Production of fuels and chemicals from renewable resources using engineered Escherichia coli

Biotechnology Advances 37 (2019) 107402

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Research review paper

Production of fuels and chemicals from renewable resources using engineered Escherichia coli

T

Chunhua Zhaoa,b, Yanping Zhanga,⁎, Yin Lia,⁎ a

CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China b University of Chinese Academy of Sciences, Beijing 100049, China

ARTICLE INFO

ABSTRACT

Keywords: Fuels and chemicals Renewable resources Lignocellulosic biomass Escherichia coli Metabolic engineering

Biotechnological production of fuels and chemicals from renewable resources is an appealing way to move from the current petroleum-based economy to a biomass-based green economy. Recently, the feedstocks that can be used for bioconversion or fermentation have been expanded to plant biomass, microbial biomass, and industrial waste. Several microbes have been engineered to produce chemicals from renewable resources, among which Escherichia coli is one of the best studied. Much effort has been made to engineer E. coli to produce fuels and chemicals from different renewable resources. In this paper, we focused on E. coli and systematically reviewed a range of fuels and chemicals that can be produced from renewable resources by engineered E. coli. Moreover, we proposed how can we further improve the efficiency for utilizing renewable resources by engineered E. coli, and how can we engineer E. coli for utilizing alternative renewable feedstocks. e.g. C1 gases and methanol. This review will help the readers better understand the current progress in this field and provide insights for further metabolic engineering efforts in E. coli.

1. Introduction The world’s energy infrastructure is still largely based on fossil fuels (Dürre, 2007). Although the price of crude oil has recently decreased, it is generally accepted that humanity’s dependence on oil is not sustainable, as evidenced by several oil crises in history (Venn, 2016). Furthermore, the global warming caused by greenhouse gas emissions from the petrochemical industry and burning of fossil fuels has become a severe problem for humanity (Dürre, 2007). Biotechnological production of fuels and chemicals has attracted increasing attention in recent decades due to the mild reaction conditions required and the environmentally friendly properties of the production processes (Choi et al., 2014; Cordova and Alper, 2016; Kung et al., 2012; Steen et al., 2010; Sun et al., 2015; Yazdani and Gonzalez, 2007). It is an alternative way to covert processes from traditional to green chemistry with the aid of biotechnology (Chen et al., 2018; Lee et al., 2012; Lee and Kim, 2015).

Many different fuels and chemicals were produced using metabolically engineered microbes (Cheon et al., 2016; Sun et al., 2015). However, most projects were based on first-generation feedstocks (1GF, mainly sucrose and starch from food crops) or pure carbohydrates (e.g. glucose). The reason is that these feedstocks are easy to obtain and can be easily metabolized by the microbes. On the laboratory scale, glucose is the preferred substrate when a fermentation or bioconversion process is performed (Dong et al., 2017; Foo et al., 2017). However, on the industrial scale, substrate costs will be considered in the first place. As a substrate for the production of fuels and chemicals, glucose will considerably increase the production cost unless it is used to produce highvalue-added fine chemicals. Under these circumstances, sucrose and starch from food crops were widely used for a number of years (Cheng et al., 2011). However, it is controversial to mass-produce fuels and bulk chemicals from food-grade materials, since this raises concerns on food security (Mohr and Raman, 2013). As a consequence, lignocellulosic biomass (wood, straw, grasses) gained more attention as a

Abbreviations: 1GF, first-generation feedstocks; 2GF, second-generation feedstocks; 3GF, third-generation feedstocks; SHF, separate hydrolysis and fermentation; SSF, simultaneous saccharification and fermentation; CBP, consolidated bioprocessing; IBP, integrated bioprocessing; HMF, 5-hydroxymethylfurfural; CCR, carbon catabolite repression; FAs, fatty acids; BT, 1,2,4-butanetriol; 1,3-PDO, 1,3-propanediol; 2,3-BDO, 2,3-butanediol; PLA, polylactic acid; TCA cycle, tricarboxylic acid cycle; ACP, acyl carrier protein; PTS, phosphotransferase system; TAGs, triacylglycerols; FAMEs, fatty acid methyl esters; FAEEs, fatty acid ethyl esters; FHL, formate hydrogen lyase; PHA, polyhydroxyalkanoates; P(LA-co-3HB), poly(lactate-3-hydroxybutyrate); PHB, P(3HB) – poly(3-hydroxybutyrate); PhLA, phenyllactic acid ⁎ Corresponding author at: Institute of Microbiology, Chinese Academy of Sciences, No. 1 West Beichen Road, Chaoyang District, Beijing 100101, China. E-mail addresses: [email protected] (Y. Zhang), [email protected] (Y. Li). https://doi.org/10.1016/j.biotechadv.2019.06.001 Received 11 November 2018; Received in revised form 23 May 2019; Accepted 2 June 2019 Available online 04 June 2019 0734-9750/ © 2019 Elsevier Inc. All rights reserved.

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second-generation feedstocks (2GF) on both the laboratory and industrial scale (Aditiya et al., 2016; Cheng et al., 2011). Different from the 1GF, these 2GF are derived from agricultural and forestry wastes, the inedible materials which do not compete with food production. Moreover, microbial waste, food waste, and industrial waste can also be taken as 2GF. The main components of most 2GF are polysaccharides such as cellulose, hemicellulose, xylan, and lignin. Therefore, most microbes cannot directly utilize these substrates for cell growth and chemical production except for certain bacteria that are natural utilizers of woody biomass such as Cellulomonas fimi from humus (Gilkes et al., 1988), Bacteroides succinogenes and Butyrivibrio fibrisolvens from rumen of ruminant (Teather and Wood, 1982), and Clostridium thermocellum (Johnson et al., 1982). Besides, some species from Bacillus (Haque et al., 2015; Xu et al., 2017) and Pseudomonas (Linger et al., 2016; Tozakidis et al., 2016) genera are also cellulose-degrading bacteria. Usually, polysaccharides like cellulose and lignin are broken down into monosaccharides, which are then used as substrates for fermentation. Four main processes of fermenting lignocellulosic biomass were developed accordingly: separate hydrolysis and fermentation (SHF), simultaneous saccharification and fermentation (SSF), consolidated bioprocessing (CBP), and integrated bioprocessing (IBP) (Putro et al., 2016). SHF is the most common approach employed in research on lignocellulosic biomass bioconversion (Kamoldeen et al., 2017; Pathania et al., 2017). In SHF, hydrolysates containing monosaccharides are often obtained through acid-catalyzed hydrolysis and enzymatic hydrolysis (Mi et al., 2017). Glucose, xylose, arabinose, galactose, mannose, and fructose are the main valuable sugars, while acetate, furfural, and 5-hydroxymethylfurfural (HMF) are inhibitory components of biomass hydrolysates (Carter et al., 2011). Many microbes have been engineered to utilize lignocellulosic biomass hydrolysates for the production of fuels and chemicals (Jang et al., 2012; Kawaguchi et al., 2016; Sheldon, 2014). Recently, some ‘non-model’ microbes have gained attention in light of their capability of performing some biosynthesis steps (Guamán et al., 2018; Yan and Fong, 2017). Oleaginous Yarrowia lipolytica is one of the representatives (Li et al., 2018; Tai and Stephanopoulos, 2013; Vasiliadou et al., 2018). Nevertheless, these microorganisms have not been studied in depth, they are mostly suitable for the production of certain chemicals rather than a series of different products. In contrast, Escherichia coli and Saccharomyces cerevisiae are two widely recognized user-friendly model microorganisms for metabolic engineering (Lian et al., 2018; Pontrelli et al., 2018). Moreover, E. coli has become arguably the best-characterized organism widely used in laboratories due to ease to culture, rapid growth, breath of genetic tools, and wealth of biochemical and physiological knowledge (Pontrelli et al., 2018). Engineered E. coli strains are also increasingly used in industry for the production of proteins and chemicals. Previous review articles also discussed different fuels and chemicals produced from 2GF or even third-generation feedstocks (3GF, mainly microalgae) using different microbes (Kawaguchi et al., 2016). However, a detailed overview on utilization of authentic lignocellulosic biomass by engineered E. coli is lacking. By focusing on this subject and revisiting 5 categories of chemicals (alcohols, organic acids, biodiesel, hydrogen, and some others) produced from a range of 2GF or 3GF by engineered E. coli, we were able to propose future research directions in this area.

