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Most Cited Synthetic and Systems Biotechnology Articles

The most cited articles published since 2014, extracted from Scopus.

The secondary metabolite bioinformatics portal: Computational tools to facilitate synthetic biology of secondary metabolite production

Volume 1, Issue 2, June 2016, Pages 69-79
Tilmann Weber | Hyun Uk Kim | Hyun Uk Kim

© 2016 The Authors. Natural products are among the most important sources of lead molecules for drug discovery. With the development of affordable whole-genome sequencing technologies and other 'omics tools, the field of natural products research is currently undergoing a shift in paradigms. While, for decades, mainly analytical and chemical methods gave access to this group of compounds, nowadays genomics-based methods offer complementary approaches to find, identify and characterize such molecules. This paradigm shift also resulted in a high demand for computational tools to assist researchers in their daily work. In this context, this review gives a summary of tools and databases that currently are available to mine, identify and characterize natural product biosynthesis pathways and their producers based on 'omics data. A web portal called Secondary Metabolite Bioinformatics Portal (SMBP at http://www.secondarymetabolites.org) is introduced to provide a one-stop catalog and links to these bioinformatics resources. In addition, an outlook is presented how the existing tools and those to be developed will influence synthetic biology approaches in the natural products field.

CRISPy-web: An online resource to design sgRNAs for CRISPR applications

Volume 1, Issue 2, June 2016, Pages 118-121
Kai Blin | Lasse Ebdrup Pedersen | Tilmann Weber | Sang Yup Lee | Sang Yup Lee

© 2016 The Authors. CRISPR/Cas9-based genome editing has been one of the major achievements of molecular biology, allowing the targeted engineering of a wide range of genomes. The system originally evolved in prokaryotes as an adaptive immune system against bacteriophage infections. It now sees widespread application in genome engineering workflows, especially using the Streptococcus pyogenes endonuclease Cas9. To utilize Cas9, so-called single guide RNAs (sgRNAs) need to be designed for each target gene. While there are many tools available to design sgRNAs for the popular model organisms, only few tools that allow designing sgRNAs for non-model organisms exist. Here, we present CRISPy-web (http://crispy.secondarymetabolites.org/), an easy to use web tool based on CRISPy to design sgRNAs for any user-provided microbial genome. CRISPy-web allows researchers to interactively select a region of their genome of interest to scan for possible sgRNAs. After checks for potential off-target matches, the resulting sgRNA sequences are displayed graphically and can be exported to text files. All steps and information are accessible from a web browser without the requirement to install and use command line scripts.

Design, analysis and application of synthetic microbial consortia

Volume 1, Issue 2, June 2016, Pages 109-117
Xiaoqiang Jia | Chang Liu | Hao Song | Mingzhu Ding | Jin Du | Qian Ma | Yingjin Yuan

© 2016 The Authors. The rapid development of synthetic biology has conferred almost perfect modification on single cells, and provided methodological support for synthesizing microbial consortia, which have a much wider application potential than synthetic single cells. Co-cultivating multiple cell populations with rational strategies based on interacting relationships within natural microbial consortia provides theoretical as well as experimental support for the successful obtaining of synthetic microbial consortia, promoting it into extensive research on both industrial applications in plenty of areas and also better understanding of natural microbial consortia. According to their composition complexity, synthetic microbial consortia are summarized in three aspects in this review and are discussed in principles of design and construction, insights and methods for analysis, and applications in energy, healthcare, etc.

Synthetic biology of microbes synthesizing polyhydroxyalkanoates (PHA)

Volume 1, Issue 4, December 2016, Pages 236-242
Guo Qiang Chen | Guo Qiang Chen | Guo Qiang Chen | Guo Qiang Chen | Guo Qiang Chen | Xiao Ran Jiang | Xiao Ran Jiang | Xiao Ran Jiang | Yingying Guo | Yingying Guo | Yingying Guo

© 2016 The Authors Microbial polyhydroxyalkanoates (PHA) have been produced as bioplastics for various purposes. Under the support of China National Basic Research 973 Project, we developed synthetic biology methods to diversify the PHA structures into homo-, random, block polymers with improved properties to better meet various application requirements. At the same time, various pathways were assembled to produce various PHA from glucose as a simple carbon source. At the end, Halomonas bacteria were reconstructed to produce PHA in changing morphology for low cost production under unsterile and continuous conditions. The synthetic biology will advance the PHA into a bio- and material industry.

