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Fermentation
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Metabolic Engineering
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Metabolic Engineering

A special issue of Fermentation (ISSN 2311-5637). This special issue belongs to the section "Microbial Metabolism, Physiology & Genetics".

Deadline for manuscript submissions: closed (30 November 2015) | Viewed by 34331

Special Issue Editor

Prof. Dr. George N. Bennett

E-Mail Website
Guest Editor
Department of Biochemistry and Cell Biology, Rice University, Houston, TX, USA
Interests: metabolic engineering; redox; microbial stress; cofactors; respiration; genetics

Special Issue Information

Dear Colleagues,

The field of metabolic engineering has developed and has impacted the commercial production of many compounds, from bulk chemicals to specialized pharmaceuticals. The process of metabolic engineering encompasses a number of inputs, so as to generate a useful system for practical implementation. These considerations and developments include: finding or making the best set of enzymes for the process and taking advantage of protein engineering methods; employing global models of host metabolism via genome scale models and reconstruction and computational methods, so as to predict optimal strategies for best integrating a pathway with a host network; using high-throughput culture and screening methods and analytical techniques, so as to allow for various possible designs to be rapidly tested; advancing the art of expressing and coordinating larger sets of genes for the formation of more complex molecules; dealing with toxic substances (that are present within desired feedstocks or which are formed as metabolic intermediates) or limitations due to high concentrations of product; analyzing the cell physiology of the modified organism via a systems biology approach to identify targets, so as to further improve the system, with an appreciation of those features that are conducive to easing the process of scaling up.  Decisions as to which of these components to prioritize during the stages of developing a metabolic engineering project for a new compound, and with regard to balancing the early implementation of the latest academic findings, while accommodating the economic and time constraints of industry, further complicate the overall management of such endeavors. The Special Issue will focus on recent examples of metabolic engineering that reflect one or more of these themes.

Prof. Dr. George N. Bennett
Guest Editor

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. Fermentation 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

  • enzyme engineering
  • metabolic models
  • gene expression
  • stress tolerance
  • scale-up
  • metabolic pathways
  • metabolic flux
  • metabolomics
  • feedstock

Published Papers (5 papers)