Tokgoz, 2008; Jeffries, 2005; Salles-Filho et al., 2017; Soccol et al., 2010). However, the majority of the ethanol is produced from corn, wheat, and sugarcane. Considering the concerns on food security, production of ethanol from non-edible feedstocks has been extensively studied by many researchers (Sun et al., 2015). Instead of using edible feedstocks, lignocellulosic materials were used for ethanol production using engineered E. coli (Dien et al., 2000; Munjal et al., 2015; Saha et al., 2011; Saha et al., 2015). The lignocellulosic biomass materials mainly contain cellulose, hemicellulose, and lignin, which means that they must be hydrolyzed before E. coli can utilize the resulting sugars. Due to the carbon catabolite repression (CCR) effect, most bacterial strains cannot simultaneously utilize pentoses and hexoses in the hydrolysates. One approach is removing the PTS by knocking out the related genes (e.g. ptsG, ptsH, ptsI, crr). However, the implementation of this approach results in a low utilization rate of glucose (Saini et al., 2017a). Another approach is using a crp mutant that rewires the CCR system (Cirino et al., 2006; Eppler and Boos, 1999; Luo et al., 2014). As for inhibitors in hydrolysates, Wang et al. found that the deletion of yqhD together with increased expression of fucO, ucpA, or pntAB can increase furfural tolerance (Wang et al., 2013). Boopathy et al. found that furfural can be converted into furfuryl alcohol by methanogenic archaea (Boopathy, 2009). These mechanisms may be used for reference in E. coli. Constructing a strain capable of co-utilizing pentoses and hexoses as well as tolerating small molecule inhibition is desirable for production of biomass-based ethanol. Dien et al. constructed an ethanologenic strain E. coli FBR4 by introducing pLOI297 (pdc, adhB) and selected a xylose-utilizing mutant FBR5 for the fermentation of corn fiber hydrolysate. The hydrolysate was over-limed prior to fermentation to partially mitigate the effect of inhibitors. In batch fermentation, 37.4 g/L ethanol with a yield of 0.48 g/g was produced. The titer and yield were even higher than what was achieved via fermentation of mixed sugars. This was mainly due to the higher initial sugar concentration in the hydrolysate (Dien et al., 2000). The mutant FBR5 consumed glucose, arabinose, and xylose almost in parallel suggesting co-utilization of pentoses and hexoses problem was solved. Saha et al. studied ethanol production from corn stover hydrolysate using E. coli FBR5. In said study, SSF was tested as well by adding cellulase, and strain FBR5 produced almost the same concentration of ethanol as in SHF (Saha et al., 2015). This suggested that the cost-effective SSF process, which avoids the need to hydrolyze the biomass in advance, is suitable for ethanol production using FBR5. However, the pentose components will not be efficiently consumed if only cellulase is used to hydrolyze the biomass. In addition to corn biomass, ethanol production from wheat straw (Saha et al., 2011) and rice husk (Tabata et al., 2017) were studied as well. Saha et al. studied ethanol fermentation from wheat straw using E. coli FBR5. The authors aimed to increase the ethanol production level to 4% (v/v) (about 40−43 g/L) by the recombinant strain. In this study, a fungal bioabatement process was chosen for the removal of inhibitors (Nichols et al., 2005). In SHF, 41.8 g/L ethanol was produced from bioabated wheat straw hydrolysate. When using non-abated wheat straw hydrolysate, there was a lag phase, but the ethanol titer still reached 41.1 g/L. This indicated that the strain can tolerate or metabolize inhibitors such as acetate, furfural, and HMF. In SSF, strain FBR5 produced 41.6 g/L ethanol with a productivity of 0.40 g/L/h (Saha et al., 2011). Previously, researchers proposed that reaching an ethanol concentration of 4% (v/v) or above in the fermentation broth could be considered as a benchmark for economically viable distillation (Zacchi and Axelsson, 1989). The ability of producing over 4% (v/v) ethanol by E. coli strain FBR5 in either SHF or SSF, with wheat straw pretreated with dilute acid and detoxified, is thus of commercial interest. In addition to SHF and SSF, converting wheat straw into ethanol by CBP, which combines cellulases synthesis, saccharification, and pentoses/ hexoses co-utilization together in one step, was investigated. Munjal et al. reported the construction of the ethanologenic E. coli strain SSY12

2. Alcohols 2.1. Ethanol Bioethanol is arguably the most successful liquid transport biofuel developed to date (Aditiya et al., 2016; Jeffries, 2005). In order to relieve the energy crisis, bio-production of ethanol from renewable resources was proposed. In the United States and Brazil, bioethanol has become a commercial product on a vast industrial scale (Elobeid and 2

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transformed with a constitutive expression system of secretory β-glucosidase gene. Using this strain, the authors tested the fermentation of a wheat straw, whereby 9.4 g/L ethanol (~1%, v/v) was obtained at the end of fermentation, with a biotransformation efficiency of 85% (Munjal et al., 2015). Results indicate that the CBP system for ethanol production needs to be further improved compared with the SHF and SSF processes, since rapid inducible expression of sufficient amounts of cellulases remains a challenge. Microalgae or seaweeds can be used as 3GF to produce various fuels. Microalgae possess high carbohydrate (cellulose on the cell wall and starch in the cytoplasm) and lipid contents that can potentially be converted into fuels. Enzymatic digestion of polysaccharides in microalgae is necessary prior to fermentation, but the harsh pretreatment used for woody biomass may not be necessary in this case due to the absence of lignin and hemicellulose in microalgae (Cheng et al., 2011). Wargacki et al. engineered a microbial platform for direct biofuel production from brown macroalgae using E. coli. The research group discovered genes from Vibrio splendidus encoding enzymes for alginate transport and metabolism. By integrating these genes and another engineered system for extracellular alginate depolymerization, the recombinant E. coli produced ethanol with a final titer of ~4.7% (v/v). This ethanol titer corresponds to a bioconversion efficiency of ~0.281 g ethanol/g biomass with a yield of ~0.41 g/g sugar (Wargacki et al., 2012). Because of the high titer of ethanol achieved, this study showed algal biomass which can be directly hydrolyzed without harsh pretreatment is very suitable as feedstock to produce ethanol. Ethanol is a bulk chemical with a relatively low selling price. Therefore, reducing production costs and increasing the product titer is the key to making ethanol derived from renewable resources competitive in the market. Judging by the presented examples, biotechnological ethanol titers are generally low, mostly due to the low sugar concentrations and inhibitory effects of certain components of biomass hydrolysates. Fortunately, E. coli can grow well in minimal mineral medium (no need to add expensive nutrients) and can be effortlessly genetically modified (strain improvement is feasible). Adaptive evolution together with mutant screening may help increase the ethanol tolerance and hydrolysate adaptability, and thus enable higher titers of ethanol production (Ingram, 1989; Stanley et al., 2010). On the other hand, new technology which can increase the sugar concentration in biomass hydrolysates is desired. For fermentation processes, SSF is better suited than SHF to reduce the cost of ethanol production, as it integrates saccharification and fermentation the same space and generates less inhibitors (Saha et al., 2011).

while E. coli cannot tolerate 2% (v/v) (~16 g/L) butanol (Dong et al., 2016). Saini et al. developed an E. coli platform to synthesize butanol from the hydrolysate of rice straw. Using a previously reported coculture system (Saini et al., 2015), 4.9 g/L butanol was produced from rice straw hydrolysate. To improve the productivity of cellulosic biobutanol, a high cell density approach was employed. As a result, all cellulose-derived glucose was consumed and the production of cellulosic biobutanol reached 5.8 g/L and a 1.2-fold increase of productivity (Saini et al., 2016). Hydrolysates of lignocellulosic biomass always contain pentoses and inhibitors besides hexoses. However, the pentose metabolism and inhibitors problem were not mentioned in this study which may hinder the improvement of butanol production. Bokinsky et al. studied the CBP of E. coli for the production of three advanced biofuels, one of which was butanol. The engineered E. coli strains expressed cellulase, xylanase, β-glucosidase, and xylobiosidase enzymes, which enabled them to grow on ionic liquid-pretreated switchgrass (mainly containing cellulose and hemicellulose components) and allowing butanol production at a level of 28 mg/L (Bokinsky et al., 2011). The results further illustrated the limitations of CBP at the current stage. However, this approach is still worthy of studying due to the user-friendly and low-cost properties of CBP (Wen et al., 2019). Renewable substrates other than lignocellulosic biomass were also investigated for butanol production using E. coli. Saini et al. investigated butanol production from crude glycerol which is abundant in the waste stream of biodiesel production. In this work, the central metabolism of E. coli was rationally rewired to improve the efficiency of glycerol metabolism in conjunction with butanol synthesis. After a series of genetic modifications, the engineered strain was capable of producing 6.9 g/L of butanol from 20 g/L crude glycerol (Saini et al., 2017b). Glycerol is more reduced than glucose with the highly reduced carbon atoms generating more reducing equivalents. However, glycerol metabolism is less efficient than glucose metabolism in E. coli. This study demonstrated the feasibility of enhancing glycerol metabolism for chemicals production. Previously, Dellomonaco and coworkers engineered the respiro-fermentative metabolism of E. coli for the production of fuels and chemicals from fatty acids (FAs). By manipulating key enzyme genes of the fad regulon and the ato operon and introducing a butanol-production pathway, an E. coli strain was constructed that was able to produce 2.05 g/L butanol with a yield of 0.18 g/g from palmitic acid. Cosolvent Brij 58 was used to help increasing the solubility of palmitic acid in this study (Dellomonaco et al., 2010). FAs are feedstocks with more highly reduced carbon atoms. Furthermore, their metabolism to the key intermediate acetyl-CoA has better atom economy, resulting in 100% carbon retention. Thus, the metabolism of FAs through β-oxidation could enable significantly higher product yields than those obtained from lignocellulose-derived sugars (Dellomonaco et al., 2010). These two advantages make them optimal feedstocks for butanol production. However, the anaerobic metabolism, the solubility of medium- and long-chain FAs, together with their transport are main problems hindering the utilization of FAs. Although the titer and yield are relatively low, above two studies proved that it is possible to synthesize butanol from crude glycerol and FAs. Like ethanol, butanol is also a bulk chemical, and increasing production titer is of highest priority for its industrial production. An efficient production strain is essential when renewable biomass is used as feedstock. So far, the most efficient E. coli strain can produce about 20 g/L butanol (Dong et al., 2017; Ohtake et al., 2017). However, due to butanol’s toxicity, it is difficult to further improve butanol titer through metabolic engineering of conventional E. coli. Under these circumstances, fermentation process optimization may be more effective. Gas stripping (Shen et al., 2011) and continuous fermentation processing (Raynaud et al., 2018) can greatly increase the titer and productivity of butanol production. According to the available literature, both lignocellulosic materials and waste glycerol are potential substitutes for current feedstocks.

