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1
Nielsen, Jens, and Jack T. Pronk. "Metabolic engineering, synthetic biology and systems biology." FEMS Yeast Research 12, no. 2 (January 4, 2012): 103. http://dx.doi.org/10.1111/j.1567-1364.2011.00783.x.
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He, Fei, Ettore Murabito, and Hans V. Westerhoff. "Synthetic biology and regulatory networks: where metabolic systems biology meets control engineering." Journal of The Royal Society Interface 13, no. 117 (April 2016): 20151046. http://dx.doi.org/10.1098/rsif.2015.1046.
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Metabolic pathways can be engineered to maximize the synthesis of various products of interest. With the advent of computational systems biology, this endeavour is usually carried out through in silico theoretical studies with the aim to guide and complement further in vitro and in vivo experimental efforts. Clearly, what counts is the result in vivo , not only in terms of maximal productivity but also robustness against environmental perturbations. Engineering an organism towards an increased production flux, however, often compromises that robustness. In this contribution, we review and investigate how various analytical approaches used in metabolic engineering and synthetic biology are related to concepts developed by systems and control engineering. While trade-offs between production optimality and cellular robustness have already been studied diagnostically and statically, the dynamics also matter. Integration of the dynamic design aspects of control engineering with the more diagnostic aspects of metabolic, hierarchical control and regulation analysis is leading to the new, conceptual and operational framework required for the design of robust and productive dynamic pathways.
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Choi, Kyeong Rok, Woo Dae Jang, Dongsoo Yang, Jae Sung Cho, Dahyeon Park, and Sang Yup Lee. "Systems Metabolic Engineering Strategies: Integrating Systems and Synthetic Biology with Metabolic Engineering." Trends in Biotechnology 37, no. 8 (August 2019): 817–37. http://dx.doi.org/10.1016/j.tibtech.2019.01.003.
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Lee, Hyang-Mi, Phuong Vo, and Dokyun Na. "Advancement of Metabolic Engineering Assisted by Synthetic Biology." Catalysts 8, no. 12 (December 4, 2018): 619. http://dx.doi.org/10.3390/catal8120619.
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Synthetic biology has undergone dramatic advancements for over a decade, during which it has expanded our understanding on the systems of life and opened new avenues for microbial engineering. Many biotechnological and computational methods have been developed for the construction of synthetic systems. Achievements in synthetic biology have been widely adopted in metabolic engineering, a field aimed at engineering micro-organisms to produce substances of interest. However, the engineering of metabolic systems requires dynamic redistribution of cellular resources, the creation of novel metabolic pathways, and optimal regulation of the pathways to achieve higher production titers. Thus, the design principles and tools developed in synthetic biology have been employed to create novel and flexible metabolic pathways and to optimize metabolic fluxes to increase the cells’ capability to act as production factories. In this review, we introduce synthetic biology tools and their applications to microbial cell factory constructions.
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Fong, Stephen S. "Computational approaches to metabolic engineering utilizing systems biology and synthetic biology." Computational and Structural Biotechnology Journal 11, no. 18 (August 2014): 28–34. http://dx.doi.org/10.1016/j.csbj.2014.08.005.
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King, Jason R., Steven Edgar, Kangjian Qiao, and Gregory Stephanopoulos. "Accessing Nature’s diversity through metabolic engineering and synthetic biology." F1000Research 5 (March 24, 2016): 397. http://dx.doi.org/10.12688/f1000research.7311.1.
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In this perspective, we highlight recent examples and trends in metabolic engineering and synthetic biology that demonstrate the synthetic potential of enzyme and pathway engineering for natural product discovery. In doing so, we introduce natural paradigms of secondary metabolism whereby simple carbon substrates are combined into complex molecules through “scaffold diversification”, and subsequent “derivatization” of these scaffolds is used to synthesize distinct complex natural products. We provide examples in which modern pathway engineering efforts including combinatorial biosynthesis and biological retrosynthesis can be coupled to directed enzyme evolution and rational enzyme engineering to allow access to the “privileged” chemical space of natural products in industry-proven microbes. Finally, we forecast the potential to produce natural product-like discovery platforms in biological systems that are amenable to single-step discovery, validation, and synthesis for streamlined discovery and production of biologically active agents.
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Chen, Bor-Sen, and Chia-Chou Wu. "Systems Biology as an Integrated Platform for Bioinformatics, Systems Synthetic Biology, and Systems Metabolic Engineering." Cells 2, no. 4 (October 11, 2013): 635–88. http://dx.doi.org/10.3390/cells2040635.
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McArthur, George H., and Stephen S. Fong. "Toward Engineering Synthetic Microbial Metabolism." Journal of Biomedicine and Biotechnology 2010 (2010): 1–10. http://dx.doi.org/10.1155/2010/459760.
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The generation of well-characterized parts and the formulation of biological design principles in synthetic biology are laying the foundation for more complex and advanced microbial metabolic engineering. Improvements inde novoDNA synthesis and codon-optimization alone are already contributing to the manufacturing of pathway enzymes with improved or novel function. Further development of analytical and computer-aided design tools should accelerate the forward engineering of precisely regulated synthetic pathways by providing a standard framework for the predictable design of biological systems from well-characterized parts. In this review we discuss the current state of synthetic biology within a four-stage framework (design, modeling, synthesis, analysis) and highlight areas requiring further advancement to facilitate true engineering of synthetic microbial metabolism.
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Ma, Jingbo, Yang Gu, Monireh Marsafari, and Peng Xu. "Synthetic biology, systems biology, and metabolic engineering of Yarrowia lipolytica toward a sustainable biorefinery platform." Journal of Industrial Microbiology & Biotechnology 47, no. 9-10 (July 4, 2020): 845–62. http://dx.doi.org/10.1007/s10295-020-02290-8.
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Jeong, Yujin, Sang-Hyeok Cho, Hookeun Lee, Hyung-Kyoon Choi, Dong-Myung Kim, Choul-Gyun Lee, Suhyung Cho, and Byung-Kwan Cho. "Current Status and Future Strategies to Increase Secondary Metabolite Production from Cyanobacteria." Microorganisms 8, no. 12 (November 24, 2020): 1849. http://dx.doi.org/10.3390/microorganisms8121849.
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Cyanobacteria, given their ability to produce various secondary metabolites utilizing solar energy and carbon dioxide, are a potential platform for sustainable production of biochemicals. Until now, conventional metabolic engineering approaches have been applied to various cyanobacterial species for enhanced production of industrially valued compounds, including secondary metabolites and non-natural biochemicals. However, the shortage of understanding of cyanobacterial metabolic and regulatory networks for atmospheric carbon fixation to biochemical production and the lack of available engineering tools limit the potential of cyanobacteria for industrial applications. Recently, to overcome the limitations, synthetic biology tools and systems biology approaches such as genome-scale modeling based on diverse omics data have been applied to cyanobacteria. This review covers the synthetic and systems biology approaches for advanced metabolic engineering of cyanobacteria.
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Muhich, Anna Jo, Amanda Agosto-Ramos, and Daniel J. Kliebenstein. "The ease and complexity of identifying and using specialized metabolites for crop engineering." Emerging Topics in Life Sciences 6, no. 2 (March 18, 2022): 153–62. http://dx.doi.org/10.1042/etls20210248.