Reactive oxygen species and antioxidant properties from mushrooms

Volume 2, Issue 1, March 2017, Pages 13-22
Carmen Sánchez

© 2016 The Author Preventive medicine and food industry have shown an increased interest in the development of natural antioxidants, since those most commonly used synthetic antioxidants may have restricted use in food. This could explain why there is currently much research on the antioxidant properties from natural products such as mushrooms. Many mushrooms have been reported to possess antioxidant properties, which enable them to neutralize free radicals. The oxygen molecule is a free radical, which lead to the generation of the reactive oxygen species and can damage the cells. Cell damage caused by free radicals appears to be a major contributor to aging and degenerative diseases. Mushrooms antioxidant components are found in fruit bodies, mycelium and culture both, which include polysaccharides, tocopherols, phenolics, carotenoids, ergosterol and ascorbic acid among others. Fruit bodies or mycelium can be manipulated to produce active compounds in a relatively short period of time, which represent a significant advantage in antioxidant compounds extraction from mushrooms. Antioxidant compounds may be extracted to be used as functional additives or mushrooms can be incorporated into our food regime, representing an alternative source of food to prevent damage caused by oxidation in the human body.

Genome and metabolic engineering in non-conventional yeasts: Current advances and applications

Volume 2, Issue 3, September 2017, Pages 198-207
Ann Kathrin Löbs | Cory Schwartz | Ian Wheeldon

© 2017 The Authors Microbial production of chemicals and proteins from biomass-derived and waste sugar streams is a rapidly growing area of research and development. While the model yeast Saccharomyces cerevisiae is an excellent host for the conversion of glucose to ethanol, production of other chemicals from alternative substrates often requires extensive strain engineering. To avoid complex and intensive engineering of S. cerevisiae, other yeasts are often selected as hosts for bioprocessing based on their natural capacity to produce a desired product: for example, the efficient production and secretion of proteins, lipids, and primary metabolites that have value as commodity chemicals. Even when using yeasts with beneficial native phenotypes, metabolic engineering to increase yield, titer, and production rate is essential. The non-conventional yeasts Kluyveromyces lactis, K. marxianus, Scheffersomyces stipitis, Yarrowia lipolytica, Hansenula polymorpha and Pichia pastoris have been developed as eukaryotic hosts because of their desirable phenotypes, including thermotolerance, assimilation of diverse carbon sources, and high protein secretion. However, advanced metabolic engineering in these yeasts has been limited. This review outlines the challenges of using non-conventional yeasts for strain and pathway engineering, and discusses the developed solutions to these problems and the resulting applications in industrial biotechnology.

A systematic study of the whole genome sequence of Amycolatopsis methanolica strain 239Tprovides an insight into its physiological and taxonomic properties which correlate with its position in the genus

Volume 1, Issue 3, September 2016, Pages 169-186
Biao Tang | Biao Tang | Feng Xie | Wei Zhao | Jian Wang | Shengwang Dai | Huajun Zheng | Xiaoming Ding | Xufeng Cen | Haican Liu | Yucong Yu | Haokui Zhou | Yan Zhou | Yan Zhou | Lixin Zhang | Michael Goodfellow | Guo Ping Zhao | Guo Ping Zhao | Guo Ping Zhao | Guo Ping Zhao