2.2. Butanol Butanol (n-butanol, syn. 1-butanol) is an important solvent and a potential biofuel which is believed to be better than ethanol because of its reduced water solubility and higher energy density. Moreover, it can completely replace gasoline or be mixed with gasoline at any ratio for existing internal combustion engines (Atsumi et al., 2008a). The ketoacid pathway and the CoA-dependent pathway are the two main pathways for butanol production (Sun et al., 2015). In nature, some Clostridium strains can produce butanol, among which the ABE (acetone-butanol-ethanol) fermentation of C. acetobutylicum is perhaps the best-known example (Jones and Woods, 1986). Due to the complex physiology and relatively unknown genetic system of clostridia, E. coli was chosen as a host for butanol production in recent years (Dellomonaco et al., 2011; Dong et al., 2017; Saini et al., 2015; Shen et al., 2011). Consequently, butanol production from lignocellulosic biomass or other renewable resources gained attention as well. Besides the pentoses and hexoses co-utilization and inhibitor resistance problem occurred in cellulosic ethanol production process, butanol toxicity is another problem for butanol production in E. coli. This further limits the fermentation concentration of butanol. Usually 0.6% (v/v) (~5 g/L) butanol will severely inhibit E. coli cell growth 3

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2.3. Isobutanol

2.4. Diols and triols

Isobutanol is an important building block used for the production of other chemicals. Additionally, it is a potential biofuel with high energy density similar to butanol, and can also be mixed with gasoline at any proportion (Sun et al., 2015). Isobutanol can be generated from 2-ketoisovalerate, an intermediate of valine biosynthesis (Atsumi et al., 2008c). Isobutanol production from glucose has been widely studied in E. coli (Atsumi et al., 2008c; Atsumi et al., 2010; Bastian et al., 2011), and in this review, we will focus on isobutanol production from lignocellulosic biomass and other renewable non-food resources. Desai et al. engineered an E. coli strain for isobutanol production from cellobiose. Cellobiose is a disaccharide product of incomplete hydrolytic cellulose. Further hydrolysis to glucose is necessary prior to use. By introducing a β-glucosidase gene together with the isobutanol synthetic pathway into E. coli, the best strain produced 7.64 g/L isobutanol from cellobiose (Desai et al., 2014). Minty et al. designed and characterized a synthetic fungal-bacterial consortium for the direct production of isobutanol from cellulosic biomass. The fungus Trichoderma reesei, which secrets cellulase enzymes to hydrolyze lignocellulosic biomass into soluble saccharides, and the bacterium E. coli, which metabolizes soluble saccharides into isobutanol were combined for co-culture. Without costly nutrient supplementation, the authors achieved isobutanol titers of up to 1.88 g/L and yields of up to 62% of the theoretical maximum from corn stover (Minty et al., 2013). This study demonstrated that combining cellulose-utilizing fungi and bacteria together is another approach to produce fuels and chemicals directly from biomass. Proteins are the dominant fraction in fast-growing photosynthetic microorganisms and sugar-based or cellulosic biorefining residues (i.e. proteins from the residual microbes) (Becker, 2007; Huo et al., 2011). The animal feed market has a limited ability to absorb the increasing protein by-products from the fast-expanding biorefinery industry (Wijffels and Barbosa, 2010). Later, it was proposed as feedstock for industrial fermentation (Zhang et al., 2008). However, they are rarely used as feedstocks to synthesize fuels because of the difficulties of deaminating protein hydrolysates. Nevertheless, Huo et al. made deamination possible by applying metabolic engineering to generate an E. coli strain that can deaminate protein hydrolysates. Three exogenous transamination and deamination cycles, which provide an irreversible metabolic force that drives deamination to completion when introduced into E. coli. Isobutanol was produced from different protein sources, including the biomass of S. cerevisiae, E. coli, Bacillus subtilis, and microalgae. The strain produced 4.04 g/L of isobutanol from biomass containing ~22 g/L of amino acids (Huo et al., 2011). This study described the blueprint of fuels and chemicals production from waste proteins generated from the current fermentation, food processing, and biofuel production industries. It will benefit the recycling of biomass resources and the recycling of nitrogen in nature. Isobutanol production from pure sugars has been well studied (Atsumi et al., 2008c; Atsumi et al., 2010). Considering the lower availability of NADPH in E. coli, a great improvement of isobutanol yield and productivity was achieved by engineered an NADH-dependent pathway replacing the NADPH-dependent pathway (Bastian et al., 2011). Thus, this pathway should be studied to improve the industrial competitiveness of isobutanol production from renewable feedstocks. In addition, pathway enhancement and engineering of key enzymes should be performed to improve the strains’ fermentation performance. The SHF process should be tested first, as the other processes are more complicated. Apart from the lignocellulosic feedstocks, employment of waste protein has opened up a new route for isobutanol production (Huo et al., 2011). The available strains may need to be further improved via rational design and non-rational approaches such as random mutagenesis and adaptive evolution to meet the requirements of practical applications.

C3 diols (1,3-propanediol and 1,2-propanediol) and C4 diols (2,3butanediol and 1,4-butanediol) are important chemicals with diverse applications. They have attracted much attention in recent decades. 1,2,4-butanetriol (BT) is an important triol with a number of industrial applications. It can be used to synthesize 1,2,4-butanetriol trinitrate, which is a good propellant and an energy-rich plasticizer. It can also be used as the raw material to synthesize polymeric materials and precursors for drug delivery (Sun et al., 2016b). As mentioned above, glycerol is a by-product generated in the production process of biodiesel. The expanding market demand for biodiesel has resulted in a large amount of glycerol currently available at low prices (Da Silva et al., 2009). Citrobacter freundii and Klebsiella pneumoniae are among the best 1,3-PDO producers fed by glycerol, but they are opportunistic pathogen, which restricts their application in industrial processes. Fortunately, the pathway can be transferred to nonpathogenic E. coli. Przystałowska et al. constructed an E. coli strain for 1,3-propanediol (1,3-PDO) production from waste glycerol. In the study, genes from C. freundii and K. pneumoniae were introduced into E. coli to enable the synthesis of 1,3-PDO from waste glycerol. In batch fermentation, the recombinant E. coli cells produced 10.6 g/L of 1,3PDO consuming 32.6 g/L of glycerol, attaining an efficiency of 0.33 g/g (Przystałowska et al., 2015). Glycerol is an optimal feedstock for the production of 1,3-PDO, as the corresponding synthetic pathway is short. However, improving the glycerol metabolism of E. coli remains challenge. This work opened a way to produce “green” 1,3-PDO from glycerol using an engineered nonpathogenic strain containing genes from pathogenic bacteria, which are the best 1,3-PDO producers. However, the strain and the fermentation process need to be optimized further in order to compete with the existing industrial strains. 2,3-Butanediol (2,3-BDO) can be produced by Klebsiella strains with high titer and yield. Unfortunately, these producers are opportunistic pathogen, thus not suitable for large scale industrial applications (Celińska and Grajek, 2009). Shin et al. studied the production of 2,3BDO from cellodextrin by engineered E. coli. Cellodextrin is a partial cellulose hydrolysis product that cannot be directly used. Through taking steps of gene deletion, synthetic operon introduction, and cellodextrinase periplasmic expression from Saccharophagus sp., they engineered an E. coli biocatalyst capable of producing 2,3-BDO from cellodextrin. The highest 2,3-BDO concentration of the CBP was 4.2 g/ L, at 84% of the theoretical yield. Additionally, by adding a commercial cellulase cocktail, 5.5 g/L 2,3-BDO was accumulated from cellulose (Shin et al., 2012). This work took a step of making production of 2,3BDO more competitive by using cellulose rather than glucose. Mazumdar et al. also made many efforts on 2,3-BDO production from renewable resources which belongs to 3GF. In fed-batch fermentation, 14.1 g/L 2,3-BDO and 4.8 g/L acetoin were produced from algal hydrolysate at the same time (Mazumdar et al., 2013). The relatively low titer of 2,3-BDO may due to the low concentration of sugars in algal hydrolysate and the high concentration of by-product acetoin. Mannitol metabolism should be enhanced to further increase the productivity. Cao et al. expressed xylonate dehydratase (encoded by yjhG) and aldehyde reductase (encoded by adhP) in E. coli for BT production. By co-expressing the entire BT biosynthesis pathway, the strain produced 0.31 g/L of BT from xylonate, representing a 1.8-fold increase over the parent strain (Cao et al., 2015). This work suggested that engineered E. coli strains have potential of BT production from renewable resources. Biological production of 1,3-PDO from glucose has been commercialized by DuPont (Nakamura and Whited, 2003; Saxena et al., 2009). Using renewable biomass-derived sugars will further reduce the feedstock costs. The main issue in the co-utilization of pentoses and hexoses may be addressed by selecting mutants such as the ethanologenic strain FBR5 (Dien et al., 2000). Crude glycerol is another attractive feedstock, but certain impurities still pose a problem. The development of a tolerant strain is therefore under consideration. In the case of four-carbon 4