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Plants produce a broad variety of specialized metabolites with distinct biological activities and potential applications. Despite this potential, most biosynthetic pathways governing specialized metabolite production remain largely unresolved across the plant kingdom. The rapid advancement of genetics and biochemical tools has enhanced our ability to identify plant specialized metabolic pathways. Further advancements in transgenic technology and synthetic biology approaches have extended this to a desire to design new pathways or move existing pathways into new systems to address long-running difficulties in crop systems. This includes improving abiotic and biotic stress resistance, boosting nutritional content, etc. In this review, we assess the potential and limitations for (1) identifying specialized metabolic pathways in plants with multi-omics tools and (2) using these enzymes in synthetic biology or crop engineering. The goal of these topics is to highlight areas of research that may need further investment to enhance the successful application of synthetic biology for exploiting the myriad of specialized metabolic pathways.
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Sajid, Moon, Chaitanya N. Channakesavula, Shane R. Stone, and Parwinder Kaur. "Synthetic Biology towards Improved Flavonoid Pharmacokinetics." Biomolecules 11, no. 5 (May 18, 2021): 754. http://dx.doi.org/10.3390/biom11050754.
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Flavonoids are a structurally diverse class of natural products that have been found to have a range of beneficial activities in humans. However, the clinical utilisation of these molecules has been limited due to their low solubility, chemical stability, bioavailability and extensive intestinal metabolism in vivo. Recently, the view has been formed that site-specific modification of flavonoids by methylation and/or glycosylation, processes that occur in plants endogenously, can be used to improve and adapt their biophysical and pharmacokinetic properties. The traditional source of flavonoids and their modified forms is from plants and is limited due to the low amounts present in biomass, intrinsic to the nature of secondary metabolite biosynthesis. Access to greater amounts of flavonoids, and understanding of the impact of modifications, requires a rethink in terms of production, more specifically towards the adoption of plant biosynthetic pathways into ex planta synthesis approaches. Advances in synthetic biology and metabolic engineering, aided by protein engineering and machine learning methods, offer attractive and exciting avenues for ex planta flavonoid synthesis. This review seeks to explore the applications of synthetic biology towards the ex planta biosynthesis of flavonoids, and how the natural plant methylation and glycosylation pathways can be harnessed to produce modified flavonoids with more favourable biophysical and pharmacokinetic properties for clinical use. It is envisaged that the development of viable alternative production systems for the synthesis of flavonoids and their methylated and glycosylated forms will help facilitate their greater clinical application.
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Bartley, Bryan, Jacob Beal, Kevin Clancy, Goksel Misirli, Nicholas Roehner, Ernst Oberortner, Matthew Pocock, et al. "Synthetic Biology Open Language (SBOL) Version 2.0.0." Journal of Integrative Bioinformatics 12, no. 2 (June 1, 2015): 902–91. http://dx.doi.org/10.1515/jib-2015-272.
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Summary Synthetic biology builds upon the techniques and successes of genetics, molecular biology, and metabolic engineering by applying engineering principles to the design of biological systems. The field still faces substantial challenges, including long development times, high rates of failure, and poor reproducibility. One method to ameliorate these problems would be to improve the exchange of information about designed systems between laboratories. The Synthetic Biology Open Language (SBOL) has been developed as a standard to support the specification and exchange of biological design information in synthetic biology, filling a need not satisfied by other pre-existing standards. This document details version 2.0 of SBOL, introducing a standardized format for the electronic exchange of information on the structural and functional aspects of biological designs. The standard has been designed to support the explicit and unambiguous description of biological designs by means of a well defined data model. The standard also includes rules and best practices on how to use this data model and populate it with relevant design details. The publication of this specification is intended to make these capabilities more widely accessible to potential developers and users in the synthetic biology community and beyond.
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Meyer, Conary, Yusuke Nakamura, Blake J. Rasor, Ashty S. Karim, Michael C. Jewett, and Cheemeng Tan. "Analysis of the Innovation Trend in Cell-Free Synthetic Biology." Life 11, no. 6 (June 11, 2021): 551. http://dx.doi.org/10.3390/life11060551.
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Cell-free synthetic biology is a maturing field that aims to assemble biomolecular reactions outside cells for compelling applications in drug discovery, metabolic engineering, biomanufacturing, diagnostics, and education. Cell-free systems have several key features. They circumvent mechanisms that have evolved to facilitate species survival, bypass limitations on molecular transport across the cell wall, enable high-yielding and rapid synthesis of proteins without creating recombinant cells, and provide high tolerance towards toxic substrates or products. Here, we analyze ~750 published patents and ~2000 peer-reviewed manuscripts in the field of cell-free systems. Three hallmarks emerged. First, we found that both patent filings and manuscript publications per year are significantly increasing (five-fold and 1.5-fold over the last decade, respectively). Second, we observed that the innovation landscape has changed. Patent applications were dominated by Japan in the early 2000s before shifting to China and the USA in recent years. Finally, we discovered an increasing prevalence of biotechnology companies using cell-free systems. Our analysis has broad implications on the future development of cell-free synthetic biology for commercial and industrial applications.
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Lacerda, Maria Priscila, Eun Joong Oh, and Carrie Eckert. "The Model System Saccharomyces cerevisiae Versus Emerging Non-Model Yeasts for the Production of Biofuels." Life 10, no. 11 (November 21, 2020): 299. http://dx.doi.org/10.3390/life10110299.
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Microorganisms are effective platforms for the production of a variety of chemicals including biofuels, commodity chemicals, polymers and other natural products. However, deep cellular understanding is required for improvement of current biofuel cell factories to truly transform the Bioeconomy. Modifications in microbial metabolic pathways and increased resistance to various types of stress caused by the production of these chemicals are crucial in the generation of robust and efficient production hosts. Recent advances in systems and synthetic biology provide new tools for metabolic engineering to design strategies and construct optimal biocatalysts for the sustainable production of desired chemicals, especially in the case of ethanol and fatty acid production. Yeast is an efficient producer of bioethanol and most of the available synthetic biology tools have been developed for the industrial yeast Saccharomyces cerevisiae. Non-conventional yeast systems have several advantageous characteristics that are not easily engineered such as ethanol tolerance, low pH tolerance, thermotolerance, inhibitor tolerance, genetic diversity and so forth. Currently, synthetic biology is still in its initial steps for studies in non-conventional yeasts such as Yarrowia lipolytica, Kluyveromyces marxianus, Issatchenkia orientalis and Pichia pastoris. Therefore, the development and application of advanced synthetic engineering tools must also focus on these underexploited, non-conventional yeast species. Herein, we review the basic synthetic biology tools that can be applied to the standard S. cerevisiae model strain, as well as those that have been developed for non-conventional yeasts. In addition, we will discuss the recent advances employed to develop non-conventional yeast strains that are efficient for the production of a variety of chemicals through the use of metabolic engineering and synthetic biology.
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Lv, Xueqin, Shixiu Cui, Yang Gu, Jianghua Li, Guocheng Du, and Long Liu. "Enzyme Assembly for Compartmentalized Metabolic Flux Control." Metabolites 10, no. 4 (March 26, 2020): 125. http://dx.doi.org/10.3390/metabo10040125.
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Enzyme assembly by ligand binding or physically sequestrating enzymes, substrates, or metabolites into isolated compartments can bring key molecules closer to enhance the flux of a metabolic pathway. The emergence of enzyme assembly has provided both opportunities and challenges for metabolic engineering. At present, with the development of synthetic biology and systems biology, a variety of enzyme assembly strategies have been proposed, from the initial direct enzyme fusion to scaffold-free assembly, as well as artificial scaffolds, such as nucleic acid/protein scaffolds, and even some more complex physical compartments. These assembly strategies have been explored and applied to the synthesis of various important bio-based products, and have achieved different degrees of success. Despite some achievements, enzyme assembly, especially in vivo, still has many problems that have attracted significant attention from researchers. Here, we focus on some selected examples to review recent research on scaffold-free strategies, synthetic artificial scaffolds, and physical compartments for enzyme assembly or pathway sequestration, and we discuss their notable advances. In addition, the potential applications and challenges in the applications are highlighted.
