Next-generation metabolic engineering of non-conventional microbial cell factories for carboxylic acid platform chemicals

doi:10.1016/j.biotechadv.2020.107605

Biotechnology Advances

Volume 43, 1 November 2020, 107605

https://doi.org/10.1016/j.biotechadv.2020.107605 Get rights and content

Abstract

Carboxylic acids contain carboxyl groups that can undergo a wide range of chemical transformation. Therefore, they serve as key platform chemicals for the production of high value-added industrial products. Currently, the majority of carboxylic acid platform chemicals is produced predominantly through traditional chemical synthesis. However, these chemical conversion processes are heavily dependent on fossil fuels and often lead to serious environmental pollution. Recently, the rapid development in metabolic engineering of microbes provide a new and promising alternative route for producing carboxylic acids as platform chemicals. We envision that these bio-based manufacturing processes using microbial cell factories will help move the industrial production of carboxylic acid platform chemicals towards a more sustainable, environmentally friendly and economically competitive direction. While Escherichia coli and Saccharomyces cerevisiae have been the workhorses for biochemical production through metabolic engineering, non-conventional microbes are emerging as suitable hosts for producing carboxylic acids to meet the needs of the industries. Here, we review the employment of metabolic engineering strategies on non-conventional microbes to serve as microbial cell factories for the production of industrially important carboxylic acid platform chemicals.

Introduction

Platform chemicals are groups of basic chemicals that are commonly used as starting materials or building blocks for manufacturing of a wide range of valuable end products. One of the most important class of platform chemicals are the carboxylic acids. The carboxyl functional groups of carboxylic acids are highly versatile and can undergo many different types of chemical reactions to form a wide range of high-value compounds. Hence, there is a huge demand for this class of platform chemicals in the global market, as they play a key role in supporting a large number of industries. Currently, industrial synthesis of carboxylic acid platform chemicals is mostly achieved from non-renewable petroleum resources through conventional chemical synthesis processes (Haynes, 2006; Luna-Flores et al., 2018; Yoneda et al., 2001). These methods still rely heavily on petrochemicals as raw materials and require toxic chemicals, including heavy metal catalysts and organic solvents that may exacerbate environmental pollution. In view of growing concerns regarding finite fossil resources and environmental issues, an increasing demand for carboxylic acid platform chemicals by renewable means is therefore apparent.

In the past decade, rapid progress in metabolic engineering of microbes has enabled sustainable production of a wide array of bioproducts such as biopharmaceuticals, biofuels and biomaterials (Carpine et al., 2017; Ferreira et al., 2018; Foo et al., 2017; Li et al., 2016; Mao et al., 2018; Runguphan and Keasling, 2014; Sanchez-Garcia et al., 2016; Shomar et al., 2018; Steen et al., 2008; Wong et al., 2018). Thus, using the tools of metabolic engineering for creating microbial cell factories to manufacture carboxylic acids to serve as platform chemicals is increasingly viewed as a highly promising alternative to chemically synthesized carboxylic acids, and thereby can reduce our dependence on fossil reserves. Indeed, the feasibility of bio-based production of carboxylic acid has been well-exemplified by industrial production of citric acid, lactic acid, itaconic acid and succinic acid (Table 1).

Recently, researchers have successfully demonstrated the potential of the production of carboxylic acid platform chemicals by developing microbial strains as production systems. Traditionally, conventional production hosts such as Escherichia coli and Saccharomyces cerevisiae have been the microbes of choice for metabolic engineering due to ease of handling and availability of established genetic tools (Yu et al., 2014). With advances in synthetic biology and development in metabolic engineering strategies, non-conventional microbes have been explored in recent years for producing carboxylic acids to serve as platform chemicals by exploiting their inherent traits such as acid tolerance and native carboxylic acid-producing capabilities, which make these microbes potentially superior hosts for biosynthesizing carboxylic acids. Herein, we review applications of microbial metabolic engineering technology to non-conventional microbes for biosynthesizing several different classes of important carboxylic acid platform chemicals, particularly short-chain fatty acids, hydroxy carboxylic acids and dicarboxylic acids.

Section snippets

Emergence of non-conventional microbes as production hosts for metabolic engineering

E. coli and S. cerevisiae have been the most widely used workhorses for metabolic engineering in production of value-added biochemicals owing to their advantageous characteristics, such as low safety risks, fast growth rates and high tractability (Yu et al., 2014). However, they lack several traits that limit their abilities to biosynthesize carboxylic acid platform chemicals. For example, they do not have outstanding tolerance to low pH (<4) and their native pathways for producing many classes

Metabolic engineering for producing short-chain fatty acids

Short-chain fatty acids are the simplest class of carboxylic acid platform chemicals. They possess C1-5 carbon chains attached to a single carboxyl function group. The short-chain carboxylic acids with linear carbon chains commonly biosynthesized in microbes are acetic, propionic and butyric acid (Singhania et al., 2013). Short-chain fatty acids with branched carbon chains, mainly isobutyric, 2-methylbutyric and isovaleric acid (IBA, 2MBA and IVA, respectively), are also found in microbes (Yu

Prospects of commercial production of platform carboxylic acids with non-conventional microbes

In this review, we have highlighted the utilization of microbes other than the conventional biotechnological workhorses, E. coli and S. cerevisiae, for production of platform carboxylic acid production. To date, carboxylic acid production using non-conventional microbes are at various stages of commercialization (Table 1). Global demands for citric acid, lactic acid and itaconic acid are supplied almost entirely through microbial fermentation. Industrial production of bio-based succinic acid

Conclusions

In recent decades, successful production of carboxylic acid platform chemicals has been achieved through biological routes by metabolic engineering microbial systems, thus enabling us to bypass the traditional method of carboxylic acid production using chemical conversion. While metabolic engineering was predominantly applied to conventional microbial hosts, such as E. coli and S. cerevisiae, advances in synthetic biology, high-throughput screening techniques and genome sequencing technologies

Ethics approval and consent to participate

This manuscript does not contain any studies with human participants or animals performed by any of the authors.

