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Metabolic Engineering

Thuan Phu Nguyen-Vo, Yunxiao Liang, Mugesh Sankaranarayanan, Eunhee Seol, Ah Yeong Chun, Somasundar Ashok, Ashish Singh Chauhan, Jung Rae Kim, Sunghoon Park
3-Hydroxypropionic acid (3-HP) is an important platform chemical, but its toxic effect at high concentrations (>200 mM) is a serious challenge for commercial production. In this study, a highly 3-HP-tolerant strain of Escherichia coli W (tolerance concentration: 400 mM in M9 minimal medium and 800 mM when yeast extract was added) was developed by adaptive laboratory evolution (ALE) with glycerol as the carbon source. Genome analysis of the adapted strain (designated as E. coli WA) indicated the presence of mutations in 13 genes, including glpK (glycerol kinase) and yieP (a less-studied global regulator)...
February 7, 2019: Metabolic Engineering
Junjun Wu, Zhe Wang, Xuguo Duan, Peng Zhou, Pingcheng Liu, Zhen Pang, Yu Wang, Xuejun Wang, Wei Li, Mingsheng Dong
Medium-chain (C6 -C10 ) chemicals are important components of fuels, commodities and fine chemicals. Numerous exciting achievements have proven reversed β-oxidation cycle as a promising platform to synthesize these chemicals. However, under native central carbon metabolism, energetic and redox constraints limit the efficient operation of reversed β-oxidation cycle. Current fermentative platform has to use different chemically and energetically inefficient ways for acetyl-CoA and NADH biosynthesis, respectively...
January 24, 2019: Metabolic Engineering
Renato de Souza Pinto Lemgruber, Kaspar Valgepea, Ryan Tappel, James B Behrendorff, Robin William Palfreyman, Manuel Plan, Mark P Hodson, Séan Dennis Simpson, Lars K Nielsen, Michael Köpke, Esteban Marcellin
Gas fermentation is emerging as an economically attractive option for the sustainable production of fuels and chemicals from gaseous waste feedstocks. Clostridium autoethanogenum can use CO and/or CO2 + H2 as its sole carbon and energy sources. Fermentation of C. autoethanogenum is currently being deployed on a commercial scale for ethanol production. Expanding the product spectrum of acetogens will enhance the economics of gas fermentation. To achieve efficient heterologous product synthesis, limitations in redox and energy metabolism must be overcome...
January 11, 2019: Metabolic Engineering
Hiroki Nishiguchi, Natsuki Hiasa, Kiyoka Uebayashi, James Liao, Hiroshi Shimizu, Fumio Matsuda
In silico kinetic modeling is an essential tool for rationally designing metabolically engineered organisms based on a system-level understanding of their regulatory mechanisms. However, an estimation of enzyme parameters has been a bottleneck in the computer simulation of metabolic dynamics. In this study, the ensemble-modeling approach was integrated with the transomics data to construct kinetic models. Kinetic metabolic models of a photosynthetic bacterium, Synechocystis sp. PCC 6803, were constructed to identify engineering targets for improving ethanol production based on an understanding of metabolic regulatory systems...
January 8, 2019: Metabolic Engineering
He Huang, Changsheng Chai, Sheng Yang, Weihong Jiang, Yang Gu
The real value of gas-fermenting clostridia, capable of using CO and CO2 , resides in their potential of being developed into cell factories to produce various bulk chemicals and fuels. This process requires rapid chromosomal integration of heterologous chemical biosynthetic pathways, which is impeded by the absence of genetic tools competent for efficient genome engineering in these anaerobes. Here, we developed a phage serine integrase-mediated site-specific genome engineering technique in Clostridium ljungdahlii, one of the major acetogenic gas-fermenting microbes...
January 8, 2019: Metabolic Engineering
Alan Costello, Nga T Lao, Niall Barron, Martin Clynes
Recent success in demonstrating the translation of circular RNA open reading frames or circular mRNA, may offer a new avenue for improving recombinant protein production from cell and cell-free expression platforms. Initiation and termination are two rate limiting steps of translation. Circular RNA as a class of RNA is defined by covalent joining of terminal ends to give a closed loop structure. By encoding a gene lacking a stop codon on a circular RNA molecule an infinite open reading frame is generated permitting continuously translating circular mRNA (CTC mRNA)...
January 4, 2019: Metabolic Engineering
Zhengtao Liu, Cheng Zhang, Sunjae Lee, Woonghee Kim, Martina Klevstig, Azadeh M Harzandi, Natasa Sikanic, Muhammad Arif, Marcus Ståhlman, Jens Nielsen, Mathias Uhlen, Jan Boren, Adil Mardinoglu
The pathogenesis of non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) has been associated with altered expression of liver-specific genes including pyruvate kinase liver and red blood cell (PKLR), patatin-like phospholipase domain containing 3 (PNPLA3) and proprotein convertase subtilisin/kexin type 9 (PCSK9). Here, we inhibited and overexpressed the expression of these three genes in HepG2 cells, generated RNA-seq data before and after perturbation and revealed the altered global biological functions with the modulation of these genes using integrated network (IN) analysis...