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Lou, Hanghang, Lifei Hu, Hongyun Lu, Tianyu Wei, and Qihe Chen. "Metabolic Engineering of Microbial Cell Factories for Biosynthesis of Flavonoids: A Review." Molecules 26, no. 15 (July 27, 2021): 4522. http://dx.doi.org/10.3390/molecules26154522.
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Flavonoids belong to a class of plant secondary metabolites that have a polyphenol structure. Flavonoids show extensive biological activity, such as antioxidative, anti-inflammatory, anti-mutagenic, anti-cancer, and antibacterial properties, so they are widely used in the food, pharmaceutical, and nutraceutical industries. However, traditional sources of flavonoids are no longer sufficient to meet current demands. In recent years, with the clarification of the biosynthetic pathway of flavonoids and the development of synthetic biology, it has become possible to use synthetic metabolic engineering methods with microorganisms as hosts to produce flavonoids. This article mainly reviews the biosynthetic pathways of flavonoids and the development of microbial expression systems for the production of flavonoids in order to provide a useful reference for further research on synthetic metabolic engineering of flavonoids. Meanwhile, the application of co-culture systems in the biosynthesis of flavonoids is emphasized in this review.
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Vilkhovoy, Michael, Abhinav Adhikari, Sandra Vadhin, and Jeffrey D. Varner. "The Evolution of Cell Free Biomanufacturing." Processes 8, no. 6 (June 8, 2020): 675. http://dx.doi.org/10.3390/pr8060675.
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Cell-free systems are a widely used research tool in systems and synthetic biology and a promising platform for manufacturing of proteins and chemicals. In the past, cell-free biology was primarily used to better understand fundamental biochemical processes. Notably, E. coli cell-free extracts were used in the 1960s to decipher the sequencing of the genetic code. Since then, the transcription and translation capabilities of cell-free systems have been repeatedly optimized to improve energy efficiency and product yield. Today, cell-free systems, in combination with the rise of synthetic biology, have taken on a new role as a promising technology for just-in-time manufacturing of therapeutically important biologics and high-value small molecules. They have also been implemented at an industrial scale for the production of antibodies and cytokines. In this review, we discuss the evolution of cell-free technologies, in particular advancements in extract preparation, cell-free protein synthesis, and cell-free metabolic engineering applications. We then conclude with a discussion of the mathematical modeling of cell-free systems. Mathematical modeling of cell-free processes could be critical to addressing performance bottlenecks and estimating the costs of cell-free manufactured products.
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Blatt-Janmaat, Kaitlyn, and Yang Qu. "The Biochemistry of Phytocannabinoids and Metabolic Engineering of Their Production in Heterologous Systems." International Journal of Molecular Sciences 22, no. 5 (February 28, 2021): 2454. http://dx.doi.org/10.3390/ijms22052454.
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The medicinal properties of cannabis and the its legal status in several countries and jurisdictions has spurred the massive growth of the cannabis economy around the globe. The value of cannabis stems from its euphoric activity offered by the unique phytocannabinoid tetrahydrocannabinol (THC). However, this is rapidly expanding beyond THC owing to other non-psychoactive phytocannabinoids with new bioactivities that will contribute to their development into clinically useful drugs. The discovery of the biosynthesis of major phytocannabinoids has allowed the exploration of their heterologous production by synthetic biology, which may lead to the industrial production of rare phytocannabinoids or novel synthetic cannabinoid pharmaceuticals that are not easily offered by cannabis plants. This review summarizes the biosynthesis of major phytocannabinoids in detail, the most recent development of their metabolic engineering in various systems, and the engineering approaches and strategies used to increase the yield.
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Davis, Jacob D., and Eberhard O. Voit. "Metrics for regulated biochemical pathway systems." Bioinformatics 35, no. 12 (November 14, 2018): 2118–24. http://dx.doi.org/10.1093/bioinformatics/bty942.
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Abstract Motivation The assessment of graphs through crisp numerical metrics has long been a hallmark of biological network analysis. However, typical graph metrics ignore regulatory signals that are crucially important for optimal pathway operation, for instance, in biochemical or metabolic studies. Here we introduce adjusted metrics that are applicable to both static networks and dynamic systems. Results The metrics permit quantitative characterizations of the importance of regulation in biochemical pathway systems, including systems designed for applications in synthetic biology or metabolic engineering. They may also become criteria for effective model reduction. Availability and implementation The source code is available at https://gitlab.com/tienbien44/metrics-bsa
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Kim, Juhyun, Manuel Salvador, Elizabeth Saunders, Jaime González, Claudio Avignone-Rossa, and Jose Ignacio Jiménez. "Properties of alternative microbial hosts used in synthetic biology: towards the design of a modular chassis." Essays in Biochemistry 60, no. 4 (November 30, 2016): 303–13. http://dx.doi.org/10.1042/ebc20160015.
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The chassis is the cellular host used as a recipient of engineered biological systems in synthetic biology. They are required to propagate the genetic information and to express the genes encoded in it. Despite being an essential element for the appropriate function of genetic circuits, the chassis is rarely considered in their design phase. Consequently, the circuits are transferred to model organisms commonly used in the laboratory, such as Escherichia coli, that may be suboptimal for a required function. In this review, we discuss some of the properties desirable in a versatile chassis and summarize some examples of alternative hosts for synthetic biology amenable for engineering. These properties include a suitable life style, a robust cell wall, good knowledge of its regulatory network as well as of the interplay of the host components with the exogenous circuits, and the possibility of developing whole-cell models and tuneable metabolic fluxes that could allow a better distribution of cellular resources (metabolites, ATP, nucleotides, amino acids, transcriptional and translational machinery). We highlight Pseudomonas putida, widely used in many different biotechnological applications as a prominent organism for synthetic biology due to its metabolic diversity, robustness and ease of manipulation.
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Pandey, Ramesh Prasad, Prakash Parajuli, and Jae Kyung Sohng. "Metabolic engineering of glycosylated polyketide biosynthesis." Emerging Topics in Life Sciences 2, no. 3 (August 6, 2018): 389–403. http://dx.doi.org/10.1042/etls20180011.
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Microbial cell factories are extensively used for the biosynthesis of value-added chemicals, biopharmaceuticals, and biofuels. Microbial biosynthesis is also realistic for the production of heterologous molecules including complex natural products of plant and microbial origin. Glycosylation is a well-known post-modification method to engineer sugar-functionalized natural products. It is of particular interest to chemical biologists to increase chemical diversity of molecules. Employing the state-of-the-art systems and synthetic biology tools, a range of small to complex glycosylated natural products have been produced from microbes using a simple and sustainable fermentation approach. In this context, this review covers recent notable metabolic engineering approaches used for the biosynthesis of glycosylated plant and microbial polyketides in different microorganisms. This review article is broadly divided into two major parts. The first part is focused on the biosynthesis of glycosylated plant polyketides in prokaryotes and yeast cells, while the second part is focused on the generation of glycosylated microbial polyketides in actinomycetes.
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Tan, Yong Quan, Bo Xue, and Wen Shan Yew. "Genetically Encodable Scaffolds for Optimizing Enzyme Function." Molecules 26, no. 5 (March 4, 2021): 1389. http://dx.doi.org/10.3390/molecules26051389.