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Research

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694 KiB  
Article
Improving Process Yield in Succinic Acid Production by Cell Recycling of Recombinant Corynebacterium glutamicum
by Toru Jojima, Ryoji Noburyu, Masako Suda, Shohei Okino, Hideaki Yukawa and Maysayuki Inui
Fermentation 2016, 2(1), 5; https://doi.org/10.3390/fermentation2010005 - 04 Mar 2016
Cited by 4 | Viewed by 5820
Abstract
Aerobically cultivated cells of Corynebacterium glutamicum produce mixed organic acids, including succinic acid (SA), from glucose when the cells are transferred to oxygen-deprived conditions. Genetic modification, including inactivation of lactate dehydrogenase and overexpression of pyruvate carboxylase, allows this microbe to be an efficient [...] Read more.
Aerobically cultivated cells of Corynebacterium glutamicum produce mixed organic acids, including succinic acid (SA), from glucose when the cells are transferred to oxygen-deprived conditions. Genetic modification, including inactivation of lactate dehydrogenase and overexpression of pyruvate carboxylase, allows this microbe to be an efficient SA producer under the conditions of oxygen deprivation. High productivity and high titers can be achieved in the production process by using the genetically engineered strain of C. glutamicum under the given conditions. However, glucose consumption for cell preparation decreases process yield (defined as the quantity of SA produced divided by the total quantity of glucose used in cell preparation and SA production). In this study, we investigated cell recycle fed-batch fermentation for SA production to improve the process yield by reducing the effect of glucose consumption for cell preparation on the process yield. A genetically stable and markerless strain, harboring nine genomic copies of the pyruvate carboxylase gene, was newly constructed and used for cell recycle fermentation. During 26 reaction cycles, only 0.7% decrease in specific productivity per reaction was observed. Overall, the process yield was improved by 79% compared to that in a single fed-batch reaction without cell recycling. Full article
(This article belongs to the Special Issue Metabolic Engineering)
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1821 KiB  
Article
Characterizing the Phenotypic Responses of Escherichia coli to Multiple 4-Carbon Alcohols with Raman Spectroscopy
by Theresah N. K. Zu, Ahmad I. M. Athamneh and Ryan S. Senger
Fermentation 2016, 2(1), 3; https://doi.org/10.3390/fermentation2010003 - 25 Jan 2016
Cited by 13 | Viewed by 4548
Abstract
The phenotypic responses of E. coli cells exposed to 1.2% (v/v) of 1-butanol, 2-butanol, isobutanol, tert-butanol, and 1,4-butanediol were studied in near real-time using Raman spectroscopy. A method of “chemometric fingerprinting” was employed that uses multivariate statistics (principal [...] Read more.
The phenotypic responses of E. coli cells exposed to 1.2% (v/v) of 1-butanol, 2-butanol, isobutanol, tert-butanol, and 1,4-butanediol were studied in near real-time using Raman spectroscopy. A method of “chemometric fingerprinting” was employed that uses multivariate statistics (principal component analysis and linear discriminant analysis) to identify E. coli phenotypic changes over a 180 min post-treatment time-course. A toxicity study showed extreme variability among the reduction in culture growth, with 1-butanol showing the greatest toxicity and 1,4-butanediol showing relatively no toxicity. Chemometric fingerprinting showed distinct phenotype clusters according to the type of alcohol: (i) 1-butanol and 2-butanol (straight chain alcohols); (ii) isobutanol and tert-butanol (branched chain alcohols); and (iii) control and 1,4-butanediol (no terminal alkyl end) treated cells. While the isobutanol and tert-butanol treated cells led to similar phenotypic responses, isobutanol was significantly more toxic. In addition, the phenotypic response was found to take place largely within 60 min of culture treatment; however, significant responses (especially for 1,4-butanediol) were still occurring at 180 min post-treatment. The methodology presented here identified different phenotypic responses to seemingly similar 4-carbon alcohols and can be used to study phenotypic responses of virtually any cell type under any set of environmental conditions or genetic manipulations. Full article
(This article belongs to the Special Issue Metabolic Engineering)
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761 KiB  
Article
Antisense-RNA-Mediated Gene Downregulation in Clostridium pasteurianum
by Michael E. Pyne, Murray Moo-Young, Duane A. Chung and C. Perry Chou
Fermentation 2015, 1(1), 113-126; https://doi.org/10.3390/fermentation1010113 - 09 Dec 2015
Cited by 11 | Viewed by 5650
Abstract
Clostridium pasteurianum is receiving growing attention for its unique metabolic properties, particularly its ability to convert waste glycerol and glycerol-rich byproducts into butanol, a prospective biofuel. Genetic tool development and whole genome sequencing have recently been investigated to advance the genetic tractability of [...] Read more.
