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Microbial Metabolic Engineering
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Microbial Metabolic Engineering

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Microbial Genetics and Genomics".

Deadline for manuscript submissions: closed (28 February 2018) | Viewed by 41644

Special Issue Editors

Prof. Dr. Isabelle Meynial-Salles

E-Mail Website
Guest Editor
Professor of University, INSA, Pathway Engineering and Evolution in Prokaryotes, Toulouse Biotechnology Institute TBI, Université de Toulouse, CNRS5504, INRA792, INSA, Toulouse, France
Interests: metabolic engineering; novel metabolic pathway; synthetic biology; evolutionary engineering
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Gilles Truan

E-Mail Website
Guest Editor
CNRS Research Director, Molecular and Metabolic Engineering team Leader, LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France
Interests: synthetic biology; enzymology

Special Issue Information

Dear Colleagues,

Due to climate change, there is a growing interest in producing chemicals, materials and more generally value added compounds by microbial cell factories from renewable non-food biomass to substitute the actual pollutant petrochemical pathways. Metabolic engineering is therefore a pillar of the Bioeconomy which will represent a strong and growing market over the next years and compete effectively and in a more sustainable way to the growing use of fossil resources.

Indeed, microorganisms have a strong potential as there are able to naturally produce lots of different metabolites of interest. However the production of compounds from natural or transformed microorganisms may be low and genetic modifications are often requested to create microorganisms in which the yield of production can effectively be competitive to the classical production of molecules from chemical engineering. This is why, since the beginning of the 1990s, metabolic engineering strategies have focused on improving, by all ways possible, the metabolic performance to obtain industrially-tailored microorganisms. More recently, the fast development of synthetic biology tools pushed the microbial metabolic engineering in a new era opening the opportunity to introduce, through rational approaches, non-natural metabolic pathways, and finally produce molecules that are completely absent in Nature’s repertoire.

This special issue will focus on the recent advances and breakthroughs issued from the Synthetic and Systems Biology community and aiming at improving not only the performance of engineered or natural producing microorganisms but also the predictability of such genetic manipulations. We will notably focus on the powerful tools for an accurate analysis of the microbial metabolism, for fast and precise genome engineering, to design via computation artificial biological molecules or pathway, for the design and creation of tailored-made non-natural enzymes and synthetic metabolic pathways and to finally develop highly efficient engineered microorganisms. Successful examples of metabolic engineering strategies using synthetic biology tools will also be described.

Prof. Dr. Isabelle Meynial-Salles
Prof. Dr. Gilles Truan
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. Genes 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 2600 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
  • Synthetic Biology tools
  • Genome Scale Model
  • Genome Engineering
  • Synthetic Metabolic Pathways

Published Papers (6 papers)