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Enzyme engineering is an indispensable tool in the field of synthetic biology, where enzymes are challenged to carry out novel or improved functions. Achieving these goals sometimes goes beyond modifying the primary sequence of the enzyme itself. The use of protein or nucleic acid scaffolds to enhance enzyme properties has been reported for applications such as microbial production of chemicals, biosensor development and bioremediation. Key advantages of using these assemblies include optimizing reaction conditions, improving metabolic flux and increasing enzyme stability. This review summarizes recent trends in utilizing genetically encodable scaffolds, developed in line with synthetic biology methodologies, to complement the purposeful deployment of enzymes. Current molecular tools for constructing these synthetic enzyme-scaffold systems are also highlighted.
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Salim, Vonny, Sara-Alexis Jarecki, Marshall Vick, and Ryan Miller. "Advances in Metabolic Engineering of Plant Monoterpene Indole Alkaloids." Biology 12, no. 8 (July 27, 2023): 1056. http://dx.doi.org/10.3390/biology12081056.
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Monoterpene indole alkaloids (MIAs) encompass a diverse family of over 3000 plant natural products with a wide range of medical applications. Further utilizations of these compounds, however, are hampered due to low levels of abundance in their natural sources, causing difficult isolation and complex multi-steps in uneconomical chemical syntheses. Metabolic engineering of MIA biosynthesis in heterologous hosts is attractive, particularly for increasing the yield of natural products of interest and expanding their chemical diversity. Here, we review recent advances and strategies which have been adopted to engineer microbial and plant systems for the purpose of generating MIAs and discuss the current issues and future developments of manufacturing MIAs by synthetic biology approaches.
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Liu, Fenghua, Lingling He, Sheng Dong, Jinsong Xuan, Qiu Cui, and Yingang Feng. "Artificial Small Molecules as Cofactors and Biomacromolecular Building Blocks in Synthetic Biology: Design, Synthesis, Applications, and Challenges." Molecules 28, no. 15 (August 3, 2023): 5850. http://dx.doi.org/10.3390/molecules28155850.
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Enzymes are essential catalysts for various chemical reactions in biological systems and often rely on metal ions or cofactors to stabilize their structure or perform functions. Improving enzyme performance has always been an important direction of protein engineering. In recent years, various artificial small molecules have been successfully used in enzyme engineering. The types of enzymatic reactions and metabolic pathways in cells can be expanded by the incorporation of these artificial small molecules either as cofactors or as building blocks of proteins and nucleic acids, which greatly promotes the development and application of biotechnology. In this review, we summarized research on artificial small molecules including biological metal cluster mimics, coenzyme analogs (mNADs), designer cofactors, non-natural nucleotides (XNAs), and non-natural amino acids (nnAAs), focusing on their design, synthesis, and applications as well as the current challenges in synthetic biology.
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Zhang, Haoran, Brian Pereira, Zhengjun Li, and Gregory Stephanopoulos. "Engineering Escherichia coli coculture systems for the production of biochemical products." Proceedings of the National Academy of Sciences 112, no. 27 (June 25, 2015): 8266–71. http://dx.doi.org/10.1073/pnas.1506781112.
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Engineering microbial consortia to express complex biosynthetic pathways efficiently for the production of valuable compounds is a promising approach for metabolic engineering and synthetic biology. Here, we report the design, optimization, and scale-up of an Escherichia coli-E. coli coculture that successfully overcomes fundamental microbial production limitations, such as high-level intermediate secretion and low-efficiency sugar mixture utilization. For the production of the important chemical cis,cis-muconic acid, we show that the coculture approach achieves a production yield of 0.35 g/g from a glucose/xylose mixture, which is significantly higher than reported in previous reports. By efficiently producing another compound, 4-hydroxybenzoic acid, we also demonstrate that the approach is generally applicable for biosynthesis of other important industrial products.
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Khan, Aqib Zafar, Muhammad Bilal, Shahid Mehmood, Ashutosh Sharma, and Hafiz M. N. Iqbal. "State-of-the-Art Genetic Modalities to Engineer Cyanobacteria for Sustainable Biosynthesis of Biofuel and Fine-Chemicals to Meet Bio–Economy Challenges." Life 9, no. 3 (June 27, 2019): 54. http://dx.doi.org/10.3390/life9030054.
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In recent years, metabolic engineering of microorganisms has attained much research interest to produce biofuels and industrially pertinent chemicals. Owing to the relatively fast growth rate, genetic malleability, and carbon neutral production process, cyanobacteria has been recognized as a specialized microorganism with a significant biotechnological perspective. Metabolically engineering cyanobacterial strains have shown great potential for the photosynthetic production of an array of valuable native or non-native chemicals and metabolites with profound agricultural and pharmaceutical significance using CO2 as a building block. In recent years, substantial improvements in developing and introducing novel and efficient genetic tools such as genome-scale modeling, high throughput omics analyses, synthetic/system biology tools, metabolic flux analysis and clustered regularly interspaced short palindromic repeats (CRISPR)-associated nuclease (CRISPR/cas) systems have been made for engineering cyanobacterial strains. Use of these tools and technologies has led to a greater understanding of the host metabolism, as well as endogenous and heterologous carbon regulation mechanisms which consequently results in the expansion of maximum productive ability and biochemical diversity. This review summarizes recent advances in engineering cyanobacteria to produce biofuel and industrially relevant fine chemicals of high interest. Moreover, the development and applications of cutting-edge toolboxes such as the CRISPR-cas9 system, synthetic biology, high-throughput “omics”, and metabolic flux analysis to engineer cyanobacteria for large-scale cultivation are also discussed.
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Ye, Jian-Wen, and Guo-Qiang Chen. "Halomonas as a chassis." Essays in Biochemistry 65, no. 2 (July 2021): 393–403. http://dx.doi.org/10.1042/ebc20200159.
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Abstract With the rapid development of systems and synthetic biology, the non-model bacteria, Halomonas spp., have been developed recently to become a cost-competitive platform for producing a variety of products including polyesters, chemicals and proteins owing to their contamination resistance and ability of high cell density growth at alkaline pH and high salt concentration. These salt-loving microbes can partially solve the challenges of current industrial biotechnology (CIB) which requires high energy-consuming sterilization to prevent contamination as CIB is based on traditional chassis, typically, Escherichia coli, Bacillus subtilis, Pseudomonas putida and Corynebacterium glutamicum. The advantages and current status of Halomonas spp. including their molecular biology and metabolic engineering approaches as well as their applications are reviewed here. Moreover, a systematic strain engineering streamline, including product-based host development, genetic parts mining, static and dynamic optimization of modularized pathways and bioprocess-inspired cell engineering are summarized. All of these developments result in the term called next-generation industrial biotechnology (NGIB). Increasing efforts are made to develop their versatile cell factories powered by synthetic biology to demonstrate a new biomanufacturing strategy under open and continuous processes with significant cost-reduction on process complexity, energy, substrates and fresh water consumption.
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Trantidou, Tatiana, Linda Dekker, Karen Polizzi, Oscar Ces, and Yuval Elani. "Functionalizing cell-mimetic giant vesicles with encapsulated bacterial biosensors." Interface Focus 8, no. 5 (August 17, 2018): 20180024. http://dx.doi.org/10.1098/rsfs.2018.0024.
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The design of vesicle microsystems as artificial cells (bottom-up synthetic biology) has traditionally relied on the incorporation of molecular components to impart functionality. These cell mimics have reduced capabilities compared with their engineered biological counterparts (top-down synthetic biology), as they lack the powerful metabolic and regulatory pathways associated with living systems. There is increasing scope for using whole intact cellular components as functional modules within artificial cells, as a route to increase the capabilities of artificial cells. In this feasibility study, we design and embed genetically engineered microbes ( Escherichia coli ) in a vesicle-based cell mimic and use them as biosensing modules for real-time monitoring of lactate in the external environment. Using this conceptual framework, the functionality of other microbial devices can be conferred into vesicle microsystems in the future, bridging the gap between bottom-up and top-down synthetic biology.
