzyme-catalyzed chemo-, regio-, and stereoselective modifications of substrates with heavily substituted functional groups or inert positions of complex skeletons; ③The strategic application of enzymatic catalysis as a key carbon-carbon bond-forming step in the construction of the skeleton of natural product. Finally, we have also discussed the current challenges and future trends of the chemoenzymatic synthesis of natural products in three facets, including the design of synthetic strategy, the development of synthetic methods, as well as persons involved in the research. Thus, the integration of interdisciplinary methods and technologies, including chemical synthesis and biocatalysis, would invigorate the synthesis of natural products. Table and Figures | Reference | Related Articles | Metrics

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Genome mining-directed discovery for natural medicinal products XI Mengyu, HU Yiling, GU Yucheng, GE Huiming Synthetic Biology Journal    2024, 5 (3): 447-473.   DOI: 10.12211/2096-8280.2023-086 Abstract （2717）   HTML （264）    PDF（pc） （5166KB）（1958）       Knowledge map    Save Natural products and their derivatives are main sources for lead compounds in drug discovery and development. Canonical natural product discovery relies largely on biological activity-guided or chromatographic identification-oriented screening strategies, which have achieved great success so far. However, the limitations of these methods, such as time consumption, labor intensity, and the noises of abundant natural products, have constrained productivities in discovering novel active natural products for drug development and combating the rising threat of drug resistance. Modern biotechnology, particularly the development of DNA sequencing and computational technology, has made it possible to study the biosynthesis of natural products, enabling us to connect genetic sequences with natural product structures for predicting the potentials of natural products produced by specific biological species at the genetic level. Therefore, genome mining-directed discovery for natural products has emerged. In addition to mining methods dependent on the conservation of genes encoding core enzymes for natural product biosynthesis, recently developed activity-oriented and intelligence-assisted genome mining strategies provide more opportunities for discovering naturally medicinal products. This article reviews the history of genome mining, highlighting advances in related databases, tools, and algorithms, with a focus on recent cases and applications of classic genome mining as well as self-resistance mechanism, evolutionary theory and artificial intelligence guided mining in the discovery of naturally active products. Since genomic information contains enormous chemical potentials, the discovery of natural products with high throughput and efficiency can accelerate the development of new drugs, new chemicals and new catalysts. Table and Figures | Reference | Related Articles | Metrics

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Synthetic biology ushers cosmetic industry into the “bio-cosmetics” era ZHANG Lu’ou, XU Li, HU Xiaoxu, YANG Ying Synthetic Biology Journal    2025, 6 (2): 479-491.   DOI: 10.12211/2096-8280.2024-056 Abstract （2554）   HTML （196）    PDF（pc） （1267KB）（2539）       Knowledge map    Save The field of synthetic biology has been profoundly transformed over the past two decades due to major advances in biotechnology. Notable instances of this seismic shift can be seen in DNA sequencing, where the cost for human whole genome sequencing (WGS) has dropped by ten million-fold in the past 20 years from nearly 3 billion USD in 2003 to less than 300 USD currently. For perspective, in the field of computer technology the effects of “Moore’s Law” has drove computation cost down by a thousand-fold in the past 20 years. Significant advances in technologies underpinning synthetic biology in recent years are transforming many major industries, and one remarkable example of synthetic biology driven transformation is the cosmetics and skincare industry. Historically, changes in skincare have been driven by changes in raw materials: from ancient plant-based concoctions to industrial-era chemicals in the twentieth century, and later to the concept of “cosmeceuticals” emerged in the U.S., integrating pharmaceutical benefits into cosmetics to meet the growing demand for anti-aging skincare products. Today, there’s an increasing demand for more potent cosmetics, alongside a growing voice for environmentally sustainable production. Traditional skincare product development often involves reformulating existing ingredients, which faces limitations in efficacy. Additionally, the reliance on chemical synthesis or natural extraction methods for production poses additional environmental cost due to the use of chemical reagents and significant energy consumption. Rapid advances in biotechnology enables us to overcome such efficacy and environmental limitations through direct synthesis of biomaterials that are safer and more cost-effective than their industrial chemical counterparts. Synthetic biology tools such as AI-assisted protein design and strain engineering are enabling the production of much more potent biomaterials at industrial scales, thus providing more effective and sustainable bioactive ingredients for skincare. For example, previously expensive and hard-to-obtain compounds such as hyaluronic acid, ceramides, and collagen are now produced at a fraction of the cost compared to the previous decade. In recent years, synthesized collagen has shown that it can be designed to be humanized to minimize adverse human immune reactions, thus greatly reducing allergy and other health risks of the end product. The incorporation of biomaterials that were once exclusive to expensive therapeutics into consumer skincare product is rapidly transforming the cosmetics industry by narrowing the gap between medical-grade treatment and consumer-grade anti-aging. This trend marks a significant leap toward more effective, safer, and environmentally sustainable cosmetics products. Ultimately, the advent of synthetic biology-based cosmetics is ushering in the transitioning from traditional industrial chemical-based cosmetics to a new era of “bio-cosmetics”. Table and Figures | Reference | Related Articles | Metrics

