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Metabolites
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Microbial Metabolic Engineering
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Microbial Metabolic Engineering

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Microbiology and Ecological Metabolomics".

Deadline for manuscript submissions: closed (15 November 2022) | Viewed by 16441

Special Issue Editors

Dr. Francois Coutte

E-Mail Website
Guest Editor
ICV—Institut Charles Viollette, UMRt BioEcoAgro N° 1158, University Lille, INRAE, University Liège, UPJV, YNCREA, University Artois, University Littoral Côte d’Opale, F-59000 Lille, France
Interests: metabolic engineering; Bacillus; lipopeptides; secondary metabolites; NRPS; genome engineering; bioprocess
Prof. Matthieu Jules

E-Mail Website
Guest Editor
Micalis Institute, Systems and synthetic microbiology division, Université Paris-Saclay, INRAE, AgroParisTech, F-78350 Jouy-en-Josas, France
Interests: bacteria; systems biology; molecular physiology; gene expression; synthetic biology; genome engineering; directed evolution

Special Issue Information

Dear Colleagues,

This Special Issue of Metabolites, "Microbial Metabolic Engineering" will be dedicated to the genetic and metabolic engineering of bacteria, yeast, microalgae or fungi for the production of primary or secondary metabolites of interest. In the global context, wherein fossil resources are running out, health and more sustainable development have become key challenges. Advances in science, synthetic biology, bioproduction, and biotechnology allow us a glimpse of a bright future for biosourced metabolites. Microorganisms as producers of many metabolites have received increasing attention and are now considered to be cellular microfactories. The topics that will be covered by this Special Issue include, but are not limited to, optimizing genetic and regulatory processes (transcriptional and translational) within cells to increase the production of metabolite of interest, heterologous expression of gene cluster, redirecting metabolic pathway through genome editing or gene knock-out, transcriptomic analysis, transporter engineering, single-cell analysis, metabolites dynamics, modelling method for strain optimization, synthetic biology, streamlined microbial chassis, engineering and culture medium optimization using renewable resources… Finally, we also invite manuscripts with innovative and integrative approaches to metabolic engineering to optimize the biosynthesis of the microbial metabolite’s precursors.

Dr. Francois Coutte
Prof. Matthieu Jules
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • metabolic engineering
  • secondary metabolites
  • gene knock-out
  • synthetic biology
  • streamlined chassis microbial cell factory

Published Papers (6 papers)