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Research

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32 pages, 6989 KiB  
Article
Deciphering the Adaptation of Corynebacterium glutamicum in Transition from Aerobiosis via Microaerobiosis to Anaerobiosis
by Julian Lange, Eugenia Münch, Jan Müller, Tobias Busche, Jörn Kalinowski, Ralf Takors and Bastian Blombach
Genes 2018, 9(6), 297; https://doi.org/10.3390/genes9060297 - 13 Jun 2018
Cited by 16 | Viewed by 5699
Abstract
Zero-growth processes are a promising strategy for the production of reduced molecules and depict a steady transition from aerobic to anaerobic conditions. To investigate the adaptation of Corynebacterium glutamicum to altering oxygen availabilities, we conceived a triple-phase fermentation process that describes a gradual [...] Read more.
Zero-growth processes are a promising strategy for the production of reduced molecules and depict a steady transition from aerobic to anaerobic conditions. To investigate the adaptation of Corynebacterium glutamicum to altering oxygen availabilities, we conceived a triple-phase fermentation process that describes a gradual reduction of dissolved oxygen with a shift from aerobiosis via microaerobiosis to anaerobiosis. The distinct process phases were clearly bordered by the bacteria’s physiologic response such as reduced growth rate, biomass substrate yield and altered yield of fermentation products. During the process, sequential samples were drawn at six points and analyzed via RNA-sequencing, for metabolite concentrations and for enzyme activities. We found transcriptional alterations of almost 50% (1421 genes) of the entire protein coding genes and observed an upregulation of fermentative pathways, a rearrangement of respiration, and mitigation of the basic cellular mechanisms such as transcription, translation and replication as a transient response related to the installed oxygen dependent process phases. To investigate the regulatory regime, 18 transcriptionally altered (putative) transcriptional regulators were deleted, but none of the deletion strains showed noticeable growth kinetics under an oxygen restricted environment. However, the described transcriptional adaptation of C. glutamicum resolved to varying oxygen availabilities provides a useful basis for future process and strain engineering. Full article
(This article belongs to the Special Issue Microbial Metabolic Engineering)
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24 pages, 2390 KiB  
Article
Genome-Guided Analysis of Clostridium ultunense and Comparative Genomics Reveal Different Strategies for Acetate Oxidation and Energy Conservation in Syntrophic Acetate-Oxidising Bacteria
by Shahid Manzoor, Anna Schnürer, Erik Bongcam-Rudloff and Bettina Müller
Genes 2018, 9(4), 225; https://doi.org/10.3390/genes9040225 - 23 Apr 2018
Cited by 21 | Viewed by 5701
Abstract
Syntrophic acetate oxidation operates close to the thermodynamic equilibrium and very little is known about the participating organisms and their metabolism. Clostridium ultunense is one of the most abundant syntrophic acetate-oxidising bacteria (SAOB) that are found in engineered biogas processes operating with high [...] Read more.
Syntrophic acetate oxidation operates close to the thermodynamic equilibrium and very little is known about the participating organisms and their metabolism. Clostridium ultunense is one of the most abundant syntrophic acetate-oxidising bacteria (SAOB) that are found in engineered biogas processes operating with high ammonia concentrations. It has been proven to oxidise acetate in cooperation with hydrogenotrophic methanogens. There is evidence that the Wood-Ljungdahl (WL) pathway plays an important role in acetate oxidation. In this study, we analysed the physiological and metabolic capacities of C. ultunense strain Esp and strain BST on genome scale and conducted a comparative study of all the known characterised SAOB, namely Syntrophaceticus schinkii, Thermacetogenium phaeum, Tepidanaerobacter acetatoxydans, and Pseudothermotoga lettingae. The results clearly indicated physiological robustness to be beneficial for anaerobic digestion environments and revealed unexpected metabolic diversity with respect to acetate oxidation and energy conservation systems. Unlike S. schinkii and Th. phaeum, C. ultunense clearly does not employ the oxidative WL pathway for acetate oxidation, as its genome (and that of P. lettingae) lack important key genes. In both of those species, a proton motive force is likely formed by chemical protons involving putative electron-bifurcating [Fe-Fe] hydrogenases rather than proton pumps. No genes encoding a respiratory Ech (energy-converting hydrogenase), as involved in energy conservation in Th. phaeum and S. schinkii, were identified in C. ultunense and P. lettingae. Moreover, two respiratory complexes sharing similarities to the proton-translocating ferredoxin:NAD+ oxidoreductase (Rnf) and the Na+ pumping NADH:quinone hydrogenase (NQR) were predicted. These might form a respiratory chain that is involved in the reduction of electron acceptors rather than protons. However, involvement of these complexes in acetate oxidation in C. ultunense and P. lettingae needs further study. This genome-based comparison provides a solid platform for future meta-proteomics and meta-transcriptomics studies and for metabolic engineering, control, and monitoring of SAOB. Full article