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Synthetic genetic circuit engineering: principles, advances and prospects GAO Ge, BIAN Qi, WANG Baojun Synthetic Biology Journal    2025, 6 (1): 45-64.   DOI: 10.12211/2096-8280.2023-096 Abstract （2498）   HTML （237）    PDF（pc） （3184KB）（2471）       Knowledge map    Save Synthetic genetic circuits are engineered gene networks comprised of redesigned genetic parts for interacting to perform customized functions in cells. With the rapid development of synthetic biology, synthetic genetic circuits have shown significant application potentials in many fields such as biomanufacturing, healthcare and environmental monitoring. However, the efforts to scale up genetic circuits are hindered by the limited number of orthogonal parts, the difficulty of functionally composing large-scale circuits, and the poor predictability of circuit behaviors. A longstanding goal of synthetic biology research is to engineer complex synthetic biological circuits, using modular genetic parts, as we do with electronic circuits. Synthetic biologists have developed various genetic toolboxes and functional assembly methods over the past few decades. Here we present an overview of the latest advances, challenges, and future prospects in genetic circuit engineering from four aspects corresponding to the four key engineering principles for circuit design, i.e. orthogonality, standardization, modularity, and automation. Firstly, the design and construction of orthogonal genetic part libraries are discussed in both prokaryotes and eukaryotes at the levels of DNA replication, transcription, and translation, respectively. Standardized characterization methods and the design of modular genetic parts are subsequently summarized. Furthermore, progress in developing modular genetic circuits are presented, providing new concepts and ways for engineering increasingly large and complex circuits. Finally, how to achieve automated design and building of genetic circuits are addressed from the advances in software, hardware and artificial intelligence, respectively, with an aim to replacing the presently time-consuming manual trial-and-error mode with the iterative "design-build-test-learn" cycle for improved efficiency and predictability of circuit design. The integration of these fundamental principles and the latest advances in information technology such as artificial intelligence and lab automation will accelerate the paradigm shift in genetic circuit engineering and synthetic biology research, making it feasible for designing synthetic lives to meet various customized needs. Table and Figures | Reference | Related Articles | Metrics

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Research progress in biosensors based on bacterial two-component systems ZHAO Jingyu, ZHANG Jian, QI Qingsheng, WANG Qian Synthetic Biology Journal    2024, 5 (1): 38-52.   DOI: 10.12211/2096-8280.2023-016 Abstract （2468）   HTML （183）    PDF（pc） （2074KB）（3077）       Knowledge map    Save Two-component systems (TCSs) in bacteria, are capable of sensing and making responses to physical, chemical, and biological stimuli within and outside the cells, and subsequently induce a wide range of cellular processes through the role played by the regulatory component and the response component in combination, which is a ubiquitous signal transduction pathway. At present, an growing number of synthetic biologists have devoted their effort to using the specific and irreplaceable properties of TCSs to design biosensors with the aim of applying in optogenetics, materials science, engineering of gut microbiome, biorefining and soil improvement, and the like. The purpose of this review is to focus on the most recent research advances in the development of biosensors based on TCSs and their potential applications. At the same time, topics of great importance are discussed on how to use novel engineering methods with synthetic biology to improve the reliability and robustness of the performance of the biosensors, such as genetic remodeling, DNA-binding domain swapping, tuning of the detection threshold and isolation of phosphorylation crosstalk as well as on how to customize the signal characteristics of TCSs to meet particular needs according to the requirements of specific applications. It would be possible in the future for scientists to combine these methods with gene synthesis on a large scale and high-throughput screening in order to speed up and give synthetic biologists a hand in the discovery of TCSs with numerous uncharacterized signal inputs and the development of genetically encoded novel biosensors that may be capable of responding to a broad range of stimuli. This allows for extending the applications of the biosensors in different fields. Table and Figures | Reference | Related Articles | Metrics