© 2016 The complete genome of methanol-utilizing Amycolatopsis methanolica strain 239Twas generated, revealing a single 7,237,391 nucleotide circular chromosome with 7074 annotated protein-coding sequences (CDSs). Comparative analyses against the complete genome sequences of Amycolatopsis japonica strain MG417-CF17T, Amycolatopsis mediterranei strain U32 and Amycolatopsis orientalis strain HCCB10007 revealed a broad spectrum of genomic structures, including various genome sizes, core/quasi-core/non-core configurations and different kinds of episomes. Although polyketide synthase gene clusters were absent from the A. methanolica genome, 12 gene clusters related to the biosynthesis of other specialized (secondary) metabolites were identified. Complete pathways attributable to the facultative methylotrophic physiology of A. methanolica strain 239T, including both the mdo/mscR encoded methanol oxidation and the hps/hpi encoded formaldehyde assimilation via the ribulose monophosphate cycle, were identified together with evidence that the latter might be the result of horizontal gene transfer. Phylogenetic analyses based on 16S rDNA or orthologues of AMETH_3452, a novel actinobacterial class-specific conserved gene against 62 or 18 Amycolatopsis type strains, respectively, revealed three major phyletic lineages, namely the mesophilic or moderately thermophilic A. orientalis subclade (AOS), the mesophilic Amycolatopsis taiwanensis subclade (ATS) and the thermophilic A. methanolica subclade (AMS). The distinct growth temperatures of members of the subclades correlated with corresponding genetic variations in their encoded compatible solutes. This study shows the value of integrating conventional taxonomic with whole genome sequence data.

Development of fungal cell factories for the production of secondary metabolites: Linking genomics and metabolism

Volume 2, Issue 1, March 2017, Pages 5-12
Jens Christian Nielsen | Jens Nielsen

© 2017 The genomic era has revolutionized research on secondary metabolites and bioinformatics methods have in recent years revived the antibiotic discovery process after decades with only few new active molecules being identified. New computational tools are driven by genomics and metabolomics analysis, and enables rapid identification of novel secondary metabolites. To translate this increased discovery rate into industrial exploitation, it is necessary to integrate secondary metabolite pathways in the metabolic engineering process. In this review, we will describe the novel advances in discovery of secondary metabolites produced by filamentous fungi, highlight the utilization of genome-scale metabolic models (GEMs) in the design of fungal cell factories for the production of secondary metabolites and review strategies for optimizing secondary metabolite production through the construction of high yielding platform cell factories.

In silico methods for linking genes and secondary metabolites: The way forward

Volume 1, Issue 2, June 2016, Pages 80-88
Shradha Khater | Swadha Anand | Debasisa Mohanty

© 2016 The Authors. In silico methods for linking genomic space to chemical space have played a crucial role in genomics driven discovery of new natural products as well as biosynthesis of altered natural products by engineering of biosynthetic pathways. Here we give an overview of available computational tools and then briefly describe a novel computational framework, namely retro-biosynthetic enumeration of biosynthetic reactions, which can add to the repertoire of computational tools available for connecting natural products to their biosynthetic gene clusters. Most of the currently available bioinformatics tools for analysis of secondary metabolite biosynthetic gene clusters utilize the "Genes to Metabolites" approach. In contrast to the "Genes to Metabolites" approach, the "Metabolites to Genes" or retro-biosynthetic approach would involve enumerating the various biochemical transformations or enzymatic reactions which would generate the given chemical moiety starting from a set of precursor molecules and identifying enzymatic domains which can potentially catalyze the enumerated biochemical transformations. In this article, we first give a brief overview of the presently available in silico tools and approaches for analysis of secondary metabolite biosynthetic pathways. We also discuss our preliminary work on development of algorithms for retro-biosynthetic enumeration of biochemical transformations to formulate a novel computational method for identifying genes associated with biosynthesis of a given polyketide or nonribosomal peptide.

A review of computational tools for design and reconstruction of metabolic pathways

Volume 2, Issue 4, December 2017, Pages 243-252
Lin Wang | Satyakam Dash | Chiam Yu Ng | Costas D. Maranas

© 2017 The Authors Metabolic pathways reflect an organism's chemical repertoire and hence their elucidation and design have been a primary goal in metabolic engineering. Various computational methods have been developed to design novel metabolic pathways while taking into account several prerequisites such as pathway stoichiometry, thermodynamics, host compatibility, and enzyme availability. The choice of the method is often determined by the nature of the metabolites of interest and preferred host organism, along with computational complexity and availability of software tools. In this paper, we review different computational approaches used to design metabolic pathways based on the reaction network representation of the database (i.e., graph or stoichiometric matrix) and the search algorithm (i.e., graph search, flux balance analysis, or retrosynthetic search). We also put forth a systematic workflow that can be implemented in projects requiring pathway design and highlight current limitations and obstacles in computational pathway design.