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Research

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13 pages, 1597 KiB  
Article
Bioengineering of Escherichia coli Nissle 1917 for Production and Excretion of Spermidine, a Key Metabolite in Human Health
by Clément Caffaratti, Caroline Plazy, Valérie Cunin, Bertrand Toussaint and Audrey Le Gouellec
Metabolites 2022, 12(11), 1061; https://doi.org/10.3390/metabo12111061 - 2 Nov 2022
Cited by 2 | Viewed by 1953
Abstract
Microbiota-derived metabolites have biological importance for their host. Spermidine, a metabolite described for its protective effect in age-related diseases, is now studied for its role in the resolution of inflammation and gut homeostasis. Strategies to modulate its production in the gastrointestinal tract are [...] Read more.
Microbiota-derived metabolites have biological importance for their host. Spermidine, a metabolite described for its protective effect in age-related diseases, is now studied for its role in the resolution of inflammation and gut homeostasis. Strategies to modulate its production in the gastrointestinal tract are of interest to increase host spermidine intakes. Here, we show that metabolic engineering can be used to increase spermidine production by the probiotic Escherichia coli Nissle 1917 (EcN), used in humans. First, we found that increasing the expression of genes involved in polyamine biosynthesis, namely the S-adenosylmethionine synthase speD and the spermidine synthase speE, resulted in an increase in spermidine produced and excreted by our engineered bacteria. The major drawback of this first attempt was the production of acetylated forms of spermidine. Next, we propose to solve this problem by increasing the expression of the spermidine exporter system MdtI/MdtJ. This second strategy had a major impact on the spermidine profile found in the culture supernatant. Our results demonstrate, for the first time, the feasibility of rationally engineering bacterial probiotic strains to increase their ability to deliver the microbiota-derived metabolite, spermidine. This work illustrates how metabolomic and synthetic biology can be used to design and improve engineered Live Biotherapeutic Products that have the potential to be used in personalized medicine. Full article
(This article belongs to the Special Issue Microbial Metabolic Engineering)
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19 pages, 2338 KiB  
Article
Rational Engineering of Non-Ubiquinone Containing Corynebacterium glutamicum for Enhanced Coenzyme Q10 Production
by Arthur Burgardt, Ludovic Pelosi, Mahmoud Hajj Chehade, Volker F. Wendisch and Fabien Pierrel
Metabolites 2022, 12(5), 428; https://doi.org/10.3390/metabo12050428 - 11 May 2022
Cited by 3 | Viewed by 2124
Abstract
Coenzyme Q10 (CoQ10) is a lipid-soluble compound with important physiological functions and is sought after in the food and cosmetic industries owing to its antioxidant properties. In our previous proof of concept, we engineered for CoQ10 biosynthesis the industrially [...] Read more.
Coenzyme Q10 (CoQ10) is a lipid-soluble compound with important physiological functions and is sought after in the food and cosmetic industries owing to its antioxidant properties. In our previous proof of concept, we engineered for CoQ10 biosynthesis the industrially relevant Corynebacterium glutamicum, which does not naturally synthesize any CoQ. Here, liquid chromatography–mass spectrometry (LC–MS) analysis identified two metabolic bottlenecks in the CoQ10 production, i.e., low conversion of the intermediate 10-prenylphenol (10P-Ph) to CoQ10 and the accumulation of isoprenologs with prenyl chain lengths of not only 10, but also 8 to 11 isopentenyl units. To overcome these limitations, the strain was engineered for expression of the Ubi complex accessory factors UbiJ and UbiK from Escherichia coli to increase flux towards CoQ10, and by replacement of the native polyprenyl diphosphate synthase IspB with a decaprenyl diphosphate synthase (DdsA) to select for prenyl chains with 10 isopentenyl units. The best strain UBI6-Rs showed a seven-fold increased CoQ10 content and eight-fold increased CoQ10 titer compared to the initial strain UBI4-Pd, while the abundance of CoQ8, CoQ9, and CoQ11 was significantly reduced. This study demonstrates the application of the recent insight into CoQ biosynthesis to improve metabolic engineering of a heterologous CoQ10 production strain. Full article
(This article belongs to the Special Issue Microbial Metabolic Engineering)
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22 pages, 3693 KiB  
Article
Bioinformatics Modelling and Metabolic Engineering of the Branched Chain Amino Acid Pathway for Specific Production of Mycosubtilin Isoforms in Bacillus subtilis
by Jean-Sébastien Guez, Françoise Coucheney, Joany Guy, Max Béchet, Pierre Fontanille, Nour-Eddine Chihib, Joachim Niehren, François Coutte and Philippe Jacques
Metabolites 2022, 12(2), 107; https://doi.org/10.3390/metabo12020107 - 24 Jan 2022
Cited by 4 | Viewed by 2770
Abstract
Mycosubtilin belongs to the family of lipopeptides. Different isoforms with various antifungal activities can be obtained according to the length and the isomery of the fatty acid. In this work, the activities of the mycosubtilin isoforms were first studied against the pathogen Aspergillus [...] Read more.
Mycosubtilin belongs to the family of lipopeptides. Different isoforms with various antifungal activities can be obtained according to the length and the isomery of the fatty acid. In this work, the activities of the mycosubtilin isoforms were first studied against the pathogen Aspergillus niger, revealing the high activity of the anteiso-C17 isoform. Modification of the mycosubtilin isoform patterns during cultures of the natural strain Bacillus subtilis ATCC 6633 was then investigated through amino acid feeding experiments. In parallel, single-gene knockouts and single-gene overexpression, leading to the overproduction of the anteiso-C15 fatty acid chains, were predicted using informatics tools which provide logical reasoning with formal models of reaction networks. In this way, it was in silico predicted that the single overexpression of the ilvA gene as well as the single knockout of the codY gene may lead to the overproduction of anteiso-C15 fatty acid chains. For the first time, it has been demonstrated that overexpression of ilvA helps to enhance the furniture of odd anteiso fatty acids leading to a favored mycosubtilin anteiso-C17 production pattern (+41%). Alternatively, a knock-out codY mutant led to a higher furniture of even iso fatty acids, leading to a favored mycosubtilin iso-C16 production pattern (+180%). These results showed that increased selective synthesis of particular isoforms of mycosubtilin through metabolic engineering is feasible, disclosing the interest of these approaches for future development of lipopeptide-producing strains. Full article