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Deep genome mining boosts the discovery of microbial terpenoids LEI Ru, TAO Hui, LIU Tiangang Synthetic Biology Journal    2024, 5 (3): 507-526.   DOI: 10.12211/2096-8280.2023-098 Abstract （2375）   HTML （181）    PDF（pc） （3116KB）（1752）       Knowledge map    Save The natural products terpenoids are widely distributed in animals (marine invertebrates), plants, microorganisms, with diverse molecular structures for bioactivities. A large number of terpenoids have been extracted directly from plants and microorganisms. However, traditional methods based on natural screening face challenges in discovering new terpenes due to the increasing number of known compounds at large quantities. The advent of next-generation sequencing and synthetic biology technologies marks the onset of the era of genome mining-driven natural product discovery, particularly in the exploration of new terpenoids. However, challenges persist in this regard, such as low efficiencies, interference of known compounds, and limited data throughput. In this review, we focus on recent advances in terpenoid discovery via microbial genome mining strategies, including the use of the precursor supplying microbial chassis (Escherichia coli, Saccharomyces cerevisiae, Aspergillus oryzae, Streptomyces albus, etc.), the microbial resources from extreme geographical environments, deep genome mining, and terpene mining platforms driven by artificial intelligence and automation techniques. To produce more terpenoids using heterologous hosts, multiple microbial chassis with enhanced precursor supply have been developed to improve their production yields and thus facilitate the discovery of structurally unique terpenoids. With the growing understanding of terpene biosynthesis machinery, the deep mining of terpenoid biosynthetic gene clusters and terpene synthases can effectively address issues related to repeated and irrelevant discoveries. Furthermore, the integration of artificial intelligence and automation platform with synthetic biology has ushered in the high-throughput intelligent discovery of terpenoids, which significantly improves the research and enables the discovery of numerous terpenoids with new structures. Finally, we address challenges and future directions for genome mining based terpenoid discovery. Driven by synthetic biology and artificial intelligence, a new chapter for the discovery of terpenoids and other natural products will open. We are looking forward to seeing more terpenoids to be developed as drugs and valuable chemicals in the future. Table and Figures | Reference | Related Articles | Metrics

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Recent advances in chemoenzymatic synthesis of important steroids ZHENG Mengmeng, LIU Benben, LIN Zhi, QU Xudong Synthetic Biology Journal    2024, 5 (5): 941-959.   DOI: 10.12211/2096-8280.2024-002 Abstract （2317）   HTML （166）    PDF（pc） （3921KB）（1668）       Knowledge map    Save Steroids exhibit a range of biological activities and are commonly described as the ‘key to life’ in nature. Steroidal-based medications have emerged as the second largest pharmaceutical category following antibiotics, owing to their remarkable bioactivities such as anti-infective, anti-inflammatory, anti-allergic, and antitumor properties. This category encompasses more than 400 drug compounds, representing approximately 17% of FDA-approved medications. The synthesis of steroidal products continues to attract significant attention due to their diverse bioactivities and physicochemical characteristics in pharmaceutical applications. With the increasing demand for steroidal drugs and the fluctuating availability of sapogenin resources, the use of Mycobacteria to convert inexpensive phytosterols to produce key intermediates for steroid drugs has been established as the most mature and sustainable industrial route. However, the complex structure of steroids, particularly their highly oxygenated skeleton, poses challenges for the well-established semi-synthesis route of complex steroid medications. Recent strides in bioinformatics and genetics have significantly advanced the studies on synthesis of steroidal compounds. This review highlights recent advancements in the synthesis of high-value steroids, including the diverse steroid drug intermediate production via external steroidal modifying enzymes expression in engineered Mycobacteria, chemo-enzymatic synthesis of complex steroids, and yeast-based de novo synthesis. It specifically highlights the significant achievements in the chemo-enzymatic synthesis, which combines the precise site- and stereoselectivity of enzymatic transformations with the efficiency of chemosynthesis, enabling the concise synthesis of complex steroidal products. Recent advancements in chemoenzymatic strategies, especially those involving P450 hydroxylase, 3-sterone-Δ1-dehydrogenase, reductase, and enzyme cascades, have significantly contributed to the efficient and straightforward synthesis of complex steroid medications. On this basis, the future research opportunities and challenges are also discussed, aiming to provide a reference for the efficient development of more value-added steroid compounds, including the development of new generation steroid intermediates, the discovery of novel steroid biocatalysts, and the establishment of steroid synthesis pathways in mycobacteria. Table and Figures | Reference | Related Articles | Metrics