In vitro reconstitution guide for targeted synthetic metabolism of chemicals, nutraceuticals and drug precursors

Volume 1, Issue 1, January 2016, Pages 25-33
Gao Yi Tan | Faying Zhu | Zixin Deng | Zixin Deng | Tiangang Liu | Tiangang Liu

© 2016 Authors. With the developments in metabolic engineering and the emergence of synthetic biology, many breakthroughs in medicinal, biological and chemical products as well as biofuels have been achieved in recent decades. As an important barrier to traditional metabolic engineering, however, the identification of ratelimiting step(s) for the improvement of specific cellular functions is often difficult. Meanwhile, in the case of synthetic biology, more and more BioBricks could be constructed for targeted purposes, but the optimized assembly or engineering of these components for high-efficiency cell factories is still a challenge. Owing to the lack of steady-state kinetic data for overall flux, balancing many multistep biosynthetic pathways is time-consuming and needs vast resources of labor and materials. A strategy called targeted engineering is proposed in an effort to solve this problem. Briefly, a targeted biosynthetic pathway is to be reconstituted in vitro and then the contribution of cofactors, substrates and each enzyme will be analyzed systematically. Next is in vivo engineering or de novo pathway assembly with the guidance of information gained from in vitro assays. To demonstrate its practical application, biosynthesis pathways for the production of important products, e.g. chemicals, nutraceuticals and drug precursors, have been engineered in Escherichia coli and Saccharomyces cerevisiae. These cases can be regarded as concept proofs indicating targeted engineering might help to create high-efficiency cell factories based upon constructed biological components.

Cell-free synthetic biology: Engineering in an open world

Volume 2, Issue 1, March 2017, Pages 23-27
Yuan Lu | Yuan Lu

© 2017 Cell-free synthetic biology emerges as a powerful and flexible enabling technology that can engineer biological parts and systems for life science applications without using living cells. It provides simpler and faster engineering solutions with an unprecedented freedom of design in an open environment than cell system. This review focuses on recent developments of cell-free synthetic biology on biological engineering fields at molecular and cellular levels, including protein engineering, metabolic engineering, and artificial cell engineering. In cell-free protein engineering, the direct control of reaction conditions in cell-free system allows for easy synthesis of complex proteins, toxic proteins, membrane proteins, and novel proteins with unnatural amino acids. Cell-free systems offer the ability to design metabolic pathways towards the production of desired products. Buildup of artificial cells based on cell-free systems will improve our understanding of life and use them for environmental and biomedical applications.

Norine: A powerful resource for novel nonribosomal peptide discovery

Volume 1, Issue 2, June 2016, Pages 89-94
M. Pupin | M. Pupin | Q. Esmaeel | A. Flissi | A. Flissi | Y. Dufresne | Y. Dufresne | P. Jacques | P. Jacques | V. Leclère | V. Leclère | V. Leclère

© 2016 The Authors. Since its first release in 2008, Norine remains the unique resource completely devoted to nonribosomal peptides (NRPs). They are very attractive microbial secondary metabolites, displaying a remarkable diversity of structure and functions. Norine (. http://bioinfo.lifl.fr/NRP) includes a database now containing more than 1160 annotated peptides and user-friendly interfaces enabling the querying of the database, through the annotations or the structure of the peptides. Dedicated tools are associated for structural comparison of the compounds and prediction of their biological activities. In this paper, we start by describing the knowledgebase and the dedicated tools. We then present some user cases to show how useful Norine is for the discovery of novel nonribosomal peptides.

