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Metabolic Engineering

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https://www.readbyqxmd.com/read/28803913/synthetic-rescue-couples-nadph-generation-to-metabolite-overproduction-in-saccharomyces-cerevisiae
#1
Siavash Partow, Patrick B Hyland, Radhakrishnan Mahadevan
Engineering the redox cofactor metabolism is known to be a key challenge in developing a platform strain for biosynthesis of valuable products. Hence, general strategies for manipulation of co-factor metabolism in industrially relevant hosts are of significance. Here, we demonstrate an improvement in α-ketoglutarate (AKG) production in S. cerevisiae using a novel approach based on synthetic rescue. Here, we first perturb the cytosolic NADPH metabolism via deletion of glucose-6-phosphate dehydrogenase (ZWF1)...
August 10, 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28802880/isobutanol-and-2-ketoisovalerate-production-by-klebsiella-pneumoniae-via-a-native-pathway
#2
Jinjie Gu, Jidong Zhou, Zhongxi Zhang, Chul Ho Kim, Biao Jiang, Jiping Shi, Jian Hao
Isobutanol is a valuable chemical and is considered a new generation biofuel. Construction of isobutanol synthesis pathways in bacteria is a hot topic in isobutanol production. Here, we show that an isobutanol synthesis pathway exists naturally in Klebsiella pneumoniae; however, this pathway is dormant in the wild-type bacterium. K. pneumoniae is a 2,3-butanediol producer, and the synthesis pathways of 2,3-butanediol, valine and isobutanol all start from condensation of two pyruvate molecules to yield α-acetolactate...
August 9, 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28800965/the-crispr-cas9-facilitated-multiplex-pathway-optimization-cfpo-technique-and-its-application-to-improve-the-escherichia-coli-xylose-utilization-pathway
#3
Xinna Zhu, Dongdong Zhao, Huanna Qiu, Feiyu Fan, Shuli Man, Changhao Bi, Xueli Zhang
One of the most important research subjects of metabolic engineering is the pursuit of balanced metabolic pathways, which requires the modulation of expression of many genes. However, simultaneously modulating multiple genes on the chromosome remains challenging in prokaryotic organisms, including the industrial workhorse - Escherichia coli. In this work, the CRISPR/Cas9-facilitated multiplex pathway optimization (CFPO) technique was developed to simultaneously modulate the expression of multiple genes on the chromosome...
August 9, 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28800966/reconstruction-of-a-metabolic-regulatory-network-in-escherichia-coli-for-purposeful-switching-from-cell-growth-mode-to-production-mode-in-direct-gaba-fermentation-from-glucose
#4
Yuki Soma, Yuri Fujiwara, Takuya Nakagawa, Keigo Tsuruno, Taizo Hanai
γ-aminobutyric acid (GABA) is a drug and functional food additive and is used as a monomer for producing the biodegradable plastic, polyamide 4. Recently, direct GABA fermentation from glucose has been developed as an alternative to glutamate-based whole cell bioconversion. Although total productivity in fermentation is determined by the specific productivity and cell amount responsible for GABA production, the optimal metabolic state for GABA production conflicts with that for bacterial cell growth. Herein, we demonstrated metabolic state switching from the cell growth mode based on the metabolic pathways of the wild type strain to a GABA production mode based on a synthetic metabolic pathway in Escherichia coli through rewriting of the metabolic regulatory network and pathway engineering...
August 8, 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28782693/co-production-of-microbial-polyhydroxyalkanoates-with-other-chemicals
#5
REVIEW
Tian Li, Dina Elhadi, Guo-Qiang Chen
Engineering microorganisms capable of simultaneously accumulating multiple products are economically attractive for biotechnology. Polyhydroxyalkanoates (PHA) or microbial bioplastics are promising as biodegradable plastics to address environmental concerns resulted from plastic wastes accumulation. Unfortunately, PHA production is still limited and cannot compete with the chemically synthesized plastics due to their high production cost. Efforts have been devoted to reduce PHA production cost by employing PHA co-production with other valuable chemicals...