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Fig. 1. Metabolic pathways of different alcohols. (A) Synthetic pathways of monohydric alcohol. PEP, phosphoenolpyruvate; OAA, oxaloacetate; Pdc, pyruvate decarboxylase; Adh, alcohol dehydrogenase; AtoDA, acetyl-CoA:acetoacetyl-CoA transferase; Adc, acetoacetate decarboxylase; AtoB, acetyl-CoA acetyltransferase; Hbd, acetoacetyl-CoA thiolase; Crt, crotonase; Ter, trans-enoyl-coenzyme A reductase; AdhE2, aldehyde/alcohol dehydrogenase; IlvBN, acetolactate synthase; IlvC, ketol-acid reductoisomerase; IlvD, dihydroxyacid dehydratase; Kdc, 2-ketoacid decarboxylase; IlvA, L-threonine dehydratase; LeuABCD, leucine biosynthesis operon. (B) Synthetic pathways of diols. FBP, Fructose-1,6-biphosphate; G3P, Glyceraldehyde-3-phosphate; DHAP, Dihydroxyacetone phosphate; Gly-3P, glycerol 3-phosphate; 3HPA, 3-Hydroxypropionaldehyde; SSA, succinyl semialdehyde; 4HB, 4-hydroxybutyrate; 4HB-CoA, 4-hydroxybutyrl-CoA; 4HBA, 4-hydroxybutyraldehyde; GlpD, glycerol-3-phosphate dehydrogenase; GlpK, glycerol kinase; Dar1, glycerol 3-phosphate dehydrogenase; Gpp2, glycerol 3-phosphate phosphatase; DhaB123, glycerol dehydratase; YqhD, 1,3-PDO oxidoreductase; MgsA, methylglyoxal synthase; YbjG, methylglyoxal reductase; GldA, glycerol dehydrogenase; FucO, 1,2-PDO oxidoreductase; Als, acetolactate synthase; Aldc, acetolactate decarboxylase; sAdh, stereospecific secondary alcohol dehydrogenase; Cat1, succinate-CoA transferase; SucA, 2-oxoglutarate decarboxylase; SucD, succinyl-CoA synthetase; 4HBd, 4-hydroxybutyrate dehydrogenase; Cat2, 4-hydroxybutyryl-CoA transferase. (C) Synthetic pathway of 1,2,4-butanetriol. Xdh, xylose dehydrogenase; YjhG, xylonate dehydratase; MdlC, benzoylformate decarboxylase; AdhP, alcohol dehydrogenase.

diols and triols, the construction of efficient engineered strains is a key step to increase the product titer and/or yield from renewable resources. In this paper, we reviewed the production of several valuable alcohols from various renewable resources. As a whole, alcohols like ethanol and isobutanol can be produced at a relatively high level, while the production of diols and triols remains at a low level. As alcohols are mostly bulk chemicals, more efforts on improving the co-utilization of pentoses and hexoses and the strains’ tolerance against inhibitors are needed to commercialize the related results. All the related pathways for the production of alcohols described above are shown in Fig. 1. The titers, yields, and productivities of all the described alcohols are listed in Table 1.

lactate under low pH conditions. However, they require complex media and produce both D- and L-lactate naturally (Abdel-Rahman et al., 2011; Sun et al., 2015). In addition, genetic tools are limited for lactic acid bacteria engineering. To overcome these limitations, E. coli was engineered for the production of pure lactate from sugars (Grabar et al., 2006; Zhou et al., 2005). By contrast, E. coli does not require complex media and can be easily engineered to produce chirally pure lactate as one of the products under anaerobic conditions. To lower the cost of feedstocks, Mazumdar et al. engineered an E. coli strain for the homofermentative production of D-lactate from inexpensive media containing only crude glycerol and mineral salts. Besides introducing the synthetic pathway, the following steps were performed: 1) deleting dld (to prevent the utilization of D-lactate); 2) deleting pflB (to inactivate pyruvate-formate lyase for carbon saving); or 3) deleting frdA, pta, and adhE (to inactivate fumarate reductase, phosphate acetyltransferase, and alcohol/acetaldehyde dehydrogenase for NADH and carbon saving). The final strain LA02Δdld(pZSglpKglpD) produced 45 g/L of D-lactate in 84 h (Mazumdar et al., 2010). Considering the high lactate titer produced by other strains (> 100 g/L) (Li et al., 2013; Sun et al., 2016a), the titer here is not very high but still comparable with those produced by some glucose-utilizing E. coli strains (Zhou et al., 2003a; Zhou et al., 2003b). The synthesis of lactate from glycerol results in an excess of reducing equivalents. Therefore, it is not favored when limited external electron acceptors are available.

3. Organic acids 3.1. Lactic acid Lactic acid (lactate) is an important compound used in both food and non-food industries, such as cosmetic and pharmaceutical industries. Moreover, lactate can be used for the production of polylactic acid (PLA), which is a biodegradable, biocompatible, and environmentally friendly alternative to petrochemical plastics (AbdelRahman et al., 2011). Some lactic acid bacteria are natural producer of 5

6

Corn fiber hydrolysate Corn stover hydrolysate Wheat straw hydrolysate Wheat straw hydrolysate Wheat straw hydrolysate Rice husk hydrolysate Brown macroalgae

Rice straw hydrolysate Switchgrass Crude glycerol Palmitic acid Cellobiose Corn stover Protein Waste glycerol Cellodextrin Cellulose Algal hydrolysate Xylonate

Ethanol

Butanol

SHF CBP

Pretreat rice husk by steam-explosion treatment Integrate gene encoding enzymes for alginate transport and metabolism together with a system for extracellular alginate depolymerization Use co-culture system and employ high-density fermentation Express cellulase and pretreat switchgrass by ionic liquid Rewire the central metabolism Manipulate fad regulon and ato operon Express β-glucosidase Fungus-bacterium co-culture Introduce three exogenous transamination and deamination cycles Express heterogenous genes of 1,3-PDO production Express cellodextrinase in periplasm As above and add commercial cellulases cocktail Block bypass and introduce synthetic pathway of 2,3-BDO Express xylonate dehydratase and aldehyde reductase SHF CBP NA NA CBP NA NA NA CBP SSF SHF CBP

9.4

SHF/CBPb

Constitutively express cellulase

5.8 0.028 6.9 2.05 7.64 1.88 4.04 10.6 4.2 5.5 14.1 0.31

2.5 37.8

41.6

SSF

Fungal abating

37.4 28.9 41.8

Titer (g/L)

SHF SHF SHF

Process

Overexpress pdc, adhB and select mutant Select substrate-selective inoculum Fungal abating

Main engineering/processing strategy

SHF: separate hydrolysis and fermentation; SSF: simultaneous saccharification and fermentation; CBP: consolidated bioprocessing; NA: not applicable. a The yield was showed on a weight basis unless otherwise indicated. b The wheat straw hydrolysate also contained cellobiose. c Refers to total yield of 2,3-BDO and acetoin.

1,2,4-Butanetriol

1,3-Propanediol 2,3-Butanediol

Isobutanol

Feedstock

Product

Table 1 Summary of alcohols production from renewable resources using E. coli.

0.30 NA 0.35 0.18 NA NA NA 0.33 NA NA 0.43c NA

0.50 0.41

0.43

NA

0.48 0.48 0.48

Yield (w/ w)a

0.363 NA 0.18 0.021 0.16 0.005 0.048 0.063 0.07 0.033 0.196 NA

0.05 0.25

0.25

0.40

0.77 0.72 0.35

Productivity (g/L/h)

(Saini et al., 2016) (Bokinsky et al., 2011) (Saini et al., 2017b) (Dellomonaco et al., 2010) (Desai et al., 2014) (Minty et al., 2013) (Huo et al., 2011) (Przystałowska et al., 2015) (Shin et al., 2012) (Shin et al., 2012) (Mazumdar et al., 2013) (Cao et al., 2015)

(Tabata et al., 2017) (Wargacki et al., 2012)

(Munjal et al., 2015)

(Saha et al., 2011)

(Dien et al., 2000) (Saha et al., 2015) (Saha et al., 2011)

References

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This reduces the yield of lactate from glycerol. Notwithstanding, the work holds great promise for the conversion of low-value glycerol streams to higher-value products like D-lactate.