Consent for publication

All authors read and approved the final manuscript. All authors give consent to publish the review in Biotechnology Advances.

Availability of data and material

All relevant data generated or analyzed during this study were included in this published article.

Funding

The Natural Science Foundation of Tianjin, China (17JCYBJC40800), the Research Foundation of Tianjin Municipal Education Commission, China (2017ZD03), the Innovative Research Team of Tianjin Municipal Education Commission, China (TD13-5013), Tianjin Municipal Science and Technology Project (18PTSYJC00140), Public Service Platform Project for Selection and Fermentation Technology of Industrial Microorganisms (17PTGCCX00190), the Open Fund of Ministry of Education Key Laboratory of Molecular

Declaration of Competing Interest

The authors declare that they have no competing interests.

Acknowledgements

This work was supported by the Natural Science Foundation of Tianjin, China (17JCYBJC40800), the Research Foundation of Tianjin Municipal Education Commission, China (2017ZD03), the Innovative Research Team of Tianjin Municipal Education Commission, China (TD13-5013), Public Service Platform Project for Selection and Fermentation Technology of Industrial Microorganisms (17PTGCCX00190), the Open Fund of Ministry of Education Key Laboratory of Molecular Microbiology and Technology, Nankai

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Research review paperNext-generation metabolic engineering of non-conventional microbial cell factories for carboxylic acid platform chemicals

Abstract

Introduction

Section snippets

Emergence of non-conventional microbes as production hosts for metabolic engineering

Metabolic engineering for producing short-chain fatty acids

Prospects of commercial production of platform carboxylic acids with non-conventional microbes

Conclusions

Ethics approval and consent to participate

Consent for publication

Availability of data and material

Funding

Declaration of Competing Interest

Acknowledgements

Metab. Eng.

Appl. Catal. B-Environ.

Curr. Opin. Biotechnol.

Coordin. Chem. Rev.

Tetrahedron.

Cancer Lett.

Metab. Eng.

Metab. Eng.

J. Biotechnol.

Algal Res.

Metab. Eng.

Bioresour. Technol.

Trends Biotechnol

J. Biotechnol.

Trends Biotechnol.

Metab. Eng.

J. Biotechnol.

Metab. Eng.

Bioresour. Technol.

Metab. Eng.

Biochem. Eng. J.

Ind. Crop. Prod.

Metab. Eng. Commun.

Metab. Eng.

J. Biotechnol.

Metab. Eng.

Enzyme Microb. Tech.

Metab. Eng.

Curr. Opin. Microbiol.

Metab. Eng.

Coordin. Chem. Rev.

Yarrowia lipolytica as an oleaginous cell factory platform for production of fatty acid-based biofuel and bioproducts

Front. Energy Res.

Recent advances in production of succinic acid from lignocellulosic biomass

Appl. Microbiol. Biotechnol.

Current advances in separation and purification of second-generation lactic acid

Sep. Purif. Rev.

Metabolic engineering of Propionibacterium freudenreichii: effect of expressing phosphoenolpyruvate carboxylase on propionic acid production

Appl. Microbiol. Biot.

On the use of metabolic control analysis in the optimization of cyanobacterial biosolar cell factories

J. Phys. Chem. B

Engineering a cyanobacterial cell factory for production of lactic acid

Appl. Environ. Microb.

Exploring metabolic engineering design principles for the photosynthetic production of lactic acid by Synechocystis sp PCC6803

Biotechnol. Biofuels.

Bacillus coagulans MA-13: a promising thermophilic and cellulolytic strain for the production of lactic acid from lignocellulosic hydrolysate

Biotechnol. Biofuels.

Seed culture pre-adaptation of Bacillus coagulans MA-13 improves lactic acid production in simultaneous saccharification and fermentation

Biotechnol. Biofuels.

Microbial production of short chain fatty acids from lignocellulosic biomass: current processes and market

Biomed. Res. Int.

Corynebacterium glutamicum chassis C1*: building and testing a novel platform host for synthetic biology and industrial biotechnology

ACS Synth. Biol.

An Ustilago maydis chassis for itaconic acid production without by-products

Microb. Biotechnol.

Organic acids from lignocellulose: Candida lignohabitans as a new microbial cell factory

J. Ind. Microbiol. Biot.

Microbial production of volatile fatty acids: current status and future perspectives

Rev. Environ. Sci. Biol.

Metabolic engineering of Aspergillus oryzae NRRL 3488 for increased production of L-malic acid

Appl. Microbiol. Biot.

Chasing bacterial chassis for metabolic engineering: a perspective review from classical to non-traditional microorganisms

Microb. Biotechnol.

Isolation and characterization of yeasts capable of efficient utilization of hemicellulosic hydrolyzate as the carbon source

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Research review paper
Next-generation metabolic engineering of non-conventional microbial cell factories for carboxylic acid platform chemicals