August 3, 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28780284/pathway-optimization-and-key-enzyme-evolution-of-n-acetylneuraminate-biosynthesis-using-an-in-vivo-aptazyme-based-biosensor
#6
Peng Yang, Jing Wang, Qingxiao Pang, Fengyu Zhang, Junshu Wang, Qian Wang, Qingsheng Qi
N-acetylneuraminate (NeuAc) biosynthesis has drawn much attention owing to its wide applications in many aspects. Previously, we engineered for the first time an artificial NeuAc biosynthetic pathway in Escherichia coli using glucose as sole substrate. However, rigorous requirements for the flux and cofactor balance make subsequent strain improvement rather difficult. In this study, an in vivo NeuAc biosensor was designed and applied for genetic screening the mutant library of NeuAc producer. Its NeuAc responsive manner was demonstrated using sfgfp as a reporter and a Ni(2+)-based selection system was developed to couple the cell growth with in vivo NeuAc concentration...
August 2, 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28778764/production-of-a-bioactive-unnatural-ginsenoside-by-metabolically-engineered-yeasts-based-on-a-new-udp-glycosyltransferase-from-bacillus-subtilis
#7
Huichao Liang, Zongfeng Hu, Tingting Zhang, Ting Gong, Jingjing Chen, Ping Zhu, Yan Li, Jinling Yang
Ginsenosides are the main bioactive constituents of Panax species, which are biosynthesized by glycosylation at C3-OH and/or C20-OH of protopanaxadiol (PPD), C6-OH and/or C20-OH of protopanaxatriol (PPT). The C12-glycosylated ginsenosides have scarcely been identified from Panax species. The C12-glycosylated ginsenosides produced from PPD by chemical semi-synthesis have been reported to exhibit higher cytotoxicity than the natural ginsenosides. However, the chemical semi-synthesis approach is not practical due to its complexity and high cost...
August 2, 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28754360/glycosylation-flux-analysis-reveals-dynamic-changes-of-intracellular-glycosylation-flux-distribution-in-chinese-hamster-ovary-fed-batch-cultures
#8
Sandro Hutter, Thomas K Villiger, David Brühlmann, Matthieu Stettler, Hervé Broly, Miroslav Soos, Rudiyanto Gunawan
N-linked glycosylation of proteins has both functional and structural significance. Importantly, the glycan structure of a therapeutic protein influences its efficacy, pharmacokinetics, pharmacodynamics and immunogenicity. In this work, we developed glycosylation flux analysis (GFA) for predicting intracellular production and consumption rates (fluxes) of glycoforms, and applied this analysis to CHO fed-batch immunoglobulin G (IgG) production using two different media compositions, with and without additional manganese feeding...
July 25, 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28739388/precise-flux-redistribution-to-glyoxylate-cycle-for-5-aminolevulinic-acid-production-in-escherichia-coli
#9
Myung Hyun Noh, Hyun Gyu Lim, Sunghoon Park, Sang Woo Seo, Gyoo Yeol Jung
Microbial production of 5-aminolevulinic acid (ALA) has received much attention because of its potential in clinical applications. Overexpression along with the deciphering of regulation of the related enzymes and an analogue transporter yielded remarkable achievements in ALA production. Nonetheless, there is significant room for carbon flux optimization to enhance ALA production. The aim of this study was precise carbon flux optimization for high ALA production in Escherichia coli expressing the ALA biosynthetic pathway...
July 21, 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28688931/membrane-engineering-a-novel-strategy-to-enhance-the-production-and-accumulation-of-%C3%AE-carotene-in-escherichia-coli
#10
Tao Wu, Lijun Ye, Dongdong Zhao, Siwei Li, Qingyan Li, Bolin Zhang, Changhao Bi, Xueli Zhang
Carotenoids are a class of terpenes of commercial interest that exert important biological functions. While various strategies have been applied to engineer β-carotene production in microbial cell factories, no work has been done to study and improve the storage of hydrophobic terpene products inside the heterologous host cells. Although the membrane is thought to be the cell compartment that accumulates hydrophobic terpenes such as β-carotene, direct evidence is still lacking. In this work, we engineered the membrane of Escherichia coli in both its morphological and biosynthetic aspects, as a means to study and improve its storage capacity for β-carotene...