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The enlightenment of the Chinese philosophy “Tao-Fa-Shu-Qi” to industrial biomanufacturing ZHANG Yi-Heng P. Job Synthetic Biology Journal    2024, 5 (6): 1231-1241.   DOI: 10.12211/2096-8280.2023-066 Abstract （2303）   HTML （275）    PDF（pc） （1617KB）（2438）       Knowledge map    Save Biomanufacturing is a green production that applies such bio-organisms as plants, animals, microorganisms, enzymes as well as in vitro synthetic enzymatic biosystems, to process and/or synthesize numerous value-added compounds, which would change the world′s future of industrial manufacturing in the energy, agricultural, chemical, and pharmaceutical industries. The competition of biomanufacturing is a key part of the battlefield of science and technology. Here we attempt to apply the ancient Chinese philosophy to provide enlightenment to the future development of industrial biomanufacturing. The ancient Chinese philosophy of “Tao-Fa-Shu-Qi” encompasses four key elements: “Tao is a way or direction, Fa is rules, Shu is techniques, and Qi is tools for accomplishing goals”. First, we define and explain the “Tao and Fa” of industrial biomanufacturing analyzes. Second, we analyze the limits and restriction set by Fa. Third, we expound this philosophy of “Tao and Fa” and how it guides way or choice of biomanufacturing type for the desired products. Based on “Tao-Fa-Shu-Qi”, we also present some predictions that a few hot products cannot be manufactured economically by seemingly-promising new techniques based on the limits and restriction of Fa. We take Amyris, a pioneering American company in synthetic biology as an example to analyze and discuss the important roles of “Tao and Fa” in the selection of biomanufactured products, far more important than “Shu and Qi”. Amyris’ failure was destined at its beginning because it went a wrong way (Tao) and ignored basic laws (Fa), although it exhibited advanced abilities of technologies and tools (“Shu and Qi”). Also, we briefly discuss opportunities and challenges of ensuring food security of China by using two disruptive technologies-making synthetic starch from lignocellulosic biomass and carbon dioxide catalyzed by in vitro synthetic enzymatic biosystems. In a word, the ancient Chinese philosophy “the way is simple, from top to down, the way guides techniques and tools” would provide top-level design methodology, identify the future research and development priorities in industrial biomanufacturing, and help effectively solve the major challenges, such as food security, dual carbon goals, and sustainable development. Table and Figures | Reference | Related Articles | Metrics

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Research progress of the CRISPR-Cas system in the detecting pathogen nucleic acids DU Yao, GAO Hongdan, LIU Jiakun, LIU Xiaorong, XING Zhihao, ZHANG Tao, MA Dongli Synthetic Biology Journal    2024, 5 (1): 202-216.   DOI: 10.12211/2096-8280.2022-068 Abstract （2282）   HTML （131）    PDF（pc） （2086KB）（3145）       Knowledge map    Save The CRISPR-Cas system consists of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) proteins, which has become the focus of molecular diagnosis because it recognizes and cleaves specific DNA or RNA sequences. Using Cas proteins (Cas12, Cas13, Cas14, Cas3, etc.) combined with signal amplification and transformation techniques (fluorescence, potentiometric, colorimetric, lateral flow assay, etc.), researchers have developed many diagnostic platforms with high sensitivity, good specificity, and low cost, which provide a new tool for detecting pathogen nucleic acids. This review presents the biological mechanism and classification of the CRISPR-Cas system, and also summarizes existing technologies for detecting pathogenic nucleic acids based on the trans-cleavage activity of Cas proteins, commenting their properties, functions and application scenarios, with future applications prospected based on the functional characteristics of the CRISPR-Cas system, which is expected to become an ideal detection platform for other multiple targets. Table and Figures | Reference | Related Articles | Metrics

