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1.
Strategy for improving L-isoleucine production efficiency in Corynebacterium glutamicum.
Wang, X
Applied microbiology and biotechnology. 2019;(5):2101-2111
Abstract
As one of the three branched-chain amino acids essential for human body, L-isoleucine is widely used in food, medicine, and feed industries. At present, L-isoleucine is mainly produced by microbial fermentation, and the main production strain is Corynebacterium glutamicum. The biosynthetic pathway of L-isoleucine in C. glutamicum is complex, and the activity of key enzymes and the transcription of key genes in the pathway are strictly regulated. The intracellularly synthesized L-isoleucine is secreted by transporters, and the activity of the transporters is also regulated. These intricate regulatory mechanisms increase the difficulty to engineer the L-isoleucine-producing C. glutamicum. This article focuses on the mechanism of L-isoleucine biosynthesis, secretion, and regulation in C. glutamicum and reviews the various metabolic engineering strategies for improving L-isoleucine production efficiency in C. glutamicum.
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2.
Challenges and tackles in metabolic engineering for microbial production of carotenoids.
Wang, C, Zhao, S, Shao, X, Park, JB, Jeong, SH, Park, HJ, Kwak, WJ, Wei, G, Kim, SW
Microbial cell factories. 2019;(1):55
Abstract
Naturally occurring carotenoids have been isolated and used as colorants, antioxidants, nutrients, etc. in many fields. There is an ever-growing demand for carotenoids production. To comfort this, microbial production of carotenoids is an attractive alternative to current extraction from natural sources. This review summarizes the biosynthetic pathway of carotenoids and progresses in metabolic engineering of various microorganisms for carotenoid production. The advances in synthetic pathway and systems biology lead to many versatile engineering tools available to manipulate microorganisms. In this context, challenges and possible directions are also discussed to provide an insight of microbial engineering for improved production of carotenoids in the future.
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3.
Recent advances in engineering Corynebacterium glutamicum for utilization of hemicellulosic biomass.
Choi, JW, Jeon, EJ, Jeong, KJ
Current opinion in biotechnology. 2019;:17-24
Abstract
Corynebacterium glutamicum has been mainly used for industrial production of amino acids, and in recent years, it has also been successfully engineered to broaden its range of substrate and product profiles. In particular, C. glutamicum has been engineered to use non-natural sugar substrates (mainly pentoses) derived from hemicellulosic feedstock, which is the second abundant component of lignocellulosic biomass. Engineering of the host in this context can greatly contribute to the development of an economic and sustainable bioprocess. The present review focuses on the recent progress in engineering C. glutamicum towards efficient utilization of pentose sugars derived in hemicellulose and for direct utilization of hemicellulose. In addition, use of C. glutamicum as a biocatalyst for bioconversion of low-value sugars derived from hemicellulose to high-value product has been reviewed.
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4.
Advances in 2-phenylethanol production from engineered microorganisms.
Wang, Y, Zhang, H, Lu, X, Zong, H, Zhuge, B
Biotechnology advances. 2019;(3):403-409
Abstract
2-Phenylethanol (2-PE) is an important flavor ingredient with a rose-like odor. Due to concerns about the toxic byproducts potentially found in 2-PE from chemical synthesis, consumers prefer the natural aroma compound, promoting the biosynthesis of 2-PE. Various microorganisms produce 2-PE naturally with low yield. Recent metabolic engineering strategies in yeasts and Escherichia coli have achieved great success in improving 2-PE bioproduction, including the alleviation of feed-back inhibition, improvement of precursor transport, enhancing activities of crucial enzymes, and reduction of by-products. Here, we review the metabolic engineering strategies applied to microorganisms for increasing bioproduction of 2-PE, address current problems, and propose further improvements.
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5.
Engineering microbial consortia by division of labor.