Development of Streptomyces sp. FR-008 as an emerging chassis

Volume 1, Issue 3, September 2016, Pages 207-214
Qian Liu | Qian Liu | Liping Xiao | Liping Xiao | Yuanjie Zhou | Yuanjie Zhou | Kunhua Deng | Kunhua Deng | Gaoyi Tan | Gaoyi Tan | Yichao Han | Xinhua Liu | Xinhua Liu | Zixin Deng | Zixin Deng | Zixin Deng | Tiangang Liu | Tiangang Liu

© 2016 The Authors Microbial-derived natural products are important in both the pharmaceutical industry and academic research. As the metabolic potential of original producer especially Streptomyces is often limited by slow growth rate, complicated cultivation profile, and unfeasible genetic manipulation, so exploring a Streptomyces as a super industrial chassis is valuable and urgent. Streptomyces sp. FR-008 is a fast-growing microorganism and can also produce a considerable amount of macrolide candicidin via modular polyketide synthase. In this study, we evaluated Streptomyces sp. FR-008 as a potential industrial-production chassis. First, PacBio sequencing and transcriptome analyses indicated that the Streptomyces sp. FR-008 genome size is 7.26 Mb, which represents one of the smallest of currently sequenced Streptomyces genomes. In addition, we simplified the conjugation procedure without heat-shock and pre-germination treatments but with high conjugation efficiency, suggesting it is inherently capable of accepting heterologous DNA. In addition, a series of promoters selected from literatures was assessed based on GusA activity in Streptomyces sp. FR-008. Compared with the common used promoter ermE*-p, the strength of these promoters comprise a library with a constitutive range of 60–860%, thus providing the useful regulatory elements for future genetic engineering purpose. In order to minimum the genome, we also target deleted three endogenous polyketide synthase (PKS) gene clusters to generate a mutant LQ3. LQ3 is thus an “updated” version of Streptomyces sp. FR-008, producing fewer secondary metabolites profiles than Streptomyces sp. FR-008. We believe this work could facilitate further development of Streptomyces sp. FR-008 for use in biotechnological applications.

FunGeneClusterS: Predicting fungal gene clusters from genome and transcriptome data

Volume 1, Issue 2, June 2016, Pages 122-129
Tammi C. Vesth | Julian Brandl | Mikael Rørdam Andersen

© 2016 The Authors. Introduction: Secondary metabolites of fungi are receiving an increasing amount of interest due to their prolific bioactivities and the fact that fungal biosynthesis of secondary metabolites often occurs from co-regulated and co-located gene clusters. This makes the gene clusters attractive for synthetic biology and industrial biotechnology applications. We have previously published a method for accurate prediction of clusters from genome and transcriptome data, which could also suggest cross-chemistry, however, this method was limited both in the number of parameters which could be adjusted as well as in user-friendliness. Furthermore, sensitivity to the transcriptome data required manual curation of the predictions. In the present work, we have aimed at improving these features. Results: FunGeneClusterS is an improved implementation of our previous method with a graphical user interface for off- and on-line use. The new method adds options to adjust the size of the gene cluster(s) being sought as well as an option for the algorithm to be flexible with genes in the cluster which may not seem to be co-regulated with the remainder of the cluster. We have benchmarked the method using data from the well-studied Aspergillus nidulans and found that the method is an improvement over the previous one. In particular, it makes it possible to predict clusters with more than 10 genes more accurately, and allows identification of co-regulated gene clusters irrespective of the function of the genes. It also greatly reduces the need for manual curation of the prediction results. We furthermore applied the method to transcriptome data from A. niger. Using the identified best set of parameters, we were able to identify clusters for 31 out of 76 previously predicted secondary metabolite synthases/synthetases. Furthermore, we identified additional putative secondary metabolite gene clusters. In total, we predicted 432 co-transcribed gene clusters in A. niger (spanning 1.323 genes, 12% of the genome). Some of these had functions related to primary metabolism, e.g. we have identified a cluster for biosynthesis of biotin, as well as several for degradation of aromatic compounds. The data identifies that suggests that larger parts of the fungal genome than previously anticipated operates as gene clusters. This includes both primary and secondary metabolism as well as other cellular maintenance functions. Conclusion: We have developed FunGeneClusterS in a graphical implementation and made the method capable of adjustments to different datasets and target clusters. The method is versatile in that it can predict co-regulated clusters not limited to secondary metabolism. Our analysis of data has shown not only the validity of the method, but also strongly suggests that large parts of fungal primary metabolism and cellular functions are both co-regulated and co-located.

