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Cell-free synthetic biology for natural product biosynthesis and discovery.
Literature Information
| DOI | 10.1039/d4cs01198h |
|---|---|
| PMID | 40104998 |
| Journal | Chemical Society reviews |
| Impact Factor | 39.0 |
| JCR Quartile | Q1 |
| Publication Year | 2025 |
| Times Cited | 5 |
| Keywords | Cell-free synthetic biology, Natural products, Biosynthetic pathways, Antimicrobial discovery |
| Literature Type | Journal Article, Review |
| ISSN | 0306-0012 |
| Pages | 4314-4352 |
| Issue | 54(9) |
| Authors | Andrew J Rice, Tien T Sword, Kameshwari Chengan, Douglas A Mitchell, Nigel J Mouncey, Simon J Moore, Constance B Bailey |
TL;DR
This review highlights the potential of cell-free synthetic biology in producing natural products, addressing challenges in isolating these compounds from their native sources and discussing advances in biosynthetic pathways, particularly for ribosomal peptides. By comparing cell-free methods with traditional whole-cell and chemical production, the study underscores the technology's significance in antimicrobial discovery and its growing application in industrial biotechnology.
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Cell-free synthetic biology · Natural products · Biosynthetic pathways · Antimicrobial discovery
Abstract
Natural products have applications as biopharmaceuticals, agrochemicals, and other high-value chemicals. However, there are challenges in isolating natural products from their native producers (e.g. bacteria, fungi, plants). In many cases, synthetic chemistry or heterologous expression must be used to access these important molecules. The biosynthetic machinery to generate these compounds is found within biosynthetic gene clusters, primarily consisting of the enzymes that biosynthesise a range of natural product classes (including, but not limited to ribosomal and nonribosomal peptides, polyketides, and terpenoids). Cell-free synthetic biology has emerged in recent years as a bottom-up technology applied towards both prototyping pathways and producing molecules. Recently, it has been applied to natural products, both to characterise biosynthetic pathways and produce new metabolites. This review discusses the core biochemistry of cell-free synthetic biology applied to metabolite production and critiques its advantages and disadvantages compared to whole cell and/or chemical production routes. Specifically, we review the advances in cell-free biosynthesis of ribosomal peptides, analyse the rapid prototyping of natural product biosynthetic enzymes and pathways, highlight advances in novel antimicrobial discovery, and discuss the rising use of cell-free technologies in industrial biotechnology and synthetic biology.
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Primary Questions Addressed
- What specific advantages does cell-free synthetic biology offer over traditional methods for isolating natural products from native producers?
- How does the application of cell-free synthetic biology enhance the rapid prototyping of biosynthetic pathways for natural products?
- In what ways can cell-free synthetic biology contribute to the discovery of novel antimicrobial compounds compared to whole-cell systems?
- What are the limitations of using cell-free systems for the biosynthesis of complex natural products, and how can these challenges be addressed?
- How might advancements in cell-free synthetic biology impact the future of industrial biotechnology and the production of high-value chemicals?
Key Findings
Research Background and Objectives
Natural products are crucial for the development of biopharmaceuticals, agrochemicals, and other valuable chemicals. However, isolating these compounds from their natural sources poses significant challenges. This review aims to explore the potential of cell-free synthetic biology as a method for synthesizing natural products, characterizing biosynthetic pathways, and producing novel metabolites.
Main Methods/Materials/Experimental Design
The review highlights the core biochemistry involved in cell-free synthetic biology and compares it to traditional methods of natural product synthesis. The main focus is on the biosynthetic gene clusters that encode the enzymes necessary for producing various natural product classes.
Key Steps in Cell-Free Synthetic Biology
Key Results and Findings
- Characterization of Biosynthetic Pathways: The review emphasizes the ability of cell-free systems to rapidly prototype and characterize biosynthetic pathways for natural products.
- Production of New Metabolites: Advances in cell-free synthetic biology have enabled the production of new metabolites, particularly in the realm of ribosomal peptides.
- Antimicrobial Discovery: The application of cell-free technologies has led to significant progress in the discovery of novel antimicrobial agents.
Main Conclusions/Significance/Innovation
The review concludes that cell-free synthetic biology offers a flexible and efficient alternative to traditional methods for natural product synthesis. It allows for the rapid prototyping of biosynthetic pathways and the production of valuable metabolites without the limitations of whole-cell systems. The innovation lies in its potential to streamline the discovery and production processes in biopharmaceutical and industrial applications.
Research Limitations and Future Directions
While the review highlights the advantages of cell-free synthetic biology, it also acknowledges certain limitations:
- Scalability: Current methods may face challenges in scaling up production for industrial applications.
- Cost: The cost of cell-free systems may be higher compared to traditional fermentation methods.
- Complexity of Pathways: Some biosynthetic pathways may still be too complex to be efficiently replicated in a cell-free environment.
Future Directions
- Improving Scalability: Research should focus on optimizing cell-free systems for larger-scale production.
- Cost Reduction: Efforts to reduce the costs associated with cell-free synthetic biology are necessary for wider adoption.
- Expanding Pathway Complexity: Further studies should aim to incorporate more complex biosynthetic pathways into cell-free systems to broaden the range of producible natural products.
Literatures Citing This Work
- Co-cultivation strategies for natural product discovery from actinomycetes: unlocking silent secondary metabolism with mycolic acid-containing bacteria. - Shumpei Asamizu - World journal of microbiology & biotechnology (2025)
- Characterizing and engineering post-translational modifications with high-throughput cell-free expression. - Derek A Wong;Zachary M Shaver;Maria D Cabezas;Martin Daniel-Ivad;Katherine F Warfel;Deepali V Prasanna;Sarah E Sobol;Regina Fernandez;Fernando Tobias;Szymon K Filip;Sophia W Hulbert;Peter Faull;Robert Nicol;Matthew P DeLisa;Emily P Balskus;Ashty S Karim;Michael C Jewett - Nature communications (2025)
- Peptidic Tryptophan Halogenation by a Promiscuous Flavin-Dependent Enzyme. - Andrew J Rice;Mayuresh G Gadgil;Paola Bisignano;Richard A Stein;Hassane S Mchaourab;Douglas A Mitchell - Angewandte Chemie (International ed. in English) (2025)
- Reaction Engineering of In Vitro Natural Product Biosynthesis: Challenges and Strategies. - Elsa Sánchez-García;Stephan Lütz;Markus Nett - Chembiochem : a European journal of chemical biology (2025)
- Protein Engineering of Biosynthetic Enzymes Unlocks Libraries of Bioactive Tilimycin Analogs. - Monica R MacDonald;James Hasselbeck;Andrew M Gulick - ACS catalysis (2025)
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