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Metabolic engineering

Qiaozhen Meng, Zhenling Peng, Jianyi Yang
Motivation: Coenzyme A (CoA)-protein binding plays an important role in various cellular functions and metabolic pathways. However, no computational methods can be employed for CoA-binding residues prediction. Results: We developed three methods for the prediction of CoA- and CoA derivatives-binding residues, including an ab-initio method SVMpred, a template-based method TemPred, and a consensus-based method CoABind. In SVMpred, a comprehensive set of features are designed from two complementary sequence profiles and the predicted secondary structure and solvent accessibility...
March 14, 2018: Bioinformatics
Joo Yeon Seok, Jina Yang, Sang Jin Choi, Hyun Gyu Lim, Un Jong Choi, Kyung-Jin Kim, Sunghoon Park, Tae Hyeon Yoo, Gyoo Yeol Jung
3-Hydroxypropionic acid (3-HP) is an important platform chemical, and biological production of 3-HP from glycerol as a carbon source using glycerol dehydratase (GDHt) and aldehyde dehydrogenase (ALDH) has been revealed to be effective because it involves a relatively simple metabolic pathway and exhibits higher yield and productivity than other biosynthetic pathways. Despite the successful attempts of 3-HP production from glycerol, the biological process suffers from problems arising from low activity and inactivation of the two enzymes...
March 12, 2018: Metabolic Engineering
Konstantinos C Tsolis, Evridiki-Pandora Tsare, Georgia Orfanoudaki, Tobias Busche, Katerina Kanaki, Reshmi Ramakrishnan, Frederic Rousseau, Joost Schymkowitz, Christian Rückert, Jörn Kalinowski, Jozef Anné, Spyridoula Karamanou, Maria I Klapa, Anastassios Economou
BACKGROUND: Members of the genus Streptomyces are Gram-positive bacteria that are used as important cell factories to produce secondary metabolites and secrete heterologous proteins. They possess some of the largest bacterial genomes and thus proteomes. Understanding their complex proteomes and metabolic regulation will improve any genetic engineering approach. RESULTS: Here, we performed a comprehensive annotation of the subcellular localization of the proteome of Streptomyces lividans TK24 and developed the Subcellular Topology of Polypeptides in Streptomyces database (SToPSdb) to make this information widely accessible...
March 15, 2018: Microbial Cell Factories
Christian Haselmair-Gosch, Silvija Miosic, Daria Nitarska, Barbara L Roth, Benjamin Walliser, Renate Paltram, Rares C Lucaciu, Lukas Eidenberger, Thomas Rattei, Klaus Olbricht, Karl Stich, Heidi Halbwirth
A recall campaign for commercial, orange flowering petunia varieties in spring 2017 caused economic losses worldwide. The orange varieties were identified as undeclared genetically engineered (GE)-plants, harboring a maize dihydroflavonol 4-reductase ( DFR, A 1 ), which was used in former scientific transgenic breeding attempts to enable formation of orange pelargonidin derivatives from the precursor dihydrokaempferol (DHK) in petunia. How and when the A 1 cDNA entered the commercial breeding process is unclear...
2018: Frontiers in Plant Science
Jonuelle Acosta, Walter Wang, David M Feldser
Tumor suppressor genes play critical roles orchestrating anti-cancer programs that are both context dependent and mechanistically diverse. Beyond canonical tumor suppressive programs that control cell division, cell death, and genome stability, unexpected tumor suppressor gene activities that regulate metabolism, immune surveillance, the epigenetic landscape, and others have recently emerged. This diversity underscores the important roles these genes play in maintaining cellular homeostasis to suppress cancer initiation and progression, but also highlights a tremendous challenge in discerning precise context-specific programs of tumor suppression controlled by a given tumor suppressor...
March 15, 2018: Oncogene
Wenlong Zhou, Yan Yang, Liang Tang, Kai Cheng, Changkun Li, Huimin Wang, Minzhi Liu, Wei Wang
Acrolein (Acr) was used as a selection agent to improve the glutathione (GSH) overproduction of the prototrophic strain W303-1b/FGPPT . After two rounds of adaptive laboratory evolution (ALE), an unexpected result was obtained wherein identical GSH production was observed in the selected isolates. Then, a threshold selection mechanism of Acr-stressed adaption was clarified based on the formation of an Acr-GSH adduct, and a diffusion coefficient (0.36 ± 0.02 μmol·min-1 ·OD600 -1 ) was calculated. Metabolomic analysis was carried out to reveal the molecular bases that triggered GSH overproduction...