July 6, 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28709932/assessing-glycolytic-flux-alterations-resulting-from-genetic-perturbations-in-e-coli-using-a-biosensor
#11
Christina E Lehning, Solvej Siedler, Mostafa M H Ellabaan, Morten O A Sommer
We describe the development of an optimized glycolytic flux biosensor and its application in detecting altered flux in a production strain and in a mutant library. The glycolytic flux biosensor is based on the Cra-regulated ppsA promoter of E. coli controlling fluorescent protein synthesis. We validated the glycolytic flux dependency of the biosensor in a range of different carbon sources in six different E. coli strains and during mevalonate production. Furthermore, we studied the flux-altering effects of genome-wide single gene knock-outs in E...
July 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28687337/a-translational-synthetic-biology-platform-for-rapid-access-to-gram-scale-quantities-of-novel-drug-like-molecules
#12
James Reed, Michael J Stephenson, Karel Miettinen, Bastiaan Brouwer, Aymeric Leveau, Paul Brett, Rebecca J M Goss, Alain Goossens, Maria A O'Connell, Anne Osbourn
Plants are an excellent source of drug leads. However availability is limited by access to source species, low abundance and recalcitrance to chemical synthesis. Although plant genomics is yielding a wealth of genes for natural product biosynthesis, the translation of this genetic information into small molecules for evaluation as drug leads represents a major bottleneck. For example, the yeast platform for artemisinic acid production is estimated to have taken >150 person years to develop. Here we demonstrate the power of plant transient transfection technology for rapid, scalable biosynthesis and isolation of triterpenes, one of the largest and most structurally diverse families of plant natural products...
July 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28663138/the-ethanol-pathway-from-thermoanaerobacterium-saccharolyticum-improves-ethanol-production-in-clostridium-thermocellum
#13
Shuen Hon, Daniel G Olson, Evert K Holwerda, Anthony A Lanahan, Sean J L Murphy, Marybeth I Maloney, Tianyong Zheng, Beth Papanek, Adam M Guss, Lee R Lynd
Clostridium thermocellum ferments cellulose, is a promising candidate for ethanol production from cellulosic biomass, and has been the focus of studies aimed at improving ethanol yield. Thermoanaerobacterium saccharolyticum ferments hemicellulose, but not cellulose, and has been engineered to produce ethanol at high yield and titer. Recent research has led to the identification of four genes in T. saccharolyticum involved in ethanol production: adhE, nfnA, nfnB and adhA. We introduced these genes into C. thermocellum and observed significant improvements to ethanol yield, titer, and productivity...
July 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28649005/crispr-cas9-coupled-recombineering-for-metabolic-engineering-of-corynebacterium-glutamicum
#14
Jae Sung Cho, Kyeong Rok Choi, Cindy Pricilia Surya Prabowo, Jae Ho Shin, Dongsoo Yang, Jaedong Jang, Sang Yup Lee
Genome engineering of Corynebacterium glutamicum, an important industrial microorganism for amino acids production, currently relies on random mutagenesis and inefficient double crossover events. Here we report a rapid genome engineering strategy to scarlessly knock out one or more genes in C. glutamicum in sequential and iterative manner. Recombinase RecT is used to incorporate synthetic single-stranded oligodeoxyribonucleotides into the genome and CRISPR/Cas9 to counter-select negative mutants. We completed the system by engineering the respective plasmids harboring CRISPR/Cas9 and RecT for efficient curing such that multiple gene targets can be done iteratively and final strains will be free of plasmids...
July 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28645641/homogenizing-bacterial-cell-factories-analysis-and-engineering-of-phenotypic-heterogeneity
#15
REVIEW
Dennis Binder, Thomas Drepper, Karl-Erich Jaeger, Frank Delvigne, Wolfgang Wiechert, Dietrich Kohlheyer, Alexander Grünberger
In natural habitats, microbes form multispecies communities that commonly face rapidly changing and highly competitive environments. Thus, phenotypic heterogeneity has evolved as an innate and important survival strategy to gain an overall fitness advantage over cohabiting competitors. However, in defined artificial environments such as monocultures in small- to large-scale bioreactors, cell-to-cell variations are presumed to cause reduced production yields as well as process instability. Hence, engineering microbial production toward phenotypic homogeneity is a highly promising approach for synthetic biology and bioprocess optimization...