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Ivanov, Ivan, Sebastián López Castellanos, Severo Balasbas, Lado Otrin, Nika Marušič, Tanja Vidaković-Koch, and Kai Sundmacher. "Bottom-Up Synthesis of Artificial Cells: Recent Highlights and Future Challenges." Annual Review of Chemical and Biomolecular Engineering 12, no. 1 (June 7, 2021): 287–308. http://dx.doi.org/10.1146/annurev-chembioeng-092220-085918.
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The bottom-up approach in synthetic biology aims to create molecular ensembles that reproduce the organization and functions of living organisms and strives to integrate them in a modular and hierarchical fashion toward the basic unit of life—the cell—and beyond. This young field stands on the shoulders of fundamental research in molecular biology and biochemistry, next to synthetic chemistry, and, augmented by an engineering framework, has seen tremendous progress in recent years thanks to multiple technological and scientific advancements. In this timely review of the research over the past decade, we focus on three essential features of living cells: the ability to self-reproduce via recursive cycles of growth and division, the harnessing of energy to drive cellular processes, and the assembly of metabolic pathways. In addition, we cover the increasing efforts to establish multicellular systems via different communication strategies and critically evaluate the potential applications.
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Moses, Melanie, George Bezerra, Benjamin Edwards, James Brown, and Stephanie Forrest. "Energy and time determine scaling in biological and computer designs." Philosophical Transactions of the Royal Society B: Biological Sciences 371, no. 1701 (August 19, 2016): 20150446. http://dx.doi.org/10.1098/rstb.2015.0446.
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Metabolic rate in animals and power consumption in computers are analogous quantities that scale similarly with size. We analyse vascular systems of mammals and on-chip networks of microprocessors, where natural selection and human engineering, respectively, have produced systems that minimize both energy dissipation and delivery times. Using a simple network model that simultaneously minimizes energy and time, our analysis explains empirically observed trends in the scaling of metabolic rate in mammals and power consumption and performance in microprocessors across several orders of magnitude in size. Just as the evolutionary transitions from unicellular to multicellular animals in biology are associated with shifts in metabolic scaling, our model suggests that the scaling of power and performance will change as computer designs transition to decentralized multi-core and distributed cyber-physical systems. More generally, a single energy–time minimization principle may govern the design of many complex systems that process energy, materials and information. This article is part of the themed issue ‘The major synthetic evolutionary transitions’.
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Kim, Kangsan, Donghui Choe, Dae-Hee Lee, and Byung-Kwan Cho. "Engineering Biology to Construct Microbial Chassis for the Production of Difficult-to-Express Proteins." International Journal of Molecular Sciences 21, no. 3 (February 2, 2020): 990. http://dx.doi.org/10.3390/ijms21030990.
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A large proportion of the recombinant proteins manufactured today rely on microbe-based expression systems owing to their relatively simple and cost-effective production schemes. However, several issues in microbial protein expression, including formation of insoluble aggregates, low protein yield, and cell death are still highly recursive and tricky to optimize. These obstacles are usually rooted in the metabolic capacity of the expression host, limitation of cellular translational machineries, or genetic instability. To this end, several microbial strains having precisely designed genomes have been suggested as a way around the recurrent problems in recombinant protein expression. Already, a growing number of prokaryotic chassis strains have been genome-streamlined to attain superior cellular fitness, recombinant protein yield, and stability of the exogenous expression pathways. In this review, we outline challenges associated with heterologous protein expression, some examples of microbial chassis engineered for the production of recombinant proteins, and emerging tools to optimize the expression of heterologous proteins. In particular, we discuss the synthetic biology approaches to design and build and test genome-reduced microbial chassis that carry desirable characteristics for heterologous protein expression.
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Theodosiou, Eleni. "Engineering Strategies for Efficient Bioconversion of Glycerol to Value-Added Products by Yarrowia lipolytica." Catalysts 13, no. 4 (March 27, 2023): 657. http://dx.doi.org/10.3390/catal13040657.
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Yarrowia lipolytica has been a valuable biotechnological workhorse for the production of commercially important biochemicals for over 70 years. The knowledge gained so far on the native biosynthetic pathways, as well as the availability of numerous systems and synthetic biology tools, enabled not only the regulation and the redesign of the existing metabolic pathways, but also the introduction of novel synthetic ones; further consolidating the position of the yeast in industrial biotechnology. However, for the development of competitive and sustainable biotechnological production processes, bioengineering should be reinforced by bioprocess optimization strategies. Although there are many published reviews on the bioconversion of various carbon sources to value-added products by Yarrowia lipolytica, fewer works have focused on reviewing up-to-date strain, medium, and process engineering strategies with an aim to emphasize the significance of integrated engineering approaches. The ultimate goal of this work is to summarize the necessary knowledge and inspire novel routes to manipulate at a systems level the yeast biosynthetic machineries by combining strain and bioprocess engineering. Due to the increasing surplus of biodiesel-derived waste glycerol and the favored glycerol-utilization metabolic pathways of Y. lipolytica over other carbon sources, the present review focuses on pure and crude glycerol-based biomanufacturing.
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Yuan, Guoliang, Md Mahmudul Hassan, Degao Liu, Sung Don Lim, Won Cheol Yim, John C. Cushman, Kasey Markel, et al. "Biosystems Design to Accelerate C3-to-CAM Progression." BioDesign Research 2020 (October 12, 2020): 1–16. http://dx.doi.org/10.34133/2020/3686791.
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Global demand for food and bioenergy production has increased rapidly, while the area of arable land has been declining for decades due to damage caused by erosion, pollution, sea level rise, urban development, soil salinization, and water scarcity driven by global climate change. In order to overcome this conflict, there is an urgent need to adapt conventional agriculture to water-limited and hotter conditions with plant crop systems that display higher water-use efficiency (WUE). Crassulacean acid metabolism (CAM) species have substantially higher WUE than species performing C3 or C4 photosynthesis. CAM plants are derived from C3 photosynthesis ancestors. However, it is extremely unlikely that the C3 or C4 crop plants would evolve rapidly into CAM photosynthesis without human intervention. Currently, there is growing interest in improving WUE through transferring CAM into C3 crops. However, engineering a major metabolic plant pathway, like CAM, is challenging and requires a comprehensive deep understanding of the enzymatic reactions and regulatory networks in both C3 and CAM photosynthesis, as well as overcoming physiometabolic limitations such as diurnal stomatal regulation. Recent advances in CAM evolutionary genomics research, genome editing, and synthetic biology have increased the likelihood of successful acceleration of C3-to-CAM progression. Here, we first summarize the systems biology-level understanding of the molecular processes in the CAM pathway. Then, we review the principles of CAM engineering in an evolutionary context. Lastly, we discuss the technical approaches to accelerate the C3-to-CAM transition in plants using synthetic biology toolboxes.
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Goelzer, Anne, and Vincent Fromion. "Resource allocation in living organisms." Biochemical Society Transactions 45, no. 4 (July 7, 2017): 945–52. http://dx.doi.org/10.1042/bst20160436.