(This article belongs to the Special Issue Microbial Metabolic Engineering)
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15 pages, 1297 KiB  
Article
Patchoulol Production with Metabolically Engineered Corynebacterium glutamicum
by Nadja A. Henke, Julian Wichmann, Thomas Baier, Jonas Frohwitter, Kyle J. Lauersen, Joe M. Risse, Petra Peters-Wendisch, Olaf Kruse and Volker F. Wendisch
Genes 2018, 9(4), 219; https://doi.org/10.3390/genes9040219 - 17 Apr 2018
Cited by 58 | Viewed by 8765
Abstract
Patchoulol is a sesquiterpene alcohol and an important natural product for the perfume industry. Corynebacterium glutamicum is the prominent host for the fermentative production of amino acids with an average annual production volume of ~6 million tons. Due to its robustness and well [...] Read more.
Patchoulol is a sesquiterpene alcohol and an important natural product for the perfume industry. Corynebacterium glutamicum is the prominent host for the fermentative production of amino acids with an average annual production volume of ~6 million tons. Due to its robustness and well established large-scale fermentation, C. glutamicum has been engineered for the production of a number of value-added compounds including terpenoids. Both C40 and C50 carotenoids, including the industrially relevant astaxanthin, and short-chain terpenes such as the sesquiterpene valencene can be produced with this organism. In this study, systematic metabolic engineering enabled construction of a patchoulol producing C. glutamicum strain by applying the following strategies: (i) construction of a farnesyl pyrophosphate-producing platform strain by combining genomic deletions with heterologous expression of ispA from Escherichia coli; (ii) prevention of carotenoid-like byproduct formation; (iii) overproduction of limiting enzymes from the 2-c-methyl-d-erythritol 4-phosphate (MEP)-pathway to increase precursor supply; and (iv) heterologous expression of the plant patchoulol synthase gene PcPS from Pogostemon cablin. Additionally, a proof of principle liter-scale fermentation with a two-phase organic overlay-culture medium system for terpenoid capture was performed. To the best of our knowledge, the patchoulol titers demonstrated here are the highest reported to date with up to 60 mg L−1 and volumetric productivities of up to 18 mg L−1 d−1. Full article
(This article belongs to the Special Issue Microbial Metabolic Engineering)
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14 pages, 16583 KiB  
Article
A Possible Trifunctional β-Carotene Synthase Gene Identified in the Draft Genome of Aurantiochytrium sp. Strain KH105
by Hiroaki Iwasaka, Ryo Koyanagi, Ryota Satoh, Akiko Nagano, Kenshi Watanabe, Kanako Hisata, Noriyuki Satoh and Tsunehiro Aki
Genes 2018, 9(4), 200; https://doi.org/10.3390/genes9040200 - 09 Apr 2018
Cited by 32 | Viewed by 5612
Abstract
Labyrinthulomycetes have been regarded as a promising industrial source of xanthophylls, including astaxanthin and canthaxanthin, polyunsaturated fatty acids such as docosahexaenoic acid and docosapentaenoic acid, ω-3 oils, and terpenic hydrocarbons, such as sterols and squalene. A Thraustochytrid, Aurantiochytrium sp. KH105 produces carotenoids, including [...] Read more.
Labyrinthulomycetes have been regarded as a promising industrial source of xanthophylls, including astaxanthin and canthaxanthin, polyunsaturated fatty acids such as docosahexaenoic acid and docosapentaenoic acid, ω-3 oils, and terpenic hydrocarbons, such as sterols and squalene. A Thraustochytrid, Aurantiochytrium sp. KH105 produces carotenoids, including astaxanthin, with strong antioxidant activity. To gain genomic insights into this capacity, we decoded its 97-Mbp genome and characterized genes for enzymes involved in carotenoid biosynthesis. Interestingly, all carotenogenic genes, as well as other eukaryotic genes, appeared duplicated, suggesting that this strain is diploid. In addition, among the five genes involved in the pathway from geranylgeranyl pyrophosphate to astaxanthin, geranylgeranyl phytoene synthase (crtB), phytoene desaturase (crtI) and lycopene cyclase (crtY) were fused into single gene (crtIBY) with no internal stop codons. Functionality of the trifunctional enzyme, CrtIBY, to catalyze the reaction from geranylgeranyl diphosphate to β-carotene was confirmed using a yeast assay system and mass spectrometry. Furthermore, analyses of differential gene expression showed characteristic up-regulation of carotenoid biosynthetic genes during stationary and starvation phases under these culture conditions. This suggests genetic engineering events to promote more efficient production of carotenoids. We also showed an occurrence of crtIBY in other Thraustochytrid species. Full article
(This article belongs to the Special Issue Microbial Metabolic Engineering)
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Review

