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Metabolic Engineering

Elena Geiser, Sandra K Przybilla, Meike Engel, Wiebke Kleineberg, Linda Büttner, Eda Sarikaya, Tim den Hartog, Jürgen Klankermayer, Walter Leitner, Michael Bölker, Lars M Blank, Nick Wierckx
The Ustilaginaceae family of smut fungi, especially Ustilago maydis, gained biotechnological interest over the last years, amongst others due to its ability to naturally produce the versatile bio-based building block itaconate. Along with itaconate, U. maydis also produces 2-hydroxyparaconate. The latter was proposed to be derived from itaconate, but the underlying biochemistry and associated genes were thus far unknown. Here, we confirm that 2-hydroxyparaconate is a secondary metabolite of U. maydis and propose an extension of U...
October 14, 2016: Metabolic Engineering
Mathias Klein, Martina Carrillo, Joeline Xiberras, Zia-Ul Islam, Steve Swinnen, Elke Nevoigt
One advantage of using glycerol as a carbon source for industrial bioprocesses is its higher degree of reduction compared to glucose. In order to exploit this reducing power for the production of reduced compounds thereby significantly increasing maximum theoretical yields, the electrons derived from glycerol oxidation must first be saved in the form of cytosolic NAD(P)H. However, the industrial platform organism Saccharomyces cerevisiae naturally uses a FAD-dependent pathway for glycerol catabolism transferring the electrons to the respiratory chain...
October 14, 2016: Metabolic Engineering
Yemin Wang, Zhengsheng Tao, Hualiang Zheng, Fei Zhang, Qingshan Long, Zixin Deng, Meifeng Tao
Many high-value secondary metabolites are assembled by very large multifunctional polyketide synthases or non-ribosomal peptide synthetases encoded by giant genes, for instance, natamycin production in an industrial strain of Streptomyces gilvosporeus. In this study, a large operon reporter-based selection system has been developed using the selectable marker gene neo to report the expression both of the large polyketide synthase genes and of the entire gene cluster, thereby facilitating the selection of natamycin-overproducing mutants by iterative random mutagenesis breeding...
October 13, 2016: Metabolic Engineering
Michael Vogt, Christian Brüsseler, Jan van Ooyen, Michael Bott, Jan Marienhagen
The pentanol isomers 2-methyl-1-butanol and 3-methyl-1-butanol represent commercially interesting alcohols due to their potential application as biofuels. For a sustainable microbial production of these compounds, Corynebacterium glutamicum was engineered for producing 2-methyl-1-butanol and 3-methyl-1-butanol via the Ehrlich pathway from 2-keto-3-methylvalerate and 2-ketoisocaproate, respectively. In addition to an already available 2-ketoisocaproate producer, a 2-keto-3-methylvalerate accumulating C. glutamicum strain was also constructed...
October 13, 2016: Metabolic Engineering
Jeong Wook Lee, Jongho Yi, Tae Yong Kim, Sol Choi, Jung Ho Ahn, Hyohak Song, Moon-Hee Lee, Sang Yup Lee
Succinic acid (SA) is a four carbon dicarboxylic acid of great industrial interest that can be produced by microbial fermentation. Here we report development of a high-yield homo-SA producing Mannheimia succiniciproducens strain by metabolic engineering. The PALFK strain (ldhA(-), pta(-), ackA(-), fruA(-)) was developed based on optimization of carbon flux towards SA production while minimizing byproducts formation through the integrated application of in silico genome-scale metabolic flux analysis, omics analyses, and reconstruction of central carbon metabolism...
October 13, 2016: Metabolic Engineering
Juyoung Jung, Jae Hyung Lim, Se Yeon Kim, Dae-Kyun Im, Joo Yeon Seok, Seung-Jae V Lee, Min-Kyu Oh, Gyoo Yeol Jung
Biosynthesis of isoprenoids via the 1-deoxy-D-xylulose-5-phosphate (DXP) pathway requires equimolar glyceraldehyde 3-phosphate and pyruvate to divert carbon flux toward the products of interest. Here, we demonstrate that precursor balancing is one of the critical steps for the production of isoprenoids in Escherichia coli. First, the implementation of the synthetic lycopene production pathway as a model system and the amplification of the native DXP pathway were accomplished using synthetic constitutive promoters and redesigned 5'-untranslated regions (5'-UTRs)...