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Bacterial inter-PKS hybrids and the biosynthetic algorithm of polyketides ZHANG Rui, JIN Wenzheng, CHEN Yijun Synthetic Biology Journal    2024, 5 (3): 548-560.   DOI: 10.12211/2096-8280.2023-090 Abstract （2257）   HTML （114）    PDF（pc） （2302KB）（1047）       Knowledge map    Save Polyketides are a class of natural products isolated from a wide variety of species. In bacteria, diverse skeletons of polyketides lead to different biological functions, including anti-bacteria, anti-fungi, anti-tumor and immunomodulation. Polyketide synthases (PKSs) are responsible for the biosynthesis of polyketides through successive Claisen condensations of short-chain fatty acids. PKSs are classified into type Ⅰ, type Ⅱ and type Ⅲ, producing different polyketide scaffolds. Bacterial PKSs often hybridize with other biosynthetic enzymes to form PKS hybrids, such as PKS-NRPS or PKS-Ripps, exhibiting more complicated and unique structures. Additionally, different types of PKS can also form inter-PKS hybrids to generate different skeletons. In this review, we summarize recent advances in the structures and biosynthetic mechanisms of bacterial inter-PKS hybrids, including type Ⅰ PKS internal hybrids, type Ⅰ/Ⅱ PKS hybrids and type Ⅰ/Ⅲ PKS hybrids with the following context: (1) In atypical type Ⅰ PKSs, some modules may iteratively catalyze multiple rounds of carbon chain growth, resulting in iterative/non-iterative PKS hybrids; (2) trans-AT PKS and cis-AT PKS can also form PKS hybrids, and the synthesis of kirromycin is a representative example; (3) Type Ⅰ PKSs synthesize unique starter units for type Ⅱ PKSs to produce polyketide scaffolds with the alkyl groups; (4) Type Ⅲ PKSs can condense malonyl-CoA to form different aromatic acids through multiple tailoring steps, and the aromatic acids subsequently act as the starter unit or extender unit into the type Ⅰ PKS assembly line. By elucidating the biosynthetic gene clusters and biosynthetic pathways of inter-PKS hybrids, the reconstructions of inter-PKS hybrids for synthesizing pharmaceutically important analogues are possible. This review also comments the discovery of new inter-PKS hybrids and the engineering of their biosynthetic machineries, to gain more insights into their biosynthetic potential for the production of diverse molecules. By comparing the biosynthetic mechanisms of PKS and discussing the progress of engineering modifications, we prospect a variety of potential inter-PKS hybrid models, highlight the direction for the genome mining of novel polyketides, and provide insights for the engineering modifications of PKS. Through further in-depth and systematic studies on various inter-PKS hybrids in bacteria, it is expected to reveal more natural conundrums, generating a large number of new natural products through adaptive transformation for the research and development of microbial drugs. Table and Figures | Reference | Related Articles | Metrics