March 14, 2018: Scientific Reports
Bart Theelen, Claudia Cafarchia, Georgios Gaitanis, Ioannis Dimitrios Bassukas, Teun Boekhout, Thomas L Dawson
Malassezia are lipid dependent basidiomycetous yeasts that inhabit the skin and mucosa of humans and other warm-blooded animals, and are a major component of the skin microbiome. They occur as skin commensals, but are also associated with various skin disorders and bloodstream infections. The genus currently comprises 17 species and has recently been assigned its own class, Malasseziomycetes. Importantly, multiple Malassezia species and/or genotypes may cause unique or similar pathologies and vary in their antifungal susceptibility...
April 1, 2018: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
Chandran Sathesh-Prabu, Sung Kuk Lee
The production of α,ω-dicarboxylic acids (DCAs) by whole-cell biocatalysis is often limited by cofactor regeneration. Here, ω-oxidation pathway genes (monooxygenase, alcohol dehydrogenase, and aldehyde dehydrogenase) were co-expressed with a xylose reductase (XR) gene to regenerate cofactors in an engineered Escherichia coli strain that co-metabolizes glucose and xylose. The resulting strain exhibited a 180% increase in DCA production compared with the control strain without XR, and produced xylitol in the presence of xylose...
March 14, 2018: Journal of Agricultural and Food Chemistry
Katia Tarasava, Rongming Liu, Andrew Garst, Ryan T Gill
Optimization of metabolic flux is a difficult and time-consuming process that often involves changing the expression levels of multiple genes simultaneously. While some pathways have a known rate limiting step, more complex metabolic networks can require a trial-and-error approach of tuning the expression of multiple genes to achieve a desired distribution of metabolic resources. Here we present an efficient method for generating expression diversity on a combinatorial scale using CRISPR interference. We use a modified native Escherichia coli Type I-E CRISPR-Cas system and an iterative cloning strategy for construction of guide RNA arrays...
March 14, 2018: Biotechnology and Bioengineering
Ramkumar T Annamalai, Tapan Girish Naik, Haley Prout, Andrew J Putnam, Jan P Stegemann
Microtissues created from the protein fibrin and containing embedded cells can be used in modular tissue engineering approaches to create larger, hierarchical and complex tissue structures. In this paper we demonstrate an emulsification-based method for the production of such fibrin microtissues containing fibroblasts and endothelial cells and designed to promote tissue vascularization. Surfactants can be beneficial in the microtissue fabrication process to reduce aggregation and to facilitate recovery of microtissues from the emulsion, thereby increasing yield...
March 14, 2018: Biomedical Materials
Peng Zhang, Xing Hu
Urea is an important precursor of the harmful carcinogenic product ethyl carbamate in fermented wines. To decipher more fully the contributions of three arginine permeases, Can1p, Gap1p and Alp1p in urea formation, various engineered strains were examined for their ability to form urea. This included seven mutants with different combinations of permease deficiency and grown in both simple and more complex media, and the wild-type strain modified to overexpress the three arginine permeases. A truncated GATA transcription factor, Gln3p1-653 , was also overexpressed in the arginine permease deficient mutants to determine whether the permeases have a synergistic effect on urea formation with other urea reducing modules...
March 13, 2018: World Journal of Microbiology & Biotechnology
Mariia Rabyk, Oleksandr Yushchuk, Ihor Rokytskyy, Maria Anisimova, Bohdan Ostash
The AdpA protein from a streptomycin producer Streptomyces griseus is a founding member of the AdpA family of pleiotropic regulators, known to be ubiquitously present in streptomycetes. Functional genomic approaches revealed a huge number of AdpA targets, leading to the claim that the AdpA regulon is the largest one in bacteria. The expression of adpA is limited at the level of translation of the rare leucyl UUA codon. All known properties of AdpA regulators were discovered on a few streptomycete strains. There are open questions about the true abundance and diversity of AdpA across actinobacterial taxa (and beyond) and about the possible evolutionary forces that shape the AdpA orthologous group in Streptomyces...
March 13, 2018: Journal of Molecular Evolution
Stephen C Heinsch, Siba R Das, Michael J Smanski
Increasing the final titer of a multi-gene metabolic pathway can be viewed as a multivariate optimization problem. While numerous multivariate optimization algorithms exist, few are specifically designed to accommodate the constraints posed by genetic engineering workflows. We present a strategy for optimizing expression levels across an arbitrary number of genes that requires few design-build-test iterations. We compare the performance of several optimization algorithms on a series of simulated expression landscapes...
2018: Frontiers in Microbiology
Tomas Strucko, Katharina Zirngibl, Filipa Pereira, Eleni Kafkia, Elsayed T Mohamed, Mandy Rettel, Frank Stein, Adam M Feist, Paula Jouhten, Kiran Raosaheb Patil, Jochen Forster
Most microbial species, including model eukaryote Saccharomyces cerevisiae, possess genetic capability to utilize many alternative nutrient sources. Yet, it remains an open question whether these manifest into assimilatory phenotypes. Despite possessing all necessary pathways, S. cerevisiae grows poorly or not at all when glycerol is the sole carbon source. Here we discover, through multiple evolved lineages, genetic determinants underlying glycerol catabolism and the associated fitness trade-offs. Most evolved lineages adapted through mutations in the HOG pathway, but showed hampered osmotolerance...