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Quantitative prediction of resource allocation for living systems has been an intensive area of research in the field of biology. Resource allocation was initially investigated in higher organisms by using empirical mathematical models based on mass distribution. A challenge is now to go a step further by reconciling the cellular scale to the individual scale. In the present paper, we review the foundations of modelling of resource allocation, particularly at the cellular scale: from small macro-molecular models to genome-scale cellular models. We enlighten how the combination of omic measurements and computational advances together with systems biology has contributed to dramatic progresses in the current understanding and prediction of cellular resource allocation. Accurate genome-wide predictive methods of resource allocation based on the resource balance analysis (RBA) framework have been developed and ensure a good trade-off between the complexity/tractability and the prediction capability of the model. The RBA framework shows promise for a wide range of applications in metabolic engineering and synthetic biology, and for pursuing investigations of the design principles of cellular and multi-cellular organisms.
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Mohany, Nurul Amira Mohammad, Alessandra Totti, Keith R. Naylor, and Harald Janovjak. "Microbial methionine transporters and biotechnological applications." Applied Microbiology and Biotechnology 105, no. 10 (April 30, 2021): 3919–29. http://dx.doi.org/10.1007/s00253-021-11307-w.
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Abstract Methionine (Met) is an essential amino acid with commercial value in animal feed, human nutrition, and as a chemical precursor. Microbial production of Met has seen intensive investigation towards a more sustainable alternative to the chemical synthesis that currently meets the global Met demand. Indeed, efficient Met biosynthesis has been achieved in genetically modified bacteria that harbor engineered enzymes and streamlined metabolic pathways. Very recently, the export of Met as the final step during its fermentative production has been studied and optimized, primarily through identification and expression of microbial Met efflux transporters. In this mini-review, we summarize the current knowledge on four families of Met export and import transporters that have been harnessed for the production of Met and other valuable biomolecules. These families are discussed with respect to their function, gene regulation, and biotechnological applications. We cover methods for identification and characterization of Met transporters as the basis for the further engineering of these proteins and for exploration of other solute carrier families. The available arsenal of Met transporters from different species and protein families provides blueprints not only for fermentative production but also synthetic biology systems, such as molecular sensors and cell-cell communication systems. Key points • Sustainable production of methionine (Met) using microbes is actively explored. • Met transporters of four families increase production yield and specificity. • Further applications include other biosynthetic pathways and synthetic biology.
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Zhang, Quanwei, Yaokang Wu, Mengyue Gong, Hongzhi Zhang, Yanfeng Liu, Xueqin Lv, Jianghua Li, Guocheng Du, and Long Liu. "Production of proteins and commodity chemicals using engineered Bacillus subtilis platform strain." Essays in Biochemistry 65, no. 2 (July 2021): 173–85. http://dx.doi.org/10.1042/ebc20210011.
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Abstract Currently, increasing demand of biochemicals produced from renewable resources has motivated researchers to seek microbial production strategies instead of traditional chemical methods. As a microbial platform, Bacillus subtilis possesses many advantages including the generally recognized safe status, clear metabolic networks, short growth cycle, mature genetic editing methods and efficient protein secretion systems. Engineered B. subtilis strains are being increasingly used in laboratory research and in industry for the production of valuable proteins and other chemicals. In this review, we first describe the recent advances of bioinformatics strategies during the research and applications of B. subtilis. Secondly, the applications of B. subtilis in enzymes and recombinant proteins production are summarized. Further, the recent progress in employing metabolic engineering and synthetic biology strategies in B. subtilis platform strain to produce commodity chemicals is systematically introduced and compared. Finally, the major limitations for the further development of B. subtilis platform strain and possible future directions for its research are also discussed.
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Yang, Dongsoo, Cindy Pricilia Surya Prabowo, Hyunmin Eun, Seon Young Park, In Jin Cho, Song Jiao, and Sang Yup Lee. "Escherichia coli as a platform microbial host for systems metabolic engineering." Essays in Biochemistry 65, no. 2 (July 2021): 225–46. http://dx.doi.org/10.1042/ebc20200172.
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Abstract Bio-based production of industrially important chemicals and materials from non-edible and renewable biomass has become increasingly important to resolve the urgent worldwide issues including climate change. Also, bio-based production, instead of chemical synthesis, of food ingredients and natural products has gained ever increasing interest for health benefits. Systems metabolic engineering allows more efficient development of microbial cell factories capable of sustainable, green, and human-friendly production of diverse chemicals and materials. Escherichia coli is unarguably the most widely employed host strain for the bio-based production of chemicals and materials. In the present paper, we review the tools and strategies employed for systems metabolic engineering of E. coli. Next, representative examples and strategies for the production of chemicals including biofuels, bulk and specialty chemicals, and natural products are discussed, followed by discussion on materials including polyhydroxyalkanoates (PHAs), proteins, and nanomaterials. Lastly, future perspectives and challenges remaining for systems metabolic engineering of E. coli are discussed.
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Choudhary, M. Iqbal, Fatima Z. Basha, Ghulam Abbas, Shamsun Nahar Khan, and S. Adnan Ali Shah. "Science at the interface of chemistry and biology: Discoveries of α-glucosidase inhibitors and antiglycation agents." Pure and Applied Chemistry 79, no. 12 (January 1, 2007): 2263–68. http://dx.doi.org/10.1351/pac200779122263.
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Diseases are manifestations of complex biological processes in living systems. Through the applications of molecular biology and genetics, many diseases are now understood at the molecular level. This has provided researchers opportunities to develop lead molecules with the capacity of blocking a particular disease mechanism. Diabetes is a complex metabolic disorder, characterized by hyperglycemia. The first objective of antidiabetic chemotherapy is to achieve normal glycemic index. Recently, major discoveries have been made to understand how the disease progresses and manifests its complications. We have used this growing understanding to work toward discovery of effective α-glucosidase inhibitors and antiglycation agents of natural and synthetic origins. Reliable bench-top biochemical assays were employed, and several new molecular entities were studied with reference to their structure-activity relationships.
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Winston, Dennis S., and David D. Boehr. "Catalyst-Based Biomolecular Logic Gates." Catalysts 12, no. 7 (June 29, 2022): 712. http://dx.doi.org/10.3390/catal12070712.
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Regulatory processes in biology can be re-conceptualized in terms of logic gates, analogous to those in computer science. Frequently, biological systems need to respond to multiple, sometimes conflicting, inputs to provide the correct output. The language of logic gates can then be used to model complex signal transduction and metabolic processes. Advances in synthetic biology in turn can be used to construct new logic gates, which find a variety of biotechnology applications including in the production of high value chemicals, biosensing, and drug delivery. In this review, we focus on advances in the construction of logic gates that take advantage of biological catalysts, including both protein-based and nucleic acid-based enzymes. These catalyst-based biomolecular logic gates can read a variety of molecular inputs and provide chemical, optical, and electrical outputs, allowing them to interface with other types of biomolecular logic gates or even extend to inorganic systems. Continued advances in molecular modeling and engineering will facilitate the construction of new logic gates, further expanding the utility of biomolecular computing.
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Tumen-Velasquez, Melissa, Christopher W. Johnson, Alaa Ahmed, Graham Dominick, Emily M. Fulk, Payal Khanna, Sarah A. Lee, et al. "Accelerating pathway evolution by increasing the gene dosage of chromosomal segments." Proceedings of the National Academy of Sciences 115, no. 27 (June 18, 2018): 7105–10. http://dx.doi.org/10.1073/pnas.1803745115.