These examples demonstrated the potential for economical succinate production from renewable lignocellulosic biomass. However, these studies all had problems with inefficient glucose utilization as ptsG was deleted. New approaches to relieving CCR without affecting glucose utilization are needed to increase productivity. In addition to the already mentioned renewable resources, some other materials were also used to produce succinate. Chan et al. used a metabolically engineered E. coli strain to produce succinate from sugarcane molasses and achieved concentration of 62 and 55.8 g/L in anaerobic bottle and 10-L bioreactor, respectively (Chan et al., 2012). Agarwal et al. employed response surface methodology to optimize medium components and cultural parameters in cane molasses fermentation for succinate production. In a 10-L bioreactor, the succinate production was improved to 26.2 g/L in 30 h (Agarwal et al., 2007). Zheng et al. engineered an E. coli expressing and secreting three hemicellulases for succinate production from hemicellulose via CBP. Xylanase expression, further lpp deletion, dsbA overexpression, and expression level optimization enabled the production of succinate from beechwood xylan at a level of 14.4 g/L (Zheng et al., 2012). Zhu et al. reported a nominal succinate yield of 1.85 mol/mol using soybean hydrolysate as feedstock (Zhu et al., 2018). Although the succinate titers of these reports are relatively low, they represent a promising step towards the goal of replacing existing environmentally hazardous chemical methods and cost-intensive biological methods for succinate production. Using pure sugars (e.g. glucose) as feedstocks, high titers and yield of succinate production have been achieved (Zhu et al., 2014a). To compete with these processes, starch-rich renewable materials are the best candidates. In the above examples, succinate production from cassava starch reached a high level, but the yield was relatively low (Chen et al., 2014). A detailed analysis of cost accounting is required to estimate the commercialization potential. If a further yield improvement is needed, metabolic evolution may be attempted (Zhu et al., 2014a). With respect to the whole production process, SSF is preferred due to its consistency. In addition to cassava starch, sugarcane is another potential carbon source for succinate production. However, current correlative studies are usually based on plasmid-harboring strains and media with added nutrients, leading to increased production costs (Chan et al., 2012). Therefore, the development of a chromosomally engineered E. coli strain with low nutritional needs is imperative. Systems engineering strategies will be implemented to reach this goal (Lee and Kim, 2015).

3.2. Succinic acid Succinic acid (succinate) is a building block chemical that can be used in the chemical, food, agricultural, and plastics industries. The U.S. Department of Energy has listed it as one of the top 12 building block chemicals (Sun et al., 2015; Zhu et al., 2014a). Succinate is an intermediate metabolite of the tricarboxylic acid (TCA) cycle and its synthetic pathway usually will be blocked during the production of other reducing products (Atsumi et al., 2008b). E. coli has been engineered to produce succinate from glucose with a high titer and yield (Meng et al., 2016; Zhu et al., 2014a). Several studies have also investigated more inexpensive feedstocks for the production of succinate in E. coli. Cassava, which has high starch and low protein content, is another renewable feedstock that can be grown on lands that do not compete with food supply (Chen et al., 2014). As starch can be mainly hydrolyzed to sugars, from which higher titer and yield of products will be obtained compared with lignocellulosic biomass. In 2014, Chen et al. reported SSF of cassava to succinate by E. coli. SSF was applied in the anaerobic stage during a two-stage fermentation. The results showed that with the improved cell density, 127.13 g/L of succinate was obtained from cassava starch at a yield of 0.71 g/g. When the liquefied crude cassava powder was used directly in SSF, 106.17 g/L of succinate was formed at a smaller yield of 0.66 g/g. Results showed 40°C was better than 37°C for both the production and specific productivity in the SSF process (Chen et al., 2014). This study told us that crude cassava powder could be another cheap raw material for succinate formation. A drawback to this process is the different temperature requirements for saccharification and fermentation. Sawisit et al. investigated three processes for the production of succinate from cassava pulp using E. coli. During batch SHF under simple anaerobic conditions, a succinate concentration of 41.46 g/L was obtained, with a yield of 0.82 g/g. In batch SSF, a succinate concentration of 80.86 g/L was attained, with a yield of 0.70 g/g. Furthermore, fed-batch SSF significantly increased the succinate concentration to 98.63 g/L (Sawisit et al., 2015). Cassava pulp is a fibrous by-product of the cassava processing industry. This work proved that cassava pulp can be used for efficient succinate production, adding great value to this waste stream, which may help to solve the environmental problem caused by cassava pulp rot (Sawisit et al., 2015). Wang et al. engineered an E. coli strain to utilize corn stalk hydrolysate for succinate production. As the hydrolysate contains pentoses and hexoses, genetic modification was necessary for E. coli to consume these sugars simultaneously. The researchers overexpressed homologous or cyanobacterial ppc and introduced mutations of ldhA, pflB, and ptsG into the E. coli strain. In a final optimized two-stage fermentation of corn stalk hydrolysate (containing 32.5 g/L glucose, 8.9 g/L xylose, and 2.2 g/L arabinose), initial aerobic growth facilitated the subsequent anaerobic succinate production with a final concentration of 57.81 g/L, and a yield of 0.87 g/g (Wang et al., 2011). Likewise, using a recombinant E. coli strain which contains mutations in the ptsG, pflB, and ldhA genes, Hodge et al. achieved 42.2 g/L succinate production with a yield of 0.72 g/g from softwood hydrolysate (Hodge et al., 2009). However, the hydrolysate needed detoxification to disinhibit cell growth and metabolism (Hodge et al., 2009). Further engineering is required for resistance to inhibitors. Recently, Liu and coworkers constructed a recombinant E. coli strain for succinate production from lignocellulosic biomass in like manner. To improve the succinate production from mixture of sugars, a pflB, ldhA, ppc, and ptsG deletion strain overexpressing ATP-forming PEPCK was used to ferment sugarcane bagasse hydrolysate. In a fed-batch fermentation, the succinate titer reached 39.3 g/L and the yield was 0.97 g/g (Liu et al., 2013).

3.3. Fatty acids (FAs) FAs have a very high volumetric energy density and are naturally accumulated by oleaginous microorganisms and many plants (Wu et al., 2014). FAs can be used as precursors for the production of biodiesel or more advanced biofuels. The first committed step of the fatty acid elongation cycle is the conversion of acetyl-CoA to malonyl-CoA. However, E. coli normally produces FAs mainly for the biosynthesis of lipids and cell membranes, and it does not accumulate FAs in the cell (Voelker and Davies, 1994). When the acyl carrier protein (ACP) thioesterase is introduced, the elongation cycle will be broken to generate free FAs. Wu et al. achieved efficient free fatty acid production from costeffective feedstock using a strain derived from E. coli MG1655 (fadD mutant) harboring a plasmid which carried the acyl-ACP thioesterase gene of Ricinus communis. When woody biomass hydrolysate was used as the carbon source, the strain was able to produce 3.79 g/L FAs with a high yield of 21.42% (Wu et al., 2014). A problem with hydrolysates fermentation by E. coli is the delayed and incomplete pentose utilization in sugar mixtures as mentioned above. Consequently, the ptsG gene was removed to relieve the CCR regulation for further glucose and xylose co-utilization. This step, however, affected glucose uptake. Using fadD mutant E. coli, Lee et al. engineered a strain capable of producing 3.3 g/ 7

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L free FAs from switchgrass hydrolysates (Lee et al., 2018), while Mi et al. constructed a strain producing 1.23 g/L of free FAs with a yield of 0.13 g/g when an enzymatic bamboo hydrolysate based on ionic liquids was used as the carbon source. To increase the efficiency of hexoses and pentoses co-utilization, the genes encoding the phosphoenolpyruvatedependent carbohydrate phosphotransferase system (PTS) should be deleted while another efficient glucose transporter is necessary. And the approaches to resisting inhibitors in hydrolysate should be studied. Overall, these studies suggested that lignocellulosic biomass hydrolysates can be used as efficient feedstocks for the production of free FAs. Compared with common alcohol fuels, FA-derived fuels offer advantages such as lower hygroscopicity and miscibility with diesel fuels (Xu et al., 2013). To make the production of FAs from renewable biomass feasible, development of an efficient strain should be a primary objective. For short-chain FAs, a lot of work has been performed (Kataoka et al., 2017; Saini et al., 2014). These strains can be directly transferred into medium containing a renewable carbon source. For medium-chain FAs, Wu et al. demonstrated production from glycerol with high titer and yield in E. coli (Wu et al., 2019). For long-chain FAs, Xu et al. reported a modular engineering approach that led to an increased titer. In fed-batch fermentation, 8.6 g/L FAs were produced (Xu et al., 2013). More engineering efforts are required if renewable resources are to be used efficiently. Among all the reviewed organic acids, succinate and some shortchain fatty acids have been obtained with high titer and yield. These chemicals are of industrial interest. For lactate and FAs, a more efficient strain is desired which can be developed using pure sugar first. The reviewed metabolic pathways of organic acids are illustrated in Fig. 2. The titers, yields, and productivities of all the described organic acids are listed in Table 2.