Engineered polyketides: Synergy between protein and host level engineering

Volume 2, Issue 3, September 2017, Pages 147-166
Jesus F. Barajas | Jacquelyn M. Blake-Hedges | Constance B. Bailey | Constance B. Bailey | Samuel Curran | Samuel Curran | Jay D. Keasling | Jay D. Keasling | Jay D. Keasling | Jay D. Keasling | Jay D. Keasling

© 2017 Metabolic engineering efforts toward rewiring metabolism of cells to produce new compounds often require the utilization of non-native enzymatic machinery that is capable of producing a broad range of chemical functionalities. Polyketides encompass one of the largest classes of chemically diverse natural products. With thousands of known polyketides, modular polyketide synthases (PKSs) share a particularly attractive biosynthetic logic for generating chemical diversity. The engineering of modular PKSs could open access to the deliberate production of both existing and novel compounds. In this review, we discuss PKS engineering efforts applied at both the protein and cellular level for the generation of a diverse range of chemical structures, and we examine future applications of PKSs in the production of medicines, fuels and other industrially relevant chemicals.

Systems metabolic engineering strategies for the production of amino acids

Volume 2, Issue 2, June 2017, Pages 87-96
Qian Ma | Qian Ma | Qian Ma | Quanwei Zhang | Qingyang Xu | Qingyang Xu | Qingyang Xu | Chenglin Zhang | Chenglin Zhang | Chenglin Zhang | Yanjun Li | Yanjun Li | Yanjun Li | Xiaoguang Fan | Xiaoguang Fan | Xiaoguang Fan | Xixian Xie | Xixian Xie | Xixian Xie | Ning Chen | Ning Chen | Ning Chen

© 2017 The Authors Systems metabolic engineering is a multidisciplinary area that integrates systems biology, synthetic biology and evolutionary engineering. It is an efficient approach for strain improvement and process optimization, and has been successfully applied in the microbial production of various chemicals including amino acids. In this review, systems metabolic engineering strategies including pathway-focused approaches, systems biology-based approaches, evolutionary approaches and their applications in two major amino acid producing microorganisms: Corynebacterium glutamicum and Escherichia coli, are summarized.

Modules for in vitro metabolic engineering: Pathway assembly for bio-based production of value-added chemicals

Volume 2, Issue 2, June 2017, Pages 65-74
Hironori Taniguchi | Kenji Okano | Kohsuke Honda

© 2017 The Authors Bio-based chemical production has drawn attention regarding the realization of a sustainable society. In vitro metabolic engineering is one of the methods used for the bio-based production of value-added chemicals. This method involves the reconstitution of natural or artificial metabolic pathways by assembling purified/semi-purified enzymes in vitro. Enzymes from distinct sources can be combined to construct desired reaction cascades with fewer biological constraints in one vessel, enabling easier pathway design with high modularity. Multiple modules have been designed, built, tested, and improved by different groups for different purpose. In this review, we focus on these in vitro metabolic engineering modules, especially focusing on the carbon metabolism, and present an overview of input modules, output modules, and other modules related to cofactor management.

Targeted mutagenesis: A sniper-like diversity generator in microbial engineering

Volume 2, Issue 2, June 2017, Pages 75-86
Xiang Zheng | Xin Hui Xing | Chong Zhang

© 2017 Mutations, serving as the raw materials of evolution, have been extensively utilized to increase the chances of engineering molecules or microbes with tailor-made functions. Global and targeted mutagenesis are two main methods of obtaining various mutations, distinguished by the range of action they can cover. While the former one stresses the mining of novel genetic loci within the whole genomic background, targeted mutagenesis performs in a more straightforward manner, bringing evolutionary escape and error catastrophe under control. In this review, we classify the existing techniques of targeted mutagenesis into two categories in terms of whether the diversity is generated in vitro or in vivo, and briefly introduce the mechanisms and applications of them separately. The inherent connections and development trends of the two classes are also discussed to provide an insight into the next generation evolution research.