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Experimental evolution is a critical tool in many disciplines, including metabolic engineering and synthetic biology. However, current methods rely on the chance occurrence of a key step that can dramatically accelerate evolution in natural systems, namely increased gene dosage. Our studies sought to induce the targeted amplification of chromosomal segments to facilitate rapid evolution. Since increased gene dosage confers novel phenotypes and genetic redundancy, we developed a method, Evolution by Amplification and Synthetic Biology (EASy), to create tandem arrays of chromosomal regions. InAcinetobacter baylyi, EASy was demonstrated on an important bioenergy problem, the catabolism of lignin-derived aromatic compounds. The initial focus on guaiacol (2-methoxyphenol), a common lignin degradation product, led to the discovery ofAmycolatopsisgenes (gcoAB) encoding a cytochrome P450 enzyme that converts guaiacol to catechol. However, chromosomal integration ofgcoABinPseudomonas putidaorA. baylyidid not enable guaiacol to be used as the sole carbon source despite catechol being a growth substrate. In ∼1,000 generations, EASy yielded alleles that in single chromosomal copy confer growth on guaiacol. Different variants emerged, including fusions between GcoA and CatA (catechol 1,2-dioxygenase). This study illustrates the power of harnessing chromosomal gene amplification to accelerate the evolution of desirable traits.
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Oyarzún, Diego A., and Madalena Chaves. "Design of a bistable switch to control cellular uptake." Journal of The Royal Society Interface 12, no. 113 (December 2015): 20150618. http://dx.doi.org/10.1098/rsif.2015.0618.
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Bistable switches are widely used in synthetic biology to trigger cellular functions in response to environmental signals. All bistable switches developed so far, however, control the expression of target genes without access to other layers of the cellular machinery. Here, we propose a bistable switch to control the rate at which cells take up a metabolite from the environment. An uptake switch provides a new interface to command metabolic activity from the extracellular space and has great potential as a building block in more complex circuits that coordinate pathway activity across cell cultures, allocate metabolic tasks among different strains or require cell-to-cell communication with metabolic signals. Inspired by uptake systems found in nature, we propose to couple metabolite import and utilization with a genetic circuit under feedback regulation. Using mathematical models and analysis, we determined the circuit architectures that produce bistability and obtained their design space for bistability in terms of experimentally tuneable parameters. We found an activation–repression architecture to be the most robust switch because it displays bistability for the largest range of design parameters and requires little fine-tuning of the promoters' response curves. Our analytic results are based on on–off approximations of promoter activity and are in excellent qualitative agreement with simulations of more realistic models. With further analysis and simulation, we established conditions to maximize the parameter design space and to produce bimodal phenotypes via hysteresis and cell-to-cell variability. Our results highlight how mathematical analysis can drive the discovery of new circuits for synthetic biology, as the proposed circuit has all the hallmarks of a toggle switch and stands as a promising design to control metabolic phenotypes across cell cultures.
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Marchetto, Francesca, Marco Roverso, Davide Righetti, Sara Bogialli, Francesco Filippini, Elisabetta Bergantino, and Eleonora Sforza. "Bioremediation of Per- and Poly-Fluoroalkyl Substances (PFAS) by Synechocystis sp. PCC 6803: A Chassis for a Synthetic Biology Approach." Life 11, no. 12 (November 26, 2021): 1300. http://dx.doi.org/10.3390/life11121300.
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One of the main concerns in industrialized countries is represented by per- and poly-fluoroalkyl substances (PFAS), persistent contaminants hardly to be dealt with by conventional wastewater treatment processes. Phyco-remediation was proposed as a green alternative method to treat wastewater. Synechocystis sp. PCC6803 is a unicellular photosynthetic organism candidate for bioremediation approaches based on synthetic biology, as it is able to survive in a wide range of polluted waters. In this work, we assessed the possibility of applying Synechocystis in PFAS-enriched waters, which was never reported in the previous literature. Respirometry was applied to evaluate short-term toxicity of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), which did not affect growth up to 0.5 and 4 mg L−1, respectively. Continuous and batch systems were used to assess the long-term effects, and no toxicity was highlighted for both compounds at quite high concentration (1 mg L−1). A partial removal was observed for PFOS and PFOA, (88% and 37%, with removal rates of about 0.15 and 0.36 mg L−1 d−1, respectively). Measurements in fractionated biomass suggested a role for Synechocystis in the sequestration of PFAS: PFOS is mainly internalized in the cell, while PFOA is somehow transformed by still unknown pathways. A preliminary bioinformatic search gave hints on transporters and enzymes possibly involved in such sequestration/transformation processes, opening the route to metabolic engineering in the perspective application of this cyanobacterium as a new phyco-remediation tool, based on synthetic biology.
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Scossa, Federico, Maria Benina, Saleh Alseekh, Youjun Zhang, and Alisdair Fernie. "The Integration of Metabolomics and Next-Generation Sequencing Data to Elucidate the Pathways of Natural Product Metabolism in Medicinal Plants." Planta Medica 84, no. 12/13 (May 29, 2018): 855–73. http://dx.doi.org/10.1055/a-0630-1899.
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AbstractPlants have always been used as medicines since ancient times to treat diseases. The knowledge around the active components of herbal preparations has remained nevertheless fragmentary: the biosynthetic pathways of many secondary metabolites of pharmacological importance have been clarified only in a few species, while the chemodiversity present in many medicinal plants has remained largely unexplored. Despite the advancements of synthetic biology for production of medicinal compounds in heterologous hosts, the native plant species are often the most reliable and economic source for their production. It thus becomes fundamental to investigate the metabolic composition of medicinal plants to characterize their natural metabolic diversity and to define the biosynthetic routes in planta of important compounds to develop strategies to further increase their content. We present here a number of case studies for selected classes of secondary metabolites and we review their health benefits and the historical developments in their structural elucidation and characterization of biosynthetic genes. We cover the cases of benzoisoquinoline and monoterpenoid indole alkaloids, cannabinoids, caffeine, ginsenosides, withanolides, artemisinin, and taxol; we show how the “early” biochemical or the more recent integrative approaches–based on omics-analyses–have helped to elucidate their metabolic pathways and cellular compartmentation. We also summarize how the knowledge generated about their biosynthesis has been used to develop metabolic engineering strategies in heterologous and native hosts. We conclude that following the advent of novel, high-throughput and cost-effective analytical technologies, the secondary metabolism of medicinal plants can now be examined under the lens of systems biology.
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Oyarzún, Diego A., and Guy-Bart V. Stan. "Synthetic gene circuits for metabolic control: design trade-offs and constraints." Journal of The Royal Society Interface 10, no. 78 (January 6, 2013): 20120671. http://dx.doi.org/10.1098/rsif.2012.0671.
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A grand challenge in synthetic biology is to push the design of biomolecular circuits from purely genetic constructs towards systems that interface different levels of the cellular machinery, including signalling networks and metabolic pathways. In this paper, we focus on a genetic circuit for feedback regulation of unbranched metabolic pathways. The objective of this feedback system is to dampen the effect of flux perturbations caused by changes in cellular demands or by engineered pathways consuming metabolic intermediates. We consider a mathematical model for a control circuit with an operon architecture, whereby the expression of all pathway enzymes is transcriptionally repressed by the metabolic product. We address the existence and stability of the steady state, the dynamic response of the network under perturbations, and their dependence on common tuneable knobs such as the promoter characteristic and ribosome binding site (RBS) strengths. Our analysis reveals trade-offs between the steady state of the enzymes and the intermediates, together with a separation principle between promoter and RBS design. We show that enzymatic saturation imposes limits on the parameter design space, which must be satisfied to prevent metabolite accumulation and guarantee the stability of the network. The use of promoters with a broad dynamic range and a small leaky expression enlarges the design space. Simulation results with realistic parameter values also suggest that the control circuit can effectively upregulate enzyme production to compensate flux perturbations.
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Davey, James A., and Corey J. Wilson. "Engineered signal-coupled inducible promoters: measuring the apparent RNA-polymerase resource budget." Nucleic Acids Research 48, no. 17 (September 5, 2020): 9995–10012. http://dx.doi.org/10.1093/nar/gkaa734.