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19 pages, 2867 KiB  
Review
Terpenoid Metabolic Engineering in Photosynthetic Microorganisms
by Konstantinos Vavitsas, Michele Fabris and Claudia E. Vickers
Genes 2018, 9(11), 520; https://doi.org/10.3390/genes9110520 - 23 Oct 2018
Cited by 64 | Viewed by 7711
Abstract
Terpenoids are a group of natural products that have a variety of roles, both essential and non-essential, in metabolism and in biotic and abiotic interactions, as well as commercial applications such as pharmaceuticals, food additives, and chemical feedstocks. Economic viability for commercial applications [...] Read more.
Terpenoids are a group of natural products that have a variety of roles, both essential and non-essential, in metabolism and in biotic and abiotic interactions, as well as commercial applications such as pharmaceuticals, food additives, and chemical feedstocks. Economic viability for commercial applications is commonly not achievable by using natural source organisms or chemical synthesis. Engineered bio-production in suitable heterologous hosts is often required to achieve commercial viability. However, our poor understanding of regulatory mechanisms and other biochemical processes makes obtaining efficient conversion yields from feedstocks challenging. Moreover, production from carbon dioxide via photosynthesis would significantly increase the environmental and potentially the economic credentials of these processes by disintermediating biomass feedstocks. In this paper, we briefly review terpenoid metabolism, outline some recent advances in terpenoid metabolic engineering, and discuss why photosynthetic unicellular organisms—such as algae and cyanobacteria—might be preferred production platforms for the expression of some of the more challenging terpenoid pathways Full article
(This article belongs to the Special Issue Microbial Metabolic Engineering)
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17 pages, 2668 KiB  
Review
Selecting the Best: Evolutionary Engineering of Chemical Production in Microbes
by Denis Shepelin, Anne Sofie Lærke Hansen, Rebecca Lennen, Hao Luo and Markus J. Herrgård
Genes 2018, 9(5), 249; https://doi.org/10.3390/genes9050249 - 11 May 2018
Cited by 31 | Viewed by 7043
Abstract
Microbial cell factories have proven to be an economical means of production for many bulk, specialty, and fine chemical products. However, we still lack both a holistic understanding of organism physiology and the ability to predictively tune enzyme activities in vivo, thus slowing [...] Read more.
Microbial cell factories have proven to be an economical means of production for many bulk, specialty, and fine chemical products. However, we still lack both a holistic understanding of organism physiology and the ability to predictively tune enzyme activities in vivo, thus slowing down rational engineering of industrially relevant strains. An alternative concept to rational engineering is to use evolution as the driving force to select for desired changes, an approach often described as evolutionary engineering. In evolutionary engineering, in vivo selections for a desired phenotype are combined with either generation of spontaneous mutations or some form of targeted or random mutagenesis. Evolutionary engineering has been used to successfully engineer easily selectable phenotypes, such as utilization of a suboptimal nutrient source or tolerance to inhibitory substrates or products. In this review, we focus primarily on a more challenging problem—the use of evolutionary engineering for improving the production of chemicals in microbes directly. We describe recent developments in evolutionary engineering strategies, in general, and discuss, in detail, case studies where production of a chemical has been successfully achieved through evolutionary engineering by coupling production to cellular growth. Full article
(This article belongs to the Special Issue Microbial Metabolic Engineering)
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