Design and construction of synthetic microbial consortia in China

Volume 1, Issue 4, December 2016, Pages 230-235
Ming Zhu Ding | Ming Zhu Ding | Hao Song | Hao Song | En Xu Wang | En Xu Wang | Yue Liu | Yue Liu | Ying Jin Yuan | Ying Jin Yuan

© 2016 The rapid development of synthetic biology enables the design, construction and optimization of synthetic microbial consortia to achieve specific functions. In China, the “973” project-“Design and Construction of Microbial Consortia” was funded by the National Basic Research Program of China in January 2014. It was proposed to address the fundamental challenges in engineering natural microbial consortia and reconstructing microbial consortia to meet industrial demands. In this review, we will introduce this “973” project, including the significance of microbial consortia, the fundamental scientific issues, the recent research progresses, and some case studies about synthetic microbial consortia in the past two and a half years.

Synthetic biology in the UK – An outline of plans and progress

Volume 1, Issue 4, December 2016, Pages 243-257
L. J. Clarke | L. J. Clarke | L. J. Clarke | L. J. Clarke | R. I. Kitney | R. I. Kitney | R. I. Kitney | R. I. Kitney

© 2016 Synthetic biology is capable of delivering new solutions to key challenges spanning the bioeconomy, both nationally and internationally. Recognising this significant potential and the associated need to facilitate its translation and commercialisation the UK government commissioned the production of a national Synthetic Biology Roadmap in 2011, and subsequently provided crucial support to assist its implementation. Critical infrastructural investments have been made, and important strides made towards the development of an effectively connected community of practitioners and interest groups. A number of Synthetic Biology Research Centres, DNA Synthesis Foundries, a Centre for Doctoral Training, and an Innovation Knowledge Centre have been established, creating a nationally distributed and integrated network of complementary facilities and expertise. The UK Synthetic Biology Leadership Council published a UK Synthetic Biology Strategic Plan in 2016, increasing focus on the processes of translation and commercialisation. Over 50 start-ups, SMEs and larger companies are actively engaged in synthetic biology in the UK, and inward investments are starting to flow. Together these initiatives provide an important foundation for stimulating innovation, actively contributing to international research and development partnerships, and helping deliver useful benefits from synthetic biology in response to local and global needs and challenges.

A brief overview of synthetic biology research programs and roadmap studies in the United States

Volume 1, Issue 4, December 2016, Pages 258-264
Tong Si | Huimin Zhao | Huimin Zhao | Huimin Zhao | Huimin Zhao | Huimin Zhao

© 2016 The Authors The United States is a leading nation in the development of synthetic biology, an emerging engineering discipline to create, control and reprogram biological systems. With strategic investment from its government agencies, the U.S. has established numerous research centers and programs in synthetic biology, enabling significant advances in foundational tool development and practical applications ranging from bioenergy, biomanufacturing, to biomedicine. To maintain its leadership in synthetic biology, U.S, has conducted several roadmap studies to provide strategic visions and action recommendations. Here we will provide a brief overview of the major research programs and roadmap studies of synthetic biology in the U.S.

Production of anthocyanins in metabolically engineered microorganisms: Current status and perspectives

Volume 2, Issue 4, December 2017, Pages 259-266
Jian Zha | Mattheos A.G. Koffas | Mattheos A.G. Koffas

© 2017 The Authors Microbial production of plant-derived natural products by engineered microorganisms has achieved great success thanks to large extend to metabolic engineering and synthetic biology. Anthocyanins, the water-soluble colored pigments found in terrestrial plants that are responsible for the red, blue and purple coloration of many flowers and fruits, are extensively used in food and cosmetics industry; however, their current supply heavily relies on complex extraction from plant-based materials. A promising alternative is their sustainable production in metabolically engineered microbes. Here, we review the recent progress on anthocyanin biosynthesis in engineered bacteria, with a special focus on the systematic engineering modifications such as selection and engineering of biosynthetic enzymes, engineering of transportation, regulation of UDP-glucose supply, as well as process optimization. These promising engineering strategies will facilitate successful microbial production of anthocyanins in industry in the near future.