plant oils. It consists of monoalkyl esters of long-chain fatty acids with short-chain alcohols, primarily methanol and ethanol, resulting in fatty acid methyl esters (FAMEs) and fatty acid ethyl esters (FAEEs) (Fig. 2) (Kalscheuer et al., 2006). Even though it is a good biofuel, it has some drawbacks. The availability and intrinsic properties of vegetable oil feedstocks make the production of biodiesel from oilseed crops uneconomic (Kalscheuer et al., 2006). By contrast, the production of biodiesel from bulk plant materials such as sugars and starch, and in particular cellulose and hemicellulose can be competitive with petroleum-based diesel fuel. Consequently, there are a number of studies describing biodiesel production from renewable resources. Kalscheuer et al. introduced an ethanol production pathway and overexpressed wax ester synthase/acyl-coenzyme A: diacylglycerol acyltransferase (WS/DGAT) in E. coli for FAEE production from sodium oleate. This pathway is relatively easy to engineer as the fatty acids are added directly in the medium. By employing an aerobic fed-batch fermentation regime, a final FAEE content of 1.28 g/L was achieved after 72 h. The conversion efficiency was 62.7% on a molar basis (Kalscheuer et al., 2006). This study proved the feasibility of microbial production of biodiesel from cheap and readily available renewable resources. Park et al. constructed a thermophilic bacterial consortium with biomassdegradation activity which was taken as a cocktail. Using an engineered E. coli strain, 900 mg/L FAEE were produced from switchgrass biomass saccharified using this cocktail (Park et al., 2012). Steen et al. engineered an E. coli strain which contained the FAEE synthetic pathway and expressed hemicellulases to produce FAEE from hemicellulose. Finally, the expression and secretion of xylanases allowed for 674 mg/L FAEE production with a yield of 9.4% of the theoretical value. The feedstock of this CBP was beechwood xylan (Steen et al., 2010). Biodiesel production in different microorganisms other than E. coli has attracted much attention (Bhatia et al., 2017; Tao et al., 2015; Yan et al., 2017). Among the studied microorganisms, Y. lipolytica is the most popular. Y. lipolytica has natural advantages over E. coli as it accumulates lipids naturally (Tai and Stephanopoulos, 2013). Considering that the available studies all showed low titers and yields of biodiesel production from renewable resources (Kalscheuer et al., 2006; Park

4. Biodiesel Biodiesel is a green energy source and a potential substitute for petroleum-based diesel fuel. It is made from renewable biomass mainly by alkali-catalyzed transesterification of triacylglycerols (TAGs) from

Fig. 2. Metabolic pathways of organic acids, biodiesel, and hydrogen. Ldh, lactate dehydrogenase; Pfl, pyruvate formate-lyase; Fhl, formate hydrogen lyase; Ppc, phosphoenolpyruvate carboxylase; Pck, phosphoenolpyruvate carboxykinase; GltA, citrate synthase; SucCD, succinyl-CoA synthetase; Frd, fumarate reductase; FumAC/FumB, fumarate hydratase; Mdh, malate dehydrogenase; AccABCD, acetyl-CoA carboxylase; FabD, fatty acyl-CoA synthetase; FabB/FabF, β-ketoacyl-ACP synthase; FabG, 3-oxoacyl-ACP reductase; FabA, 3-hydroxydecanoyl-ACP dehydratase; FabI, enoyl-ACP reductase; TesA/TesB, acyl-CoA thioesterase. 8

Biotechnology Advances 37 (2019) 107402 (Mazumdar et al., 2010) (Chen et al., 2014) (Chen et al., 2014) (Sawisit et al., 2015) (Sawisit et al., 2015) (Sawisit et al., 2015) (Wang et al., 2011) (Hodge et al., 2009) (Chan et al., 2012) (Liu et al., 2013) (Zhu et al., 2018) (Agarwal et al., 2007) (Zheng et al., 2012) (Wu et al., 2014) (Lee et al., 2018) (Mi et al., 2017)

et al., 2012; Steen et al., 2010), there is still a lot of engineering work to do. The engineering of synthetic pathways for biodiesel production and biomass utilization are two major research directions for the future. In general, E. coli seems not to be suitable for biodiesel production. Other better producers of biodiesel may be used to metabolize renewable biomass instead. 5. Hydrogen

NA SSF SSF SHF SSFa SSFb SHF SHF NA SHF SHF NA CBP SHF SHF SHF

45 127.13 106.17 41.46 80.86 98.63 57.81 42.2 55.8 39.3 35.6 26.2 14.4 3.79 3.3 1.23

0.83 0.71 0.66 0.82 0.70 0.72 0.87 0.72 0.96 0.97 1.21 NA 0.37 0.21 0.24 0.13

0.536 1.77 1 0.84 0.84 1.03 0.80 0.78 0.77 0.33 1.78 0.87 0.12 0.053 0.05 0.017

In recent years, hydrogen has gained much attention as it is an efficient and clean energy resource. Traditionally, hydrogen was produced chemically by the process of steam reforming and the water-gas shift reaction, or as a by-product of petroleum refining (Maeda et al., 2008). Recently, biological production of hydrogen become a research hotspot. Photosynthesis and fermentation are two main pathways for hydrogen production. In nature, green algae can produce hydrogen by utilizing only water and sunlight, while for bacterial fermentative hydrogen production, light is not necessary (Sun et al., 2015). The formate hydrogen lyase (FHL) complex is a key enzyme of hydrogen generation (Fig. 2). In some bacteria, the hydrogenase component of the FHL complex can produce hydrogen from NADH/NADPH. Because its FHL complex has been characterized the most extensively at both the physiological and genetic levels (Yoshida et al., 2005), E. coli is commonly used as a host for hydrogen production. Here, we will discuss some studies on hydrogen production from renewable resources using E. coli. Yoshida et al. constructed an E. coli strain by combining the inactivation of the FHL repressor (hycA) with the overexpression of FHL and its activator (fhlA). Subsequent optimization of environmental conditions and substrates enabled a maximum initial hydrogen production rate of 99 mmol/h/g cells (dry weight). In order to improve the volumetric hydrogen productivity, a biohydrogen reactor with high cell density was constructed. The final volumetric hydrogen production rate of the engineered strain reached 23.6 g/L/h at a cell density of 93 g cells (dry weight)/L (Yoshida et al., 2005). This study thus established a method for hydrogen production directly from formate, which is currently readily available (Li et al., 2012). Hydrogen production from other cheap substrates and biomass materials was also studied by researchers. Cofré et al. achieved the direct biotransformation of crude glycerol into ethanol and hydrogen by E. coli MG1655 using batch and fed-batch operating modes. The strain produced 132 and 782 mmol hydrogen in batch and fed-batch fermentation, respectively. Importantly, the authors found no difference between the use of crude glycerol instead of food-grade glycerol as the main carbon source. Additionally, they found the use of crude glycerol without any prior purification step was possible. Whereafter, pilot scale fed-batch fermentation was performed to determine the flexibility of the process, and the results indicated that scaling up the process was feasible (Cofré et al., 2016). Perego and coworkers studied the kinetics of hydrogen evolution by E. coli growing on corn starch hydrolysate. By exploring different pH conditions, the total hydrogen evolution value without pH control reached 14.4 mmol (Perego et al., 1998). By combining with other processes listed in the ssudy, this hydrogen process will be very attractive with regards the energy recovery and the waste treatment. This work is thus an instructive example for the development of biological hydrogen production in the future. To date, many relevant studies of hydrogen production have been reported (Zhang et al., 2007; Zhu et al., 2014b). However, the efficient hydrogen production systems are mostly cell-free, and are consequently not suitable for large-scale industrial applications but can provide guiding opinions for in vivo experimentation. By identifying the limiting steps in vitro, in vivo hydrogen production by E. coli may be improved significantly. In addition, combination of green algae and E. coli is another potential strategy for low-cost hydrogen production. Green algae have a natural hydrogen-producing machinery, while E. coli is fast-growing and easily genetically manipulated. Thus, transferring the hydrogen-producing machinery into E. coli or creating a hybrid of green

Fatty acids

NA: not applicable. a Batch SSF. b Fed-batch SSF.

Overexpress GlpK-GlpD, delete pflB, pta, adhE, frdA, dld Two-stage fermentation at 40°C As above and liquefy cassava powder Hydrolyze cassava pulp by enzymatic treat (SHF) Add cellulase complex with batch fermentation (SSF) Add cellulase complex with fed-batch fermentation Overexpress ppc, delete ldhA, pflB, ptsG Detoxify the hydrolysate Block competitive pathways and introduce sucrose-utilizing genes (cscKAB) Overexpress PEPCK, delete pflB, ldhA, ppc, ptsG Overexpress gal operon and (pycA plus fdh1) module Optimize medium components and cultural parameters Express hemicellulases, overexpress dsbA, delete lpp Overexpress acyl-ACP thioesterase and FabZ, delete fadD and ptsG Overexpress acyl-ACP thioesterase and FabZ, delete fadD Overexpress TesA and FabZ, delete fadD Crude glycerol Cassava starch Crude cassava powder Cassava pulp Cassava pulp Cassava pulp Corn stalk hydrolysate Softwood hydrolysate Sugarcane molasses Sugarcane bagasse hydrolysate Soybean hydrolysate Cane molasses Beechwood xylan Woody biomass hydrolysate Switchgrass hydrolysate Bamboo hydrolysate Lactic acid Succinic acid

Main engineering/processing strategy Feedstock Product

Table 2 Summary of organic acids production from renewable resources using E. coli.