July 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28627452/engineering-of-unconventional-yeast-yarrowia-lipolytica-for-efficient-succinic-acid-production-from-glycerol-at-low-ph
#16
Zhiyong Cui, Cuijuan Gao, Jiaojiao Li, Jin Hou, Carol Sze Ki Lin, Qingsheng Qi
Yarrowia lipolytica is considered as a potential candidate for succinic acid production because of its innate ability to accumulate citric acid cycle intermediates and its tolerance to acidic pH. Previously, a succinate-production strain was obtained through the deletion of succinate dehydrogenase subunit encoding gene Ylsdh5. However, the accumulation of by-product acetate limited further improvement of succinate production. Meanwhile, additional pH adjustment procedure increased the downstream cost in industrial application...
July 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28625755/multilevel-engineering-of-the-upstream-module-of-aromatic-amino-acid-biosynthesis-in-saccharomyces-cerevisiae-for-high-production-of-polymer-and-drug-precursors
#17
Miguel Suástegui, Chiam Yu Ng, Anupam Chowdhury, Wan Sun, Mingfeng Cao, Emma House, Costas D Maranas, Zengyi Shao
A multilevel approach was implemented in Saccharomyces cerevisiae to optimize the precursor module of the aromatic amino acid biosynthesis pathway, which is a rich resource for synthesizing a great variety of chemicals ranging from polymer precursor, to nutraceuticals and pain-relief drugs. To facilitate the discovery of novel targets to enhance the pathway flux, we incorporated the computational tool YEASTRACT for predicting novel transcriptional repressors and OptForce strain-design for identifying non-intuitive pathway interventions...
July 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28624535/atp-free-biosynthesis-of-a-high-energy-phosphate-metabolite-fructose-1-6-diphosphate-by-in-vitro-metabolic-engineering
#18
Wei Wang, Meixia Liu, Chun You, Zhimin Li, Yi-Heng Percival Zhang
Fructose 1,6-diphosphate (FDP) is a widely used medicine and is also a precursor of two important three-carbon phosphates - glyceraldehyde 3-phosphate (GA3P) and dihydroxyacetone phosphate (DHAP) for the biosynthesis of numerous fine chemicals. An in vitro synthetic cofactor-free enzymatic pathway comprised of four hyperthermophilic enzymes was designed to produce FDP from starch and pyrophosphate. All of four hyperthermophilic enzymes (i.e., alpha-glucan phosphorylase from Thermotaga maritima, phosphoglucomutase from Thermococcus kodakarensis, glucose 6-phosphate isomerase from Thermus thermophilus, and pyrophosphate phosphofructokinase from T...
July 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28619444/single-step-production-of-the-simvastatin-precursor-monacolin-j-by-engineering-of-an-industrial-strain-of-aspergillus-terreus
#19
Xuenian Huang, Yajing Liang, Yong Yang, Xuefeng Lu
Monacolin J is a key precursor for the synthesis of simvastatin (Zocor), an important drug for treating hypercholesterolemia. Industrially, monacolin J is manufactured through alkaline hydrolysis of lovastatin, a fungal polyketide produced by Aspergillus terreus. Multistep chemical processes for the conversion of lovastatin to simvastatin are laborious, cost expensive and environmentally unfriendly. A biocatalysis process for monacolin J conversion to simvastatin has been developed. However, direct bioproduction of monacolin J has not yet been achieved...
July 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28606738/engineering-high-level-production-of-fatty-alcohols-by-saccharomyces-cerevisiae-from-lignocellulosic-feedstocks
#20
Leo d'Espaux, Amit Ghosh, Weerawat Runguphan, Maren Wehrs, Feng Xu, Oliver Konzock, Ishaan Dev, Melissa Nhan, Jennifer Gin, Amanda Reider Apel, Christopher J Petzold, Seema Singh, Blake A Simmons, Aindrila Mukhopadhyay, Héctor García Martín, Jay D Keasling
Fatty alcohols in the C12-C18 range are used in personal care products, lubricants, and potentially biofuels. These compounds can be produced from the fatty acid pathway by a fatty acid reductase (FAR), yet yields from the preferred industrial host Saccharomyces cerevisiae remain under 2% of the theoretical maximum from glucose. Here we improved titer and yield of fatty alcohols using an approach involving quantitative analysis of protein levels and metabolic flux, engineering enzyme level and localization, pull-push-block engineering of carbon flux, and cofactor balancing...
July 2017: Metabolic Engineering
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