(This article belongs to the Special Issue Microbial Metabolic Engineering)
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27 pages, 8071 KiB  
Article
Changes in Oxygen Availability during Glucose-Limited Chemostat Cultivations of Penicillium chrysogenum Lead to Rapid Metabolite, Flux and Productivity Responses
by Qi Yang, Wenli Lin, Jiawei Xu, Nan Guo, Jiachen Zhao, Gaoya Wang, Yongbo Wang, Ju Chu and Guan Wang
Metabolites 2022, 12(1), 45; https://doi.org/10.3390/metabo12010045 - 7 Jan 2022
Cited by 1 | Viewed by 1988
Abstract
Bioreactor scale-up from the laboratory scale to the industrial scale has always been a pivotal step in bioprocess development. However, the transition of a bioeconomy from innovation to commercialization is often hampered by performance loss in titer, rate and yield. These are often [...] Read more.
Bioreactor scale-up from the laboratory scale to the industrial scale has always been a pivotal step in bioprocess development. However, the transition of a bioeconomy from innovation to commercialization is often hampered by performance loss in titer, rate and yield. These are often ascribed to temporal variations of substrate and dissolved oxygen (for instance) in the environment, experienced by microorganisms at the industrial scale. Oscillations in dissolved oxygen (DO) concentration are not uncommon. Furthermore, these fluctuations can be exacerbated with poor mixing and mass transfer limitations, especially in fermentations with filamentous fungus as the microbial cell factory. In this work, the response of glucose-limited chemostat cultures of an industrial Penicillium chrysogenum strain to different dissolved oxygen levels was assessed under both DO shift-down (60% → 20%, 10% and 5%) and DO ramp-down (60% → 0% in 24 h) conditions. Collectively, the results revealed that the penicillin productivity decreased as the DO level dropped down below 20%, while the byproducts, e.g., 6-oxopiperidine-2-carboxylic acid (OPC) and 6-aminopenicillanic acid (6APA), accumulated. Following DO ramp-down, penicillin productivity under DO shift-up experiments returned to its maximum value in 60 h when the DO was reset to 60%. The result showed that a higher cytosolic redox status, indicated by NADH/NAD+, was observed in the presence of insufficient oxygen supply. Consistent with this, flux balance analysis indicated that the flux through the glyoxylate shunt was increased by a factor of 50 at a DO value of 5% compared to the reference control, favoring the maintenance of redox status. Interestingly, it was observed that, in comparison with the reference control, the penicillin productivity was reduced by 25% at a DO value of 5% under steady state conditions. Only a 14% reduction in penicillin productivity was observed as the DO level was ramped down to 0. Furthermore, intracellular levels of amino acids were less sensitive to DO levels at DO shift-down relative to DO ramp-down conditions; this difference could be caused by different timescales between turnover rates of amino acid pools (tens of seconds to minutes) and DO switches (hours to days at steady state and minutes to hours at ramp-down). In summary, this study showed that changes in oxygen availability can lead to rapid metabolite, flux and productivity responses, and dynamic DO perturbations could provide insight into understanding of metabolic responses in large-scale bioreactors. Full article
(This article belongs to the Special Issue Microbial Metabolic Engineering)
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17 pages, 4166 KiB  
Article
Metabolic Detoxification of 2-Oxobutyrate by Remodeling Escherichia coli Acetate Bypass
by Yu Fang, Shuyan Zhang, Jianli Wang, Lianghong Yin, Hailing Zhang, Zhen Wang, Jie Song, Xiaoqing Hu and Xiaoyuan Wang
Metabolites 2021, 11(1), 30; https://doi.org/10.3390/metabo11010030 - 4 Jan 2021
Cited by 7 | Viewed by 2221
Abstract
2-Oxobutyrate (2-OBA), as a toxic metabolic intermediate, generally arrests the cell growth of most microorganisms and blocks the biosynthesis of target metabolites. In this study, we demonstrated that using the acetate bypass to replace the pyruvate dehydrogenase complex (PDHc) in Escherichia coli could [...] Read more.
2-Oxobutyrate (2-OBA), as a toxic metabolic intermediate, generally arrests the cell growth of most microorganisms and blocks the biosynthesis of target metabolites. In this study, we demonstrated that using the acetate bypass to replace the pyruvate dehydrogenase complex (PDHc) in Escherichia coli could recharge the intracellular acetyl-CoA pool to alleviate the metabolic toxicity of 2-OBA. Furthermore, based on the crystal structure of pyruvate oxidase (PoxB), two candidate residues in the substrate-binding pocket of PoxB were predicted by computational simulation. Site-directed saturation mutagenesis was performed to attenuate 2-OBA-binding affinity, and one of the variants, PoxBF112W, exhibited a 20-fold activity ratio of pyruvate/2-OBA in substrate selectivity. PoxBF112W was employed to remodel the acetate bypass in E. coli, resulting in l-threonine (a precursor of 2-OBA) biosynthesis with minimal inhibition from 2-OBA. After metabolic detoxification of 2-OBA, the supplies of intracellular acetyl-CoA and NADPH (nicotinamide adenine dinucleotide phosphate) used for l-threonine biosynthesis were restored. Therefore, 2-OBA is the substitute for pyruvate to engage in enzymatic reactions and disturbs pyruvate metabolism. Our study makes a straightforward explanation of the 2-OBA toxicity mechanism and gives an effective approach for its metabolic detoxification. Full article
(This article belongs to the Special Issue Microbial Metabolic Engineering)
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Review