October 7, 2016: Metabolic Engineering
Jin Chen, Michael A Henson
Synthesis gas fermentation is one of the most promising routes to convert synthesis gas (syngas; mainly comprised of H2 and CO) to renewable liquid fuels and chemicals by specialized bacteria. The most commonly studied syngas fermenting bacterium is Clostridium ljungdahlii, which produces acetate and ethanol as its primary metabolic byproducts. Engineering of C. ljungdahlii metabolism to overproduce ethanol, enhance the synthesize of the native byproducts lactate and 2,3-butanediol, and introduce the synthesis of non-native products such as butanol and butyrate has substantial commercial value...
October 5, 2016: Metabolic Engineering
Mahmoud Kamal Ahmadi, Lei Fang, Nicholas Moscatello, Blaine A Pfeifer
In this report, the heterologous production of salicylate (SA) is the basis for metabolic extension to salicylate 2-O-β-d-glucoside (SAG), a natural product implicated in plant-based defense mechanisms. Production was optimized through a combination of metabolic engineering, gene expression variation, and co-culture design. When combined, SA and SAG production titers reached ~0.9g/L and ~2.5g/L, respectively. The SAG compound was then tested for anti-inflammatory properties relative to SA and acetylsalicylate (aspirin)...
October 5, 2016: Metabolic Engineering
Richard Kelwick, Alexander J Webb, James T MacDonald, Paul S Freemont
Cell-free transcription-translation systems were originally applied towards in vitro protein production. More recently, synthetic biology is enabling these systems to be used within a systematic design context for prototyping DNA regulatory elements, genetic logic circuits and biosynthetic pathways. The Gram-positive soil bacterium, Bacillus subtilis, is an established model organism of industrial importance. To this end, we developed several B. subtilis-based cell-free systems. Our improved B. subtilis WB800N-based system was capable of producing 0...
September 30, 2016: Metabolic Engineering
Wenqin Bai, Yi-Shu Tai, Jingyu Wang, Jilong Wang, Pooja Jambunathan, Kevin J Fox, Kechun Zhang
Dicarboxylic acids are attractive biosynthetic targets due to their broad applications and their challenging manufacturing process from fossil fuel feedstock. Mesaconate is a branched, unsaturated dicarboxylic acid that can be used as a co-monomer to produce hydrogels and fire-retardant materials. In this study, we engineered nonphosphorylative metabolism to produce mesaconate from d-xylose and l-arabinose. This nonphosphorylative metabolism is orthogonal to the intrinsic pentose metabolism in Escherichia coli and has fewer enzymatic steps and a higher theoretical yield to TCA cycle intermediates than the pentose phosphate pathway...
September 30, 2016: Metabolic Engineering
Dina Elhadi, Li Lv, Xiao-Ran Jiang, Hong Wu, Guo-Qiang Chen
Microbial morphology engineering has recently become interesting for biotechnology. Genes ftsZ and mreB encoding proteins of bacterial fission ring and skeletons, respectively, are essential for cell growth, they both are the most important genes keeping the bacterial shapes including the cell length and width, respectively. Clustered regularly interspaced short palindromic repeats interference, abbreviated as CRISPRi, was for the first time used in this study to regulate expression intensities of ftsZ or/and mreB in E...
September 28, 2016: Metabolic Engineering
Hung Li, Claire R Shen, Chun-Hung Huang, Li-Yu Sung, Meng-Ying Wu, Yu-Chen Hu
Cyanobacteria hold promise as a cell factory for producing biofuels and bio-derived chemicals, but genome engineering of cyanobacteria such as Synechococcus elongatus PCC 7942 poses challenges because of their oligoploidy nature and long-term instability of the introduced gene. CRISPR-Cas9 is a newly developed RNA-guided genome editing system, yet its application for cyanobacteria engineering has yet to be reported. Here we demonstrated that CRISPR-Cas9 system can effectively trigger programmable double strand break (DSB) at the chromosome of PCC 7942 and provoke cell death...
September 27, 2016: Metabolic Engineering
Ziwei Dai, Jason W Locasale
Quantitative and qualitative knowledge of metabolic rates (i.e. fluxes) over a metabolic network and in specific cellular compartments gives insights into the regulation of metabolism and helps to understand the contribution of metabolic alterations to pathology. In this review we introduce methodology to resolve metabolic fluxes from stable isotope labeling and relevant techniques in model development, model simplification, flux uncertainty analysis and experimental design that together is termed metabolic flux analysis...