Clostridium pasteurianum is receiving growing attention for its unique metabolic properties, particularly its ability to convert waste glycerol and glycerol-rich byproducts into butanol, a prospective biofuel. Genetic tool development and whole genome sequencing have recently been investigated to advance the genetic tractability of this potential industrial host. Nevertheless, methodologies for tuning gene expression through plasmid-borne expression and chromosomal gene downregulation are still absent. Here we demonstrate plasmid-borne heterologous gene expression and gene knockdown using antisense RNA in C. pasteurianum. We first employed a common thermophilic β-galactosidase (lacZ) gene reporter system from Thermoanaerobacterium thermosulfurogenes to characterize two promoters involved in the central fermentative metabolism of C. pasteurianum. Due to a higher level of constitutive lacZ expression compared to the ferredoxin gene (fdx) promoter, the thiolase (thl) promoter was selected to drive expression of asRNA. Expression of a lacZ asRNA resulted in 52%–58% downregulation of β-galactosidase activity compared to the control strain throughout the duration of culture growth. Subsequent implementation of our asRNA approach for downregulation of the native hydrogenase I gene (hydA) in C. pasteurianum resulted in altered end product distribution, characterized by an increase in production of reduced metabolites, particularly butyrate (40% increase) and ethanol (25% increase). Knockdown of hydA was also accompanied by increased acetate formation and lower levels of 1,3-propanediol, signifying a dramatic shift in cellular metabolism in response to inhibition of the hydrogenase enzyme. The methodologies described herein for plasmid-based heterologous gene expression and antisense-RNA-mediated gene knockdown should promote rational metabolic engineering of C. pasteurianum for enhanced production of butanol as a prospective biofuel. Full article
(This article belongs to the Special Issue Metabolic Engineering)
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1373 KiB  
Article
Activity of Lactobacillus brevis Alcohol Dehydrogenase on Primary and Secondary Alcohol Biofuel Precursors
by Ibrahim Halloum, Brian Thompson, Shawn Pugh and David R. Nielsen
Fermentation 2015, 1(1), 24-37; https://doi.org/10.3390/fermentation1010024 - 05 Aug 2015
Cited by 7 | Viewed by 7395
Abstract
The R-specific alcohol dehydrogenase (ADH) from Lactobacillus brevis LB19 (LbADH) was studied with respect to its ability to reduce a series of 3- through 5-carbon 2-alkanones and aldehydes of relevance as biofuel precursors. Although active on all substrates tested, Lb [...] Read more.
The R-specific alcohol dehydrogenase (ADH) from Lactobacillus brevis LB19 (LbADH) was studied with respect to its ability to reduce a series of 3- through 5-carbon 2-alkanones and aldehydes of relevance as biofuel precursors. Although active on all substrates tested, LbADH displays a marked preference for longer chain substrates. Interestingly, however, 2-alkanones were found to impose substrate inhibition towards LbADH, whereas aldehyde substrates rendered no such effect. Inhibition caused by 2-alkanones was furthermore found to intensify with increasing chain length. Despite demonstrating both primary and secondary ADH activities, a preliminary sequence analysis suggests that LbADH remains distinct from other, previously characterized primary-secondary ADHs. In addition to further characterizing the substrate range of this industrially important enzyme, this study suggests that LbADH has the potential to serve as a useful enzyme for the engineering of various novel alcohol biofuel pathways. Full article
(This article belongs to the Special Issue Metabolic Engineering)
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Review

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746 KiB  
Review
Metabolic Engineering for Production of Small Molecule Drugs: Challenges and Solutions
by Herbert M. Huttanus, Jiayuan Sheng and Xueyang Feng
Fermentation 2016, 2(1), 4; https://doi.org/10.3390/fermentation2010004 - 19 Feb 2016
Cited by 6 | Viewed by 10173
Abstract
Production of small molecule drugs in a recombinant host is becoming an increasingly popular alternative to chemical synthesis or production in natural hosts such as plants due to the ease of growing microorganisms with higher titers and less cost. While there are a [...] Read more.
Production of small molecule drugs in a recombinant host is becoming an increasingly popular alternative to chemical synthesis or production in natural hosts such as plants due to the ease of growing microorganisms with higher titers and less cost. While there are a wide variety of well-developed cloning techniques to produce small molecule drugs in a heterologous host, there are still many challenges towards efficient production. Therefore, this paper reviews some of these recently developed tools for metabolic engineering and categorizes them according to a chronological series of steps for a generalized method of drug production in a heterologous host, including 1) pathway discovery from a natural host, 2) pathway assembly in the recombinant host, and 3) pathway optimization to increase titers and yield. Full article
(This article belongs to the Special Issue Metabolic Engineering)
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