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20 pages, 962 KiB  
Review
Advances in Cell Engineering of the Komagataella phaffii Platform for Recombinant Protein Production
by Cristina Bustos, Johan Quezada, Rhonda Veas, Claudia Altamirano, Stephanie Braun-Galleani, Patrick Fickers and Julio Berrios
Metabolites 2022, 12(4), 346; https://doi.org/10.3390/metabo12040346 - 14 Apr 2022
Cited by 15 | Viewed by 3789
Abstract
Komagataella phaffii (formerly known as Pichia pastoris) has become an increasingly important microorganism for recombinant protein production. This yeast species has gained high interest in an industrial setting for the production of a wide range of proteins, including enzymes and biopharmaceuticals. During [...] Read more.
Komagataella phaffii (formerly known as Pichia pastoris) has become an increasingly important microorganism for recombinant protein production. This yeast species has gained high interest in an industrial setting for the production of a wide range of proteins, including enzymes and biopharmaceuticals. During the last decades, relevant bioprocess progress has been achieved in order to increase recombinant protein productivity and to reduce production costs. More recently, the improvement of cell features and performance has also been considered for this aim, and promising strategies with a direct and substantial impact on protein productivity have been reported. In this review, cell engineering approaches including metabolic engineering and energy supply, transcription factor modulation, and manipulation of routes involved in folding and secretion of recombinant protein are discussed. A lack of studies performed at the higher-scale bioreactor involving optimisation of cultivation parameters is also evidenced, which highlights new research aims to be considered. Full article
(This article belongs to the Special Issue Microbial Metabolic Engineering)
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