Roell, GW, Zha, J, Carr, RR, Koffas, MA, Fong, SS, Tang, YJ
Microbial cell factories. 2019;(1):35
Abstract
During microbial applications, metabolic burdens can lead to a significant drop in cell performance. Novel synthetic biology tools or multi-step bioprocessing (e.g., fermentation followed by chemical conversions) are therefore needed to avoid compromised biochemical productivity from over-burdened cells. A possible solution to address metabolic burden is Division of Labor (DoL) via natural and synthetic microbial consortia. In particular, consolidated bioprocesses and metabolic cooperation for detoxification or cross feeding (e.g., vitamin C fermentation) have shown numerous successes in industrial level applications. However, distributing a metabolic pathway among proper hosts remains an engineering conundrum due to several challenges: complex subpopulation dynamics/interactions with a short time-window for stable production, suboptimal cultivation of microbial communities, proliferation of cheaters or low-producers, intermediate metabolite dilution, transport barriers between species, and breaks in metabolite channeling through biosynthesis pathways. To develop stable consortia, optimization of strain inoculations, nutritional divergence and crossing feeding, evolution of mutualistic growth, cell immobilization, and biosensors may potentially be used to control cell populations. Another opportunity is direct integration of non-bioprocesses (e.g., microbial electrosynthesis) to power cell metabolism and improve carbon efficiency. Additionally, metabolic modeling and 13C-metabolic flux analysis of mixed culture metabolism and cross-feeding offers a computational approach to complement experimental research for improved consortia performance.
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6.
Regulation and metabolic engineering strategies for permeases of Saccharomyces cerevisiae.
Zhang, P, Chen, Q, Fu, G, Xia, L, Hu, X
World journal of microbiology & biotechnology. 2019;(7):112
Abstract
Microorganisms have evolved permeases to incorporate various essential nutrients and exclude harmful products, which assists in adaptation to different environmental conditions for survival. As permeases are directly involved in the utilization of and regulatory response to nutrient sources, metabolic engineering of microbial permeases can predictably influence nutrient metabolism and regulation. In this mini-review, we have summarized the mechanisms underlying the general regulation of permeases, and the current advancements and future prospects of metabolic engineering strategies targeting the permeases in Saccharomyces cerevisiae. The different types of permeases and their regulatory mechanisms have been discussed. Furthermore, methods for metabolic engineering of permeases have been highlighted. Understanding the mechanisms via which permeases are meticulously regulated and engineered will not only facilitate research on regulation of global nutrition and yeast metabolic engineering, but can also provide important insights for future studies on the synthesis of valuable products and elimination of harmful substances in S. cerevisiae.
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7.
Repurposing peroxisomes for microbial synthesis for biomolecules.
Gao, J, Zhou, YJ
Methods in enzymology. 2019;:83-111
Abstract
Microbial synthesis represents an alternative approach for the sustainable production of chemicals, fuels, and medicines. However, construction of biosynthetic pathways always suffers from side reactions, toxicity of intermediates, or low efficiency of substrate channeling. Subcellular compartmentalization may contribute to a more efficient production of target products by reducing side reactions and toxic effects within a compact insular space. The peroxisome, a type of organelle that is involved in catabolism of fatty acids and reactive oxygen species, has attracted a great deal of attention in the construction of eukaryotic cell factories with little impact on essential cellular function. In this chapter, we will systematically review recent advances in peroxisomal compartmentalization for microbial production of valuable biomolecules. Additionally, detailed experimental designs and protocols are also described. We hope a comprehensive understanding of peroxisomes will promote their application in metabolic engineering and synthetic biology.
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8.
Computational Approaches to Design and Test Plant Synthetic Metabolic Pathways.