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Advances in microbial production of liquid biofuels GUO Shuyuan, ZHANG Qiannan, Gulikezi· MAIMAITIREXIATI, YANG Yiqun, YU Tao Synthetic Biology Journal    2025, 6 (1): 18-44.   DOI: 10.12211/2096-8280.2023-040 Abstract （2035）   HTML （142）    PDF（pc） （1947KB）（1179）       Knowledge map    Save With the socioeconomic development, the dependence of human beings on fossil fuels has led to their shortage and climate change. This has created an urgent need for alternatives that are renewable and environmentally friendly, and biofuels are one of them. Nowadays, widely recognized biofuels like fuel ethanol and biodiesel face challenges in terms of their production capacity due to limitation on raw materials such as grains and edible oils and high cost as well. Hence, the integration of metabolic engineering and synthetic biology has opened avenues for utilizing diverse substrates from other renewable sources, such as solar energy, light energy, electric energy, and waste biomass. Microbial cell factories, including microalgae, bacteria, and yeast, play a crucial role in synthesizing biofuels. The review comments on the evolution of the four generations of biofuels, encompassing fuel ethanol, biodiesel, bio-gasoline, jet and aviation fuels. We also discuss how microorganisms can be explored for producing the third- and fourth-generation biofuels from a variety of unconventional substrates such as carbon dioxide, methanol, and methane, multi-energy coupling to synthesize biofuels from lignocellulose by bacterial or yeast, CO2 conversion by microalgae or electrochemical-biological systems, the conversion of methanol and methane by methyltrophic microbes, and the application of synthetic biology. Furthermore, we overview biosynthetic pathways and engineering strategies for optimizing biofuels production. These strategies can convert raw materials to various fuel products, including fatty acids and esters, advanced alcohols and esters, isoprenoids, and polyketides. Finally, we highlight some challenges in biofuels production, including raw material supply and cost issue, low production yield, and limited product variety. Meanwhile, to address these challenges, we propose corresponding solutions. For example, by optimizing carbon fixation pathways, and converting carbon dioxide into low-carbon substrates like methanol, autotrophic microorganisms, methylotrophic microorganisms, and other cell factories can utilize carbon dioxide as the major raw material to synthesize various biofuels, which can benefit the application of biofuels and further promote their industrial production. Table and Figures | Reference | Related Articles | Metrics

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Design and synthesis of engineered extracellular vesicles and their biomedical applications LIU Duo, LIU Peiyuan, LI Lianyue, WANG Yaxin, CUI Yuhui, XUE Huimin, WANG Hanjie Synthetic Biology Journal    2024, 5 (1): 154-173.   DOI: 10.12211/2096-8280.2023-010 Abstract （2027）   HTML （128）    PDF（pc） （2668KB）（2337）       Knowledge map    Save In recent years, extracellular vesicles have received increasing attention due to their close association with the occurrence and development of diseases. As mechanism underlying the regulation of extracellular vesicles on the development of diseases and other kinds of biological functions has been explored persistently, their utilization as drug carriers has also been tested by scientists for targeted therapy. Extracellular vesicles as drug carriers have several intrinsic advantages compared to artificial carriers, such as higher biocompatibility, lower immunogenicity, better capacity for biofilm fusion, and particular natural homing effect on intracellular communications. However, the biomedical applications of extracellular vesicles also face challenges with their complicated surface modification, poor drug loading capacity and low product yield. Engineered extracellular vesicles refer to the artificial modification of natural extracellular vesicles to particularly fit with target recipient cells or tissues, which can achieve precise delivery of contained functional molecules and support production at a large scale, thus showing a broad prospect for their biomedical applications. Synthetic biology technology can realize the de novo design and reengineering of chassis cells to support the standardized and modular synthesis of extracellular vesicles. This article first reviews the methods and applications of surface modification and functional molecule encapsulation of extracellular vesicles, and then summarizes strategies for their preparation and production, such as extraction, and purification. In the second section, we envision the role of synthetic biology in promoting the customized design and synthesis of engineered extracellular vesicles to further facilitate fine control on attributes, improve efficiency, and expand applications to make them widely used in human health as soon as possible. Table and Figures | Reference | Related Articles | Metrics