Process

Titer (g/L)

Yield (w/w)

Productivity (g/L/h)

References

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algae and E. coli may be an interesting subject. Cyanobacteria have the characteristics of both bacteria and green algae and are also worth studying for hydrogen production.

carried out by growing the cells in LB supplemented with arabinose/ xylan or xylose/xylan, the PHA titer increased to 2.2 and 3.7 g/L, respectively (Salamanca-Cardona et al., 2014a). This study demonstrated that it is better to accumulate sugars before PHA production when using plant biomass as feedstock. Later, the authors reported further genetic modifications to the strain in order to increase the lactate fraction in the P(LA-co-3HB) copolymer. Deletion of the pflA gene led to an increased content of lactate repeating units by over 3-fold compared with the wild type (Salamanca-Cardona et al., 2014b). Oh et al. developed a membrane-based process for the production of concentrated sugar solution from rice bran and tested PHA production from rice bran hydrolysate. Biosynthesis of P(3HB) (PHB) and P(3HB-co-LA) by flask cultures of the engineered E. coli was achieved at 2.68 and 1.12 g/L, respectively (Oh et al., 2015). Results suggested that rice bran may be a good renewable feedstock for the production of biopolymers by recombinant E. coli. Gao et al. expressed a β-glucosidase in E. coli to hydrolyze cellulose for PHB production. When carboxymethylcellulose was used as sole carbon source, PHB accumulation in recombinant E. coli harboring the relative plasmids reached 0.05 g/L (Gao et al., 2015). These described systems offer platforms for the conversion of other abundant renewable biomass resources into biopolymers regardless of the low titer. The production mechanisms of natural PHA producers may provide insights for further improvement of E. coli.

6. Other chemicals 6.1. Natural products Natural products, derived from the secondary metabolism of bacteria, fungi and plants, have recently been attracting extensive attention worldwide. Their important applications in industry and drug discovery make natural products an invaluable resource for humans (Mitchell, 2011; Rodrigues et al., 2016). Benefitting from the development of synthetic biology and biotechnology, the fermentation of natural products is becoming increasingly economical and popular (Mitchell, 2011). The gene cluster responsible for the synthesis of a given compound can be cloned into model microorganisms and then further optimized by engineering the promoters, RBS, and even the entire genome (Ajikumar et al., 2010; Ro et al., 2006). The synthesis of natural products from renewable biomass using E. coli as a host was studied as well. Frederix et al. developed an E. coli strain for one-pot limonene production from cellulose and switchgrass pretreated with ionic liquids. Limonene is a natural product responsible for the aroma of many plant essential oils. It can be used as a food additive and medicine. Furthermore, it is also a terpene and a candidate for a biological jet-fuel precursor. Ionic liquids inhibition is an initial challenge in the abovementioned study. Thus, a spontaneous E. coli mutant that is tolerant to the ionic liquid was first characterized. YbjJ, which was identified to be a key enzyme for ionic liquid tolerance, was overexpressed, and a yield of ~400 mg/L limonene was obtained with switchgrass hydrolysate. Next, CBP was performed. In the absence of the ionic liquid, a strain carrying cellulose-degradation and limonene production plasmids generated approximately 35 mg/L limonene. In the presence of 150 mM ionic liquid, a titer of 10 mg/L was obtained (Frederix et al., 2016). The major contribution of this study is the development of a one-pot biofuel production process that can directly convert both saccharified ionic liquid-pretreated hydrolysate and non-saccharified cellulose into a natural product in the presence of an inhibitory ionic liquid. To achieve more efficient renewable feedstock utilization and natural products production in E. coli, more standardized parts and devices (e.g. promoter library, metabolic pathway, detecting sensor) should be constructed via synthetic biology technique.

6.3. Aromatics Aromatics are important feedstocks for the global chemical industry. They are defined as compounds with a benzene ring structure. Traditionally, most aromatics were produced via petroleum refining. However, a consensus is emerging that the petroleum-based economy is unsustainable, and the chemical industry is being pushed to move from fossil fuel-derived feedstocks to renewable bio-derived alternatives (Krömer et al., 2013). The biosynthesis of aromatics through bioconversion or fermentation is gaining increasing attention due to the development of synthetic biology (Yang et al., 2018). Phenyllactic acid (PhLA) is an aromatic compound with antimicrobial properties. It can be used as a precursor for pharmaceuticals and biopolymers. Glucose was used as feedstock to study PhLA production, however, 1 g of glucose is theoretically converted into 0.37 g of PhLA (Kawaguchi et al., 2014). To lower the cost, it is necessary to use low-cost, renewable materials as an alternative to glucose. Kawaguchi et al. reported SHF and SSF of paper pulp from the kraft process for PhLA production using recombinant E. coli. The PhLA-producing strain was derived from a phenylalanine-producing E. coli strain by introducing the plasmid pHS-GpprA, which harbors the phenylpyruvate reductase gene (pprA) derived from Wickerhamia fluorescens TK1 (Fujita et al., 2013). SHF of kraft pulp was first conducted to confirm the inhibitory effects of saccharification products derived from the pulp on PhLA fermentation. After 72 h of fermentation, 1.8 mM phenylalanine was accumulated, and almost the same amount of PhLA was produced. When SSF for PhLA production from kraft pulp was conducted, 14.7 mM PhLA was obtained (Kawaguchi et al., 2014). The low titer and yield were influenced by the amounts of NADPH and glutamate available for the E. coli cells, as well as the negative effects of inhibitors from the hydrolysate. Using the same strain, Kawaguchi et al. then tested PhLA production from pretreated sorghum bagasse. Under SHF and SSF conditions, the PhLA titer was 0.34 and 1.7 g/L, respectively. In this paper, the effects of potential fermentation inhibitors on PhLA production were investigated. Hydroxybenzaldehydes, p-coumaric acid, furfural, and trans-ferulic acid all inhibited PhLA production to different extents (Kawaguchi et al., 2015). Anyhow, PhLA production from renewable resource was proved to be feasible. Further metabolic engineering is required to enhance the cost-efficiency.

6.2. Polymers Biopolymers are biodegradable and can be produced from renewable resources instead of fossil fuels, which can offer advantages compared with traditional polymers. Therefore, such polymers have gained commercial interest in recent years (Karthikeyan et al., 2015). Polyhydroxyalkanoates (PHA) are the best known biopolymers, with valuable properties (Tan et al., 2014). Many bacterial strains, including Actinomycetes spp., Bacillus spp., Clostridium spp., as well as some cyanobacteria can naturally produce PHA (Lu et al., 2009). PHA are produced by these organisms as a form of energy- and carbon storage that enables them to survive under stressful, nutrient-scarce conditions. By analyzing the synthetic pathway of PHA, recombinant strains were also developed for PHA production, including E. coli. An approach that couples the hydrolysis and fermentative steps is an attractive strategy for the production of PHA from plant derived carbon sources. Salamanca-Cardona et al. engineered an E. coli strain expressing β-xylosidase and endoxylanase for PHA production from beechwood xylan. Plasmids containing the PHA pathway genes and xylanase were used to transform E. coli. When a CBP system was examined based on this strain, poly(lactate-3-hydroxybutyrate) (P(LA-co-3HB)) was produced at a level of less than 0.1 g/L. When PHA production was 10

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0.018 NA NA 23.6 NA NA NA NA 0.046 0.077 NA NA 0.004 0.01 0.011 0.007 NA 0.627a NA 0.094 NA 0.48a NA NA NA NA NA 0.11 NA 0.017 0.14 0.017 0.087 11.15d

(Kalscheuer et al., 2006) (Park et al., 2012) (Steen et al., 2010) (Yoshida et al., 2005) (Cofré et al., 2016) (Perego et al., 1998) (Frederix et al., 2016) (Frederix et al., 2016) (Salamanca-Cardona et al., 2014a) (Salamanca-Cardona et al., 2014a) (Oh et al., 2015) (Gao et al., 2015) (Kawaguchi et al., 2014) (Kawaguchi et al., 2014) (Kawaguchi et al., 2015) (Kawaguchi et al., 2015) (Jong et al., 2016)