Küken, A, Nikoloski, Z
Plant physiology. 2019;(3):894-906
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Abstract
Successfully designed and implemented plant-specific synthetic metabolic pathways hold promise to increase crop yield and nutritional value. Advances in synthetic biology have already demonstrated the capacity to design artificial biological pathways whose behavior can be predicted and controlled in microbial systems. However, the transfer of these advances to model plants and crops faces the lack of characterization of plant cellular pathways and increased complexity due to compartmentalization and multicellularity. Modern computational developments provide the means to test the feasibility of plant synthetic metabolic pathways despite gaps in the accumulated knowledge of plant metabolism. Here, we provide a succinct systematic review of optimization-based and retrobiosynthesis approaches that can be used to design and in silico test synthetic metabolic pathways in large-scale plant context-specific metabolic models. In addition, by surveying the existing case studies, we highlight the challenges that these approaches face when applied to plants. Emphasis is placed on understanding the effect that metabolic designs can have on native metabolism, particularly with respect to metabolite concentrations and thermodynamics of biochemical reactions. In addition, we discuss the computational developments that may help to transform the identified challenges into opportunities for plant synthetic biology.
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9.
CF-Targeter: A Rational Biological Cell Factory Targeting Platform for Biosynthetic Target Chemicals.
Ding, S, Cai, P, Yuan, L, Tian, Y, Tu, W, Zhang, D, Cheng, X, Sun, D, Chen, J, Hu, QN
ACS synthetic biology. 2019;(10):2280-2286
Abstract
Biosynthesis is a promising method for chemical synthesis. However, due to varieties between different microorganism hosts, yield and heterologous pathways needed for production of target chemical may also vary from different strains. One of the main challenges in metabolic engineering is to select an appropriate chassis host for specified target chemical production. However, with thousands of microorganisms existing in nature and extremely complicated metabolism within them, it is still time-consuming and error-prone work to achieve such a goal only through experimental methods, even with some existing computational methods. Hence, more efficient methods should be proposed to assist in selecting appropriate chassis hosts. In this article, based on symbolic reaction repositories and a pathway search algorithm which performed 1 400 000 searches for per target compound, we established a biological reasoning system for appropriate chassis host selection by coupling with various GEM-models. By using a supercomputer to calculate the biosynthetic pathways for more than 1 month, nearly 50 000 000 biosynthetic pathways are computed for production of 6026 compounds within 70 microorganisms. With retrieved organisms for specified target production, several heterologous biosynthetic pathways can be shown in length order, and then the maximum theoretical yields and thermodynamic feasibility can be calculated in real time under customized growth conditions and physiological states. From the computation results, the system not only identifies experimentally validated pathways but also outputs more efficient solutions with less heterologous steps or higher maximum possible theoretical yield by engineering other organism hosts. CF-targeter is available at http://www.rxnfinder.org/cf_targeter/.
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10.
Improvement of phytochemical production by plant cells and organ culture and by genetic engineering.
Nielsen, E, Temporiti, MEE, Cella, R
Plant cell reports. 2019;(10):1199-1215
Abstract
Plants display an amazing ability to synthesize a vast array of secondary metabolites that are an inexhaustible source of phytochemicals, bioactive molecules some of which impact the human health. Phytochemicals present in medicinal herbs and spices have long been used as natural remedies against illness. Plant tissue culture represents an alternative to whole plants as a source of phytochemicals. This approach spares agricultural land that can be used for producing food and other raw materials, thus favoring standardized phytochemical production regardless of climatic adversities and political events. Over the past 20 years, different strategies have been developed to increase the synthesis and the extraction of phytochemicals from tissue culture often obtaining remarkable results. Moreover, the availability of genomics and metabolomics tools, along with improved recombinant methods related to the ability to overexpress, silence or disrupt one or more genes of the pathway of interest promise to open new exciting possibilities of metabolic engineering. This review provides a general framework of the cellular and molecular tools developed so far to enhance the yield of phytochemicals. Additionally, some emerging topics such as the culture of cambial meristemoid cells, the selection of plant cell following the expression of genes encoding human target proteins, and the bioextraction of phytochemicals from plant material have been addressed. Altogether, the herein described techniques and results are expected to improve metabolic engineering tools aiming at improving the production of phytochemicals of pharmaceutical and nutraceutical interest.