January 4, 2019: Metabolic Engineering
Rebekah McKenna, T Noelle Lombana, Masaki Yamada, Kiran Mukhyala, Karthik Veeravalli
Escherichia coli (E. coli) is a promising platform for expression of full-length antibodies owing to its several advantages as a production host (fast growth, well characterized genetics, low manufacturing cost), however, low titers from shake flask (typically <5mg/L) has limited its use for production of research-grade material in antibody discovery programs. In this work, we used global transcriptional machinery engineering (gTME) with high throughput screening to increase the expression of full-length antibodies in E...
January 2, 2019: Metabolic Engineering
Yanli Qi, Hui Liu, Xiulai Chen, Liming Liu
The microbial membrane serves as a biological barrier that separates the interior of cells from the external environment, thus playing an important role in tolerance to stress conditions during industrial bioprocessing. Accordingly, engineering or regulation of membrane functions provides a great opportunity to improve the robustness of industrial strains and may enable increased titers, yield, and production of the targeted metabolites. In this review, we summarize the recent progress in metabolic engineering strategies to enhance membrane integrity, regulate membrane fluidity, and tune membrane permeability...
December 31, 2018: Metabolic Engineering
Indro N Ghosh, Julia Martien, Alexander S Hebert, Yaoping Zhang, Joshua J Coon, Daniel Amador-Noguez, Robert Landick
Efficient microbial production of the next-generation biofuel isobutanol (IBA) is limited by metabolic bottlenecks. Overcoming these bottlenecks will be aided by knowing the optimal ratio of enzymes for efficient flux through the IBA biosynthetic pathway. OptSSeq (Optimization by Selection and Sequencing) accomplishes this goal by tracking growth rate-linked selection of optimal expression elements from a combinatorial library. The 5-step pathway to IBA consists of Acetolactate synthase (AlsS), Keto-acid reductoisomerase (KARI), Di-hydroxyisovalerate dehydratase (DHID), Ketoisovalerate decarboxylase (Kivd) and Alcohol dehydrogenase (Adh)...
December 27, 2018: Metabolic Engineering
Mengyi Li, Xiangbin Chen, Xuemei Che, Haoqian Zhang, Lin-Ping Wu, Hetong Du, Guo-Qiang Chen
Polyhydroxyalkanoates (PHA) composed of both short-chain-length (SCL) and medium-chain-length (MCL) monomers (SCL-co-MCL PHA) combine the advantages of high strength and elasticity provided by SCL PHA and MCL PHA, respectively. Synthesis of SCL-co-MCL PHA, namely, copolymers of 3-hydroxybutyrate (3HB) and MCL 3-hydroxyalkanoates (3HA) such as 3-hydroxydecanoate (3HD) and longer chain 3HA, has been a challenge for a long time. This study aims to engineer Pseudomonas entomophila for synthesizing P(3HB-co-MCL 3HA) via weakening its β-oxidation pathway combined with insertion of 3HB synthesis pathway consisting of β-ketothiolase (phaA) and acetoacetyl-CoA reductase (phaB)...
December 21, 2018: Metabolic Engineering
Marilise Nogueira, Eugenia M A Enfissi, Ralf Welsch, Peter Beyer, Matias D Zurbriggen, Paul D Fraser
The high-value ketocarotenoid astaxanthin, a natural red colorant with powerful antioxidant activity, is synthesised from β-carotene by a hydroxylase and an oxygenase enzyme, which perform the addition of two hydroxyl and keto moieties, respectively. Several routes of intermediates, depending on the sequence of action of these enzymes, lead to the formation of astaxanthin. In the present study, the enzyme activities of 3, 3' β-carotene hydroxylase (CRTZ) and 4, 4' β-carotene oxygenase (CRTW) have been combined through the creation of "new to nature" enzyme fusions in order to overcome leakage of non-endogenous intermediates and pleotropic effects associated with their high levels in plants...
December 20, 2018: Metabolic Engineering
Kerry Hollands, Christopher M Baron, Katharine J Gibson, Kristen J Kelly, Elizabeth A Krasley, Lisa A Laffend, Ryan M Lauchli, Lori A Maggio-Hall, Mark J Nelson, Jahnavi C Prasad, Yixin Ren, Barbara A Rice, Gregory H Rice, Steven C Rothman
Oligosaccharides present in human breast milk have been linked to beneficial effects on infant health. Inclusion of these human milk oligosaccharides (HMOs) in infant formula can recapitulate these health benefits. As a result, there is substantial commercial interest in a cost-effective source of HMOs as infant formula ingredients. Here we demonstrate that the yeast species Saccharomyces cerevisiae and Yarrowia lipolytica both can be engineered to produce 2'-fucosyllactose (2'FL), which is the most abundant oligosaccharide in human breast milk, at high titer and productivity...