Engineering of Yarrowia lipolytica for production of astaxanthin

Volume 2, Issue 4, December 2017, Pages 287-294
Kanchana Rueksomtawin Kildegaard | Belén Adiego-Pérez | Belén Adiego-Pérez | David Doménech Belda | David Doménech Belda | Jaspreet Kaur Khangura | Carina Holkenbrink | Irina Borodina

© 2017 The Authors Astaxanthin is a red-colored carotenoid, used as food and feed additive. Astaxanthin is mainly produced by chemical synthesis, however, the process is expensive and synthetic astaxanthin is not approved for human consumption. In this study, we engineered the oleaginous yeast Yarrowia lipolytica for de novo production of astaxanthin by fermentation. First, we screened 12 different Y. lipolytica isolates for β-carotene production by introducing two genes for β-carotene biosynthesis: bi-functional phytoene synthase/lycopene cyclase (crtYB) and phytoene desaturase (crtI) from the red yeast Xanthophyllomyces dendrorhous. The best strain produced 31.1 ± 0.5 mg/L β-carotene. Next, we optimized the activities of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG1) and geranylgeranyl diphosphate synthase (GGS1/crtE) in the best producing strain and obtained 453.9 ± 20.2 mg/L β-carotene. Additional downregulation of the competing squalene synthase SQS1 increased the β-carotene titer to 797.1 ± 57.2 mg/L. Then we introduced β-carotene ketolase (crtW) from Paracoccus sp. N81106 and hydroxylase (crtZ) from Pantoea ananatis to convert β-carotene into astaxanthin. The constructed strain accumulated 10.4 ± 0.5 mg/L of astaxanthin but also accumulated astaxanthin biosynthesis intermediates, 5.7 ± 0.5 mg/L canthaxanthin, and 35.3 ± 1.8 mg/L echinenone. Finally, we optimized the copy numbers of crtZ and crtW to obtain 3.5 mg/g DCW (54.6 mg/L) of astaxanthin in a microtiter plate cultivation. Our study for the first time reports engineering of Y. lipolytica for the production of astaxanthin. The high astaxanthin content and titer obtained even in a small-scale cultivation demonstrates a strong potential for Y. lipolytica-based fermentation process for astaxanthin production.

Novel polysaccharide-protein conjugates provide an immunogenic 13-valent pneumococcal conjugate vaccine for S. pneumoniae

Volume 2, Issue 1, March 2017, Pages 49-58
Allison E.B. Turner | Allison E.B. Turner | Jonas E. Gerson | Jonas E. Gerson | Helen Y. So | Daniel J. Krasznai | Adrienne J. St. Hilaire | Donald F. Gerson | Donald F. Gerson

© 2016 The Authors Pneumonia remains the single leading cause of childhood death worldwide. Despite the commercial availability of multiple pneumococcal conjugate vaccines (PCVs), high dosage cost and supply shortages prevent PCV delivery to much of the developing world. The current work presents high-yield pneumococcal conjugates that are immunogenic in animals and suitable for use in human vaccine development. The 13-valent pneumococcal conjugate vaccine (PCV-13) investigated in this research incorporated serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. Pneumococcal polysaccharides (PnPSs) and CRM197carrier protein were produced and purified in-house, and used to prepare PnPS-CRM conjugates using unique, cyanide-free, in vacuo glycation conjugation methods. In vitro characterization confirmed the generation of higher molecular weight PnPS-CRM conjugates low in free protein. In vivo animal studies were performed to compare PnuVax's PCV-13 to the commercially available PCV-13, Prevnar®13 (Pfizer, USA). A boost dose was provided to all groups post-dose 1 at t = 14 days. Post-dose 2 results at t = 28 days showed that all 13 serotypes in PnuVax's PCV-13 were boostable. Per serotype IgG GMCs demonstrated that PnuVax's PCV-13 is immunogenic for all 13 serotypes, with 10 of the 13 serotypes statistically the same or higher than Prevnar®13 post-dose 2. As a result, the novel polysaccharide-protein conjugates developed in this work are highly promising for use in human PCV development. The in vacuo conjugation technique applied in this work could also be readily adapted to develop many other conjugate vaccines.

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