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Research progress and biotechnological applications of the prime editing XU Zhimeng, XIE Zhen Synthetic Biology Journal    2024, 5 (1): 1-15.   DOI: 10.12211/2096-8280.2023-038 Abstract （1942）   HTML （158）    PDF（pc） （2307KB）（1568）       Knowledge map    Save Prime Editor (PE) is an innovative gene editing tool based on the Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein (CRISPR/Cas) system, which has revolutionized multiple fields, including genetics, medicine, and agriculture. Emerging as a successor to Base Editor (BE), PE has gained worldwide attention due to its ability to introduce base substitutions, insertions, and deletions without causing double-strand DNA breaks, which significantly reduces the risk of off-target effect and unwanted genetic change. Notwithstanding its immense potential, researchers need to address PE's long encoding sequence and low editing efficiency for its maximal applications. Researchers have been working relentlessly to explore and enhance the editing efficiency and safety of PE by modifying its protein scaffold, optimizing the guide RNA design, and identifying cellular factors that influence its activity. Improved PE variants have been developed with enhanced accuracy and efficiency as well as decreased off-target effect when compared with their initial versions, demonstrating their potential in gene editing-related applications. Several strategies have been investigated to enhance PE performance, including: ① Modifying the structure of PE proteins to increase their efficiency, specificity, and binding affinity, thereby significantly improving their editing activity. ② Optimizing the design of pegRNAs, such as modifying the length, composition, or structure, that can boost PE's editing efficiency. ③ Identifying and manipulating cellular factors, such as proteins and RNAs, that bear functional relationships with the PE system, thus greatly enhancing its gene editing capabilities. ④ Developing automated design tools to facilitate the customization of the PE system for specific applications, vastly improving its practicality in research and clinical settings. Finally, this article summarizes the applications of PE in engineering animals and plants and developing gene therapy. Despite much room for further improvement in PE, significant advances have been made in improving its editing efficiency and safety. The rapid development of Cas9 and BE for treating genetic diseases stands as compelling testimony to the potential of PE in advancing gene editing technologies and applications. With continued research and development, PE holds great promise for improving human health and well-being. Table and Figures | Reference | Related Articles | Metrics

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In vitro BioTransformation (ivBT): a new frontier of industrial biomanufacturing SHI Ting, SONG Zhan, SONG Shiyi, ZHANG Yi-Heng P. Job Synthetic Biology Journal    2024, 5 (6): 1437-1460.   DOI: 10.12211/2096-8280.2024-004 Abstract （1929）   HTML （208）    PDF（pc） （2717KB）（2077）       Knowledge map    Save Huge challenges, such as food security, energy security, climate change, dual-carbon target, and so on, motivate human society to seek disruptive and innovative solutions. In vitro biotransformation (ivBT), bridging the gap between whole-cell-based fermentation and enzyme-based biocatalysis, is an emerging biomanufacturing platform designed for the production of biocommodities (e.g., synthetic starch, healthy sweeteners, organic acids, etc.) and bioenergy. In ivBT, in vitro synthetic enzymatic biosystem (ivSEB) is its high-efficiency biocatalyst. Based on the Chinese philosophy that “Tao is simple”, ivSEB is the in vitro reconstruction of artificial (non-natural) enzymatic pathways with a number of natural enzymes, artificial enzymes, and/or (biomimetic or natural) coenzymes, and/or artificial membrane, without living cell’s constraints, such as cell duplication, bioenergetics, basic metabolisms, regulation, and so on. ivBT enables it to surpass the limitations of whole-cell fermentation and has multiple advantages, such as theoretical product yield, at least 10-time volumetric productivity, tolerance to toxic substrate/product, and so on. This review defines the concept of ivBT, presents its design principles, distinguishes it from other seemingly-like concepts, such as cell-free protein synthesis and cascade enzyme biocatalysis, introduces several representative examples, and discusses its challenges and opportunities. The development of ivBT is based on the linear strategy of “Design-Build-GoNG-Optimization”, leading to super-biomanufacturing machines that can meet national needs, such as food security and new energy system. To address food security, we propose two out-of-the-box solutions: (1) in vitro biotransformation of cellulose to starch, possibly increasing the starch supply by a factor of 10; (2) artificial starch synthesis from CO2 by combining ivBT and chemical catalysis. Furthermore, the revolutionary production of starch could open a door to the starch-based carbohydrate economy, wherein starch is a high-density hydrogen carrier, more than 2.5 times that of compressed hydrogen, and an ultra-high electricity storage compound, more than 10 times of lithium-ion battery. In a word, ivBT featuring ultra-high energy efficiency and potentially-low-cost production could become a third industrial biomanufacturing platform and help solve huge challenges. Table and Figures | Reference | Related Articles | Metrics