December 14, 2018: Metabolic Engineering
Matthias G Steiger, Alice Rassinger, Diethard Mattanovich, Michael Sauer
We engineered Aspergillus niger using a gene responsible for citric acid transport, which has a significant impact on citric acid secretion when overexpressed.. The transport gene was identified by a homology search using an itaconic acid transporter from Ustilago maydis as template. The encoding homologous protein CexA belongs to the major facilitator superfamily subclass DHA1 and members of this family work as drug-H+ antiporter. The disruption of this gene completely abolishes citric acid secretion, which indicates that this protein is the main citric acid transporter in A...
December 13, 2018: Metabolic Engineering
Camil A C Diaz, R Kyle Bennett, Eleftherios T Papoutsakis, Maciek R Antoniewicz
Overcoming carbon catabolite repression presents a significant challenge, largely due to the complex regulatory networks governing substrate catabolism, even in microbial cells. In this work, we have engineered an E. coli strain, which we have named X2G, that not only exhibits a reversed substrate preference for xylose over glucose, but also demonstrates an unusual ability to produce significant amounts of glucose. We obtained this non-intuitive phenotype by deleting four genes in upper central metabolism: ptsI, glk, pfkA, and zwf, which respectively encode Enzyme I of the phosphotransferase system, glucokinase, the dominant isozyme of phosphofructokinase, and glucose-6-phosphate dehydrogenase...
December 7, 2018: Metabolic Engineering
Kento Tokuyama, Yoshihiro Toya, Fumio Matsuda, Brady Cress, Mattheos A G Koffas, Hiroshi Shimizu
Starvation of essential nutrients, such as nitrogen, sulfur, magnesium, and phosphorus, leads cells into stationary phase and potentially enhances target metabolite production because cells do not consume carbon for the biomass synthesis. The overall metabolic behavior changes depend on the type of nutrient starvation in Escherichia coli. In the present study, we determined the optimum nutrient starvation type for producing malonyl-CoA-derived metabolites such as 3-hydroxypropionic acid (3HP) and naringenin in E...
December 6, 2018: Metabolic Engineering
Lei Li, Keke Wei, Xiaocao Liu, Yuanjie Wu, Guosong Zheng, Shaoxin Chen, Weihong Jiang, Yinhua Lu
Chromosomal integration of genes and pathways is of particular importance for large-scale and long-term fermentation in industrial biotechnology. However, stable, multi-copy integration of long DNA segments (e.g., large gene clusters) remains challenging. Here, we describe a plug-and-play toolkit that allows for high-efficiency, single-step, multi-locus integration of natural product (NP) biosynthetic gene clusters (BGCs) in actinomycetes, based on the innovative concept of "multiple integrases-multiple attB sites"...
December 5, 2018: Metabolic Engineering
Daniela M Correia, Cintia R Sargo, Adilson J Silva, Sophia T Santos, Roberto C Giordano, Eugénio C Ferreira, Teresa C Zangirolami, Marcelo P A Ribeiro, Isabel Rocha
In the last years, Salmonella has been extensively studied not only due to its importance as a pathogen, but also as a host to produce pharmaceutical compounds. However, the full exploitation of Salmonella as a platform for bioproduct delivery has been hampered by the lack of information about its metabolism. Genome-scale metabolic models can be valuable tools to delineate metabolic engineering strategies as long as they closely represent the actual metabolism of the target organism. In the present study, a 13 C-MFA approach was applied to map the fluxes at the central carbon pathways of S...
December 4, 2018: Metabolic Engineering
Thomas Amann, Anders Holmgaard Hansen, Stefan Kol, Henning Gram Hansen, Johnny Arnsdorf, Saranya Nallapareddy, Bjørn Voldborg, Gyun Min Lee, Mikael Rørdam Andersen, Helene Faustrup Kildegaard
Recombinant Chinese hamster ovary (CHO) cells are able to provide biopharmaceuticals that are essentially free of human viruses and have N-glycosylation profiles similar, but not identical, to humans. Due to differences in N-glycan moieties, two members of the serpin superfamily, alpha-1-antitrypsin (A1AT) and plasma protease C1 inhibitor (C1INH), are currently derived from human plasma for treating A1AT and C1INH deficiency. Deriving therapeutic proteins from human plasma is generally a cost-intensive process and also harbors a risk of transmitting infectious particles...
December 1, 2018: Metabolic Engineering
Abigail N Leistra, Nicholas C Curtis, Lydia M Contreras
Non-coding RNAs (ncRNAs) are versatile and powerful controllers of gene expression that have been increasingly linked to cellular metabolism and phenotype. In bacteria, identified and characterized ncRNAs range from trans-acting, multi-target small non-coding RNAs to dynamic, cis-encoded regulatory untranslated regions and riboswitches. These native regulators have inspired the design and construction of many synthetic RNA devices. In this work, we review the design, characterization, and impact of ncRNAs in engineering both native and exogenous metabolic pathways in bacteria...
December 1, 2018: Metabolic Engineering
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