September 22, 2016: Metabolic Engineering
Sol Choi, Hyun Uk Kim, Tae Yong Kim, Sang Yup Lee
To address climate change and environmental problems, it is becoming increasingly important to establish biorefineries for the production of chemicals from renewable non-food biomass. Here we report the development of Escherichia coli strains capable of overproducing a four-carbon platform chemical 4-hybroxybutyric acid (4-HB). Because 4-HB production is significantly affected by aeration level, genome-scale metabolic model-based engineering strategies were designed under aerobic and microaerobic conditions with emphasis on oxidative/reductive TCA branches and glyoxylate shunt...
September 20, 2016: Metabolic Engineering
Songyuan Li, Christian Bille Jendresen, Alexander Grünberger, Carlotta Ronda, Sheila Ingemann Jensen, Stephan Noack, Alex Toftgaard Nielsen
Production of proteins and biochemicals in microbial cell factories is often limited by carbon and energy spent on excess biomass formation. To address this issue, we developed several genetic growth switches based on CRISPR interference technology. We demonstrate that growth of Escherichia coli can be controlled by repressing the DNA replication machinery, by targeting dnaA and oriC, or by blocking nucleotide synthesis through pyrF or thyA. This way, total GFP-protein production could be increased by up to 2...
September 16, 2016: Metabolic Engineering
Michael J Opperman, Yair Shachar-Hill
Pseudomonas aeruginosa is a metabolically versatile wide-ranging opportunistic pathogen. In humans P. aeruginosa causes infections of the skin, urinary tract, blood, and the lungs of Cystic Fibrosis patients. In addition, P. aeruginosa's broad environmental distribution, relatedness to biotechnologically useful species, and ability to form biofilms have made it the focus of considerable interest. We used (13)C metabolic flux analysis (MFA) and flux balance analysis to understand energy and redox production and consumption and to explore the metabolic phenotypes of one reference strain and five strains isolated from the lungs of cystic fibrosis patients...
September 13, 2016: Metabolic Engineering
Seong Keun Kim, Gui Hwan Han, Wonjae Seong, Haseong Kim, Seon-Won Kim, Dae-Hee Lee, Seung-Goo Lee
Methods for simple and efficient regulation of metabolic pathway genes are essential for maximizing product titers and conversion yields, and for minimizing the metabolic burden caused by heterologous expression of multiple genes often in the operon context. Clustered regularly interspaced short palindromic repeats (CRISPR) interference (CRISPRi) is emerging as a promising tool for transcriptional modulation. In this study, we developed a regulatable CRISPRi system for fine-tuning biosynthetic pathways and thus directing carbon flux toward target product synthesis...
August 26, 2016: Metabolic Engineering
Zhihao Wang, Siu Hung Joshua Chan, Suresh Sudarsan, Lars M Blank, Peter Ruhdal Jensen, Christian Solem
The performance of Corynebacterium glutamicum cell factories producing compounds which rely heavily on NADPH has been reported to depend on the sugar being metabolized. While some aspects of this phenomenon have been elucidated, there are still many unresolved questions as to how sugar metabolism is linked to redox and to the general metabolism. We here provide new insights into the regulation of the metabolism of this important platform organism by systematically characterizing mutants carrying various lesions in the fructose operon...
August 20, 2016: Metabolic Engineering
Takahisa Kogure, Takeshi Kubota, Masako Suda, Kazumi Hiraga, Masayuki Inui
Corynebacterium glutamicum with the ability to simultaneously utilize glucose/pentose mixed sugars was metabolically engineered to overproduce shikimate, a valuable hydroaromatic compound used as a starting material for the synthesis of the anti-influenza drug oseltamivir. To achieve this, the shikimate kinase and other potential metabolic activities for the consumption of shikimate and its precursor dehydroshikimate were inactivated. Carbon flux toward shikimate synthesis was enhanced by overexpression of genes for the shikimate pathway and the non-oxidative pentose phosphate pathway...
August 20, 2016: Metabolic Engineering
Maureen McKeague, Yen-Hsiang Wang, Aaron Cravens, Maung Nyan Win, Christina D Smolke
Engineered microbial biosynthesis of plant natural products can support manufacturing of complex bioactive molecules and enable discovery of non-naturally occurring derivatives. Purine alkaloids, including caffeine (coffee), theophylline (antiasthma drug), theobromine (chocolate), and other methylxanthines, play a significant role in pharmacology and food chemistry. Here, we engineered the eukaryotic microbial host Saccharomyces cerevisiae for the de novo biosynthesis of methylxanthines. We constructed a xanthine-to-xanthosine conversion pathway in native yeast central metabolism to increase endogenous purine flux for the production of 7-methylxanthine, a key intermediate in caffeine biosynthesis...
August 9, 2016: Metabolic Engineering
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