March 10, 2018: Metabolic Engineering
Wonsik Lee, Truc Do, Ge Zhang, Daniel Kahne, Timothy C Meredith, Suzanne Walker
Targeted modification of bacterial chromosomes is necessary to understand new drug targets, investigate virulence factors, elucidate cell physiology, and validate results of -omics-based approaches. For some bacteria, reverse genetics remains a major bottleneck to progress in research. Here we describe a compound-centric strategy that combines new negative selection markers with known positive selection markers to achieve simple, efficient one-step genome engineering of bacterial chromosomes. The method was inspired by the observation that certain non-essential metabolic pathways contain essential late steps, suggesting that antibiotics targeting a late step can be used to select for the absence of genes that control flux into the pathway...
March 13, 2018: ACS Infectious Diseases
Gert Peters, Brecht De Paepe, Lien De Wannemaeker, Dries Duchi, Jo Maertens, Jeroen Lammertyn, Marjan De Mey
Transcriptional biosensors have various applications in metabolic engineering, including dynamic pathway control and high-throughput screening of combinatorial strain libraries. Previously, various biosensors have been created from naturally occurring transcription factors (TFs), largely relying on native sequences with- out the possibility to modularly optimize their response curve. The lack of design and engineering techniques thus greatly hinders the development of custom biosensors. In view of the intended application this is detrimental...
March 13, 2018: Biotechnology and Bioengineering
Kevin W George, Mitchell Thompson, Joonhoon Kim, Edward E K Baidoo, George Wang, Veronica Teixeira Benites, Christopher J Petzold, Leanne Jade G Chan, Suzan Yilmaz, Petri Turhanen, Paul D Adams, Jay D Keasling, Taek Soon Lee
Isopentenyl pyrophosphate (IPP) toxicity presents a challenge in engineered microbial systems since its formation is unavoidable in terpene biosynthesis. In this work, we develop an experimental platform to study IPP toxicity in isoprenol-producing Escherichia coli. We first characterize the physiological response to IPP accumulation, demonstrating that elevated IPP levels are linked to growth inhibition, reduced cell viability, and plasmid instability. We show that IPP toxicity selects for pathway "breakage", using proteomics to identify a reduction in phosphomevalonate kinase (PMK) as a probable recovery mechanism...
March 9, 2018: Metabolic Engineering
Yi-Feng Wu, Yu Zhao, Xin-Yan Liu, Shuai Gao, Ai-Xia Cheng, Hong-Xiang Lou
Liverworts, a section of the bryophyte plants which pioneered the colonization of terrestrial habitats, produce cyclic bisbibenzyls as a secondary metabolite. These compounds are generated via the phenylpropanoid pathway, similar with flavonoid biosynthesis for which bHLH transcription factors have been identified as one of the improtant regulators in higher plants. Here, a bHLH homolog (PabHLH) was isolated from the liverwort species Plagiochasma appendiculatum and its contribution to bisbibenzyl biosynthesis was explored...
March 8, 2018: Plant & Cell Physiology
Yujia Zhao, Jingjing Fan, Chen Wang, Xudong Feng, Chun Li
Oleanolic acid is a plant-derived pentacyclic triterpenoid compound with various biological activities. Recently, biosynthesis of oleanolic acid in microbes has been demonstrated as a promising and green way, but the production is too low for industrialization. To improve oleanolic acid production, this study constructed a novel pathway for biosynthesis of oleanolic acid in Saccharomyces cerevisiae by improving the pairing efficiency between cytochrome P450 monooxygenase and reductase. Furthermore, to improve the transcriptional efficiency of heterologous genes, the cellular galactose regulatory network was reconstructed by knocking out galactose metabolic genes GAL80 and GAL1...
February 23, 2018: Bioresource Technology
Nodumo Nokulunga Zulu, Krzysztof Zienkiewicz, Katharina Vollheyde, Ivo Feussner
Diatoms are the most dominant phytoplankton species in oceans and they continue to receive a great deal of attention because of their significant contributions in ecosystems and the environment. Due to triacylglycerol (TAG) profiles that are abundant in medium-chain fatty acids, diatoms have emerged to be better feed stocks for biofuel production, in comparison to the commonly studied green microalgal species (chlorophytes). Importantly, diatoms are also known for their high levels of the essential ω3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and are considered to be a promising alternative source of these components...
March 7, 2018: Progress in Lipid Research
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