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Abstract Inducible promoters are a central regulatory component in synthetic biology, metabolic engineering, and protein production for laboratory and commercial uses. Many of these applications utilize two or more exogenous promoters, imposing a currently unquantifiable metabolic burden on the living system. Here, we engineered a collection of inducible promoters (regulated by LacI-based transcription factors) that maximize the free-state of endogenous RNA polymerase (RNAP). We leveraged this collection of inducible promotors to construct simple two-channel logical controls that enabled us to measure metabolic burden – as it relates to RNAP resource partitioning. The two-channel genetic circuits utilized sets of signal-coupled transcription factors that regulate cognate inducible promoters in a coordinated logical fashion. With this fundamental genetic architecture, we evaluated the performance of each inducible promoter as discrete operations, and as coupled systems to evaluate and quantify the effects of resource partitioning. Obtaining the ability to systematically and accurately measure the apparent RNA-polymerase resource budget will enable researchers to design more robust genetic circuits, with significantly higher fidelity. Moreover, this study presents a workflow that can be used to better understand how living systems adapt RNAP resources, via the complementary pairing of constitutive and regulated promoters that vary in strength.
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Júlvez, Jorge, and Stephen G. Oliver. "A unifying modelling formalism for the integration of stoichiometric and kinetic models." Journal of The Royal Society Interface 17, no. 169 (August 2020): 20200341. http://dx.doi.org/10.1098/rsif.2020.0341.
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Current research on systems and synthetic biology relies heavily on mathematical models of the systems under study. The usefulness of such models depends on the quantity and quality of biological data, and on the availability of appropriate modelling formalisms that can gather and accommodate such data so that they can be exploited properly. Given our incomplete knowledge of biological systems and the fact that they consist of many subsystems, biological data are usually uncertain and heterogeneous. These facts hinder the use of mathematical models and computational methods. In the scope of dynamic biological systems, e.g. metabolic networks, this difficulty can be overcome by the novel modelling formalism of flexible nets (FNs). We show that an FN can combine, in a natural way, a stoichiometric model and a kinetic model. Moreover, the resulting net admits nonlinear dynamics and can be analysed in both transient and steady states.
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Belov, D. V., and S. N. Belyaev. "Prospects for recycling plastic waste based on polyethylene glycol terephthalate using living systems (a review)." Proceedings of Universities. Applied Chemistry and Biotechnology 12, no. 2 (July 4, 2022): 238–53. http://dx.doi.org/10.21285/2227-2925-2022-12-2-238-253.
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In recent years, the biodegradation of polyethylene glycol terephthalate has become an important direction in solving the problem of environmental pollution with plastic waste. This review generalizes the latest data on various microorganisms capable of biodegrading polyethylene glycol terephthalate. The mechanisms of enzymatic reactions of polyethylene glycol terephthalate hydrolysis and the structure of biodegradation enzymes are elucidated. Challenges to the industrial implementation of polyethylene glycol terephthalate biodegradation are considered along with proposals on the promotion of appropriate waste disposal technologies. Biodegradation comprises a promising method for the environmentally friendly and efficient disposal of waste plastics. So far, no commercial biodegradation technologies for recycling polyethylene glycol terephthalate have been developed. This area is attracting increased research attention, which is expected to result in the appearance of cost-effective and high-tech biodegradation processes. Future advances are likely to be based on synthetic biology and metabolic engineering strategies capable of constructing artificial microbial consortia and modifying microbial polyethylene glycol terephthalate hydrolases aimed at a more complete biodegradation and bioconversion of polyethylene glycol terephthalate and other complex polymers.
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Clavijo-Buriticá, Diana Carolina, Catalina Arévalo-Ferro, and Andrés Fernando González Barrios. "A Holistic Approach from Systems Biology Reveals the Direct Influence of the Quorum-Sensing Phenomenon on Pseudomonas aeruginosa Metabolism to Pyoverdine Biosynthesis." Metabolites 13, no. 5 (May 16, 2023): 659. http://dx.doi.org/10.3390/metabo13050659.
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Computational modeling and simulation of biological systems have become valuable tools for understanding and predicting cellular performance and phenotype generation. This work aimed to construct, model, and dynamically simulate the virulence factor pyoverdine (PVD) biosynthesis in Pseudomonas aeruginosa through a systemic approach, considering that the metabolic pathway of PVD synthesis is regulated by the quorum-sensing (QS) phenomenon. The methodology comprised three main stages: (i) Construction, modeling, and validation of the QS gene regulatory network that controls PVD synthesis in P. aeruginosa strain PAO1; (ii) construction, curating, and modeling of the metabolic network of P. aeruginosa using the flux balance analysis (FBA) approach; (iii) integration and modeling of these two networks into an integrative model using the dynamic flux balance analysis (DFBA) approximation, followed, finally, by an in vitro validation of the integrated model for PVD synthesis in P. aeruginosa as a function of QS signaling. The QS gene network, constructed using the standard System Biology Markup Language, comprised 114 chemical species and 103 reactions and was modeled as a deterministic system following the kinetic based on mass action law. This model showed that the higher the bacterial growth, the higher the extracellular concentration of QS signal molecules, thus emulating the natural behavior of P. aeruginosa PAO1. The P. aeruginosa metabolic network model was constructed based on the iMO1056 model, the P. aeruginosa PAO1 strain genomic annotation, and the metabolic pathway of PVD synthesis. The metabolic network model included the PVD synthesis, transport, exchange reactions, and the QS signal molecules. This metabolic network model was curated and then modeled under the FBA approximation, using biomass maximization as the objective function (optimization problem, a term borrowed from the engineering field). Next, chemical reactions shared by both network models were chosen to combine them into an integrative model. To this end, the fluxes of these reactions, obtained from the QS network model, were fixed in the metabolic network model as constraints of the optimization problem using the DFBA approximation. Finally, simulations of the integrative model (CCBM1146, comprising 1123 reactions and 880 metabolites) were run using the DFBA approximation to get (i) the flux profile for each reaction, (ii) the bacterial growth profile, (iii) the biomass profile, and (iv) the concentration profiles of metabolites of interest such as glucose, PVD, and QS signal molecules. The CCBM1146 model showed that the QS phenomenon directly influences the P. aeruginosa metabolism to PVD biosynthesis as a function of the change in QS signal intensity. The CCBM1146 model made it possible to characterize and explain the complex and emergent behavior generated by the interactions between the two networks, which would have been impossible to do by studying each system’s individual components or scales separately. This work is the first in silico report of an integrative model comprising the QS gene regulatory network and the metabolic network of P. aeruginosa.
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Palur, Dileep Sai Kumar, Shannon R. Pressley, and Shota Atsumi. "Microbial Production of Human Milk Oligosaccharides." Molecules 28, no. 3 (February 3, 2023): 1491. http://dx.doi.org/10.3390/molecules28031491.
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Human milk oligosaccharides (HMOs) are complex nonnutritive sugars present in human milk. These sugars possess prebiotic, immunomodulatory, and antagonistic properties towards pathogens and therefore are important for the health and well-being of newborn babies. Lower prevalence of breastfeeding around the globe, rising popularity of nutraceuticals, and low availability of HMOs have inspired efforts to develop economically feasible and efficient industrial-scale production platforms for HMOs. Recent progress in synthetic biology and metabolic engineering tools has enabled microbial systems to be a production system of HMOs. In this regard, the model organism Escherichia coli has emerged as the preferred production platform. Herein, we summarize the remarkable progress in the microbial production of HMOs and discuss the challenges and future opportunities in unraveling the scope of production of complex HMOs. We focus on the microbial production of five HMOs that have been approved for their commercialization.