6.4. Enzymes Enzymes are key factors in the biotechnology industry. For SSF, CBP, and IBP systems, enzymes like cellulase are essential components to degrade lignocellulosic biomass. Therefore, enzyme production is just as important as strain development. Like other chemicals, the production of enzymes from renewable resources was investigated as well. Song et al. studied cellulase production by E. coli from the agricultural by-product rice bran. After testing the effect of vessel pressure on the production of cellulase, they found the maximal production of cellulase from rice bran by E. coli JM109/LBH-10 with a shift in the vessel pressure from 0.08 to 0.04 MPa after 24 h was 636.8 U/mL (Jong et al., 2016). This process can be directly applied to industrial-scale production of cellulases. All the reviewed examples indicate that biodiesel, hydrogen, and some other chemicals were all produced from renewable resources at low levels. Therefore, developing efficient strains using pure sugars is most important. After that, problems of using biomass-derived sugars are to be solved. The titers, yields, and productivities of biodiesel, hydrogen, and other chemicals are listed in Table 3. 7. Updated progress and the pros and cons on metabolic engineering of E. coli In very recent years, improved versions of E. coli cell factories for bulk chemical production were developed. Mid-long chain alcohols (Dong et al., 2017; Ohtake et al., 2017), fatty alcohols (Fatma et al., 2018; Liu et al., 2016), aldehydes (Ku et al., 2017), organic acids (Khunnonkwao et al., 2018; Martinez et al., 2018; Song et al., 2013; Yang et al., 2017b), amino acids (Mundhada et al., 2016; Song et al., 2015), and others (Pontrelli et al., 2018) were produced with higher titers and/or yields. At the same time, the production of fine chemicals including natural products by E. coli is rapidly developing. Naringenin (Whitaker et al., 2017), astaxanthin (Park et al., 2018), glucoraphanin (Yang et al., 2017a), arbutin (Shen et al., 2017), β-carotene (Wu et al., 2017), lycopene (Wu et al., 2018), resveratrol (Shrestha et al., 2018), isoprene (Liu et al., 2019), and other natural products (Greunke et al., 2018) can now be produced by engineered E. coli. However, often this is accompanied by low titers. For the synthesis of natural products, complex pathways and insufficient precursor supply are major barriers. Further engineering efforts are required to increase the efficiency. For instance, creating more simple and convenient regulatory elements through synthetic biology. Most importantly, the presented studies were all done using pure sugars, which makes it difficult to adapt the developed strains to renewable resources currently. E. coli is widely used by biologists as a model microorganism. It does not need complex medium and grow fast. It can be genetically modified with plethoric tools. The biochemical and physiological properties of E. coli are clear (Pontrelli et al., 2018). Therefore, it was used to produce a variety of fuels and chemicals described in this paper and the relevant studies are still standing. Although studied in detail, there are still some disadvantages and concerns in using E. coli as a host for metabolic engineering. It shows limited capability to produce glycosylated products, proteins which are difficult to assemble (Glasscock et al., 2018; Mueller et al., 2018), or proteins containing many disulfide bonds. Moreover, it is not suitable for culturing under extreme temperatures or pH values (Pontrelli et al., 2018). Additionally, E. coli is not as tolerant to various inhibitors as yeast. In industrial applications, E. coli cells cannot be used as feed additives like yeast to reduce the overall process cost. Additionally, the safety concerns will be raised when using E. coli as host. Even so, E. coli is no doubt one of the best-developed cell factories for metabolic engineering. It can therefore not be said that E. coli or yeast is better a priori. If inhibitor issues matter the most, yeast will be selected first. Otherwise, different aspects need to be considered such as product titers and yields, media, and downstream processing. Actually, E. coli can be engineered to tolerate some inhibitors (Wang

NA: not applicable. a Yield on molar basis. b mmol. c U/mL. d U/g.

Cellulase

Phenyllactic acid

PHA

Limonene

Hydrogen

Sodium oleate Switchgrass hydrolysate Beechwood xylan Formate Crude glycerol Corn starch hydrolysate Switchgrass hydrolysate Switchgrass Arabinose/xylan Xylose/xylan Rice bran hydrolysate Carboxymethylcellulose Kraft pulp hydrolysate Kraft pulp Sorghum bagasse hydrolysate Sorghum bagasse Rice bran Biodiesel

Introduce ethanol pathway and overexpress WS/DGAT Express cellulase and pretreat switchgrass by ionic liquid Introduce FAEE pathway and express hemicellulases Overexpress FHL and FhlA, delete hycA NA Explore different pH conditions Overexpress YbjJ As above and overexpress cellulase Introduce PHA pathway and express xylanase As above Develop a membrane-based process to degrade rice bran Express β-glucosidase Overexpress pprA As above and add Cellic CTec2 for hydrolyzation Overexpress pprA As above and add Cellic CTec2 for hydrolyzation Explore different vessel pressure

NA SHF CBP NA NA SHF SHF CBP CBP CBP SHF CBP SHF SSF SHF SSF CBP

1.28 0.9 0.674 NA 782b 14.4b 0.4 0.035 2.2 3.7 2.68 0.05 0.297 2.44 0.34 1.7 636.8c

Productivity (g/L/h) Main engineering/processing strategy Feedstock Product

Table 3 Summary of biodiesel, hydrogen, and some other chemicals production from renewable resources using E. coli.

Process

Titer (g/L)

Yield (w/w)

References

C. Zhao, et al.

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et al., 2013). With regard to the waste E. coli cells, Huo et al. proved that it is possible to utilize them as substrates for fermentation (Huo et al., 2011). On the other hand, yeast is definitely the first choice for the manufacture of food-grade products. To avoid safety concerns, nonfood grade chemicals and all fuels may be produced using E. coli as long as it is cost-effective.

carbon metabolism in E. coli in recent years (Bar-Even, 2016; He et al., 2018; Yishai et al., 2017; Zelcbuch et al., 2016). In terms of new biotechnological approaches, we believe that E. coli can do even more in the future.

8. Perspectives

The global energy- and environmental problems have pushed biotechnology into more sustainable ways. Production of fuels and chemicals using microbes is challenged by efficient utilization of renewable resources. Due to the features of simple culture, rapid growth, breath of genetic tools, and wealth of biochemical and physiological knowledge, E. coli has been engineered to produce alcohols, organic acids, biodiesel, hydrogen, and some other chemicals, using cheap feedstocks. Among these chemicals, ethanol and succinate are closest to industrialization as they can be produced with high titer and yield from authentic renewable resources such as lignocellulosic biomass or waste resources, as opposed to pure glucose or other monosaccharides. However, the titers and yields of the other investigated fuels and chemicals are currently generally low, which means that more efforts need to be made to increase the competitiveness of the corresponding bioprocesses. Efficient strain construction, co-utilization of pentoses and hexoses, detoxification of hydrolysates, and process optimization are future directions for improving the utilization of renewable resources.

9. Concluding remarks

In this review, 2GF such as plant biomass (corn fiber, corn stover, corn stalks, wheat straw, rice husk, rice straw, rice bran, switchgrass, beechwood xylan, cassava, sorghum bagasse), microbial biomass (waste protein), and industrial wastes (kraft pulp, crude glycerol, cane molasses) and 3GF (microalgae or seaweeds) were described as renewable resources. Most of them comprise lignocellulosic biomass, requiring the production of hydrolysates as the direct feedstock. As described in this review, the co-utilization of pentoses and hexoses is a general problem which must be solved (Chiang et al., 2013; Eiteman et al., 2008; Zuroff and Curtis, 2012). Disabling PTS is helpful to relieve CCR, but it does not address the pentose utilization issue. Moreover, the pentose and hexose consumption rates are relatively constant with only one strain. In recent years, synthetic consortia have attracted attention as they can be be more efficient than previous approaches (Brenner et al., 2008; Jones and Wang, 2018). A synthetic consortium consisting of a glucoseselective strain and a xylose-selective strain was developed and showed great potential (Eiteman et al., 2009; Saini et al., 2017a). Therefore, the co-culture approach will play an important role in the co-utilization of pentoses and hexoses in the future. Furthermore, finding solutions to increase the strains’ tolerance toward inhibitors in hydrolysates and industrial wastes is another task. Upstream gene manipulation and metabolic evolution can be performed to improve the strains’ tolerance to inhibitors. The optimization of downstream pretreatment processes or enzyme-assisted biomass degradation will help reduce the amounts of inhibitors in hydrolysates and industrial wastes (Sheldon, 2014). To facilitate 2GF and 3GF utilization, process engineering should also be implemented. Currently, SHF is the most widely used approach to utilize lignocellulosic biomass (Putro et al., 2016). However, SHF needs extra processing equipment which would increase the cost. While CBP is difficult to implement, because one strain can hardly produce enough enzymes for saccharification and for product synthesis. In this case, SSF will be a better choice. The enzymes for saccharification in SSF can be purchased or obtained from another strain (co-culture). In the future, finding or engineering new hydrolases which can function under mild conditions will be a subject of great interest. Hydrolases of this kind are helpful to make the saccharification and fermentation processes more efficient under the same conditions (e.g. same temperature, same neutral pH). In addition to biomass, industrial waste, and microalgae, there are also other cheap renewable resources. One-carbon compounds such as CO, CO2, methanol, formaldehyde, and formate are becoming new favorites for metabolic engineering (Cotton et al., 2018; Gong et al., 2016; Whitaker et al., 2017). Cyanobacteria can naturally utilize CO2 and they have been engineered to produce interesting chemicals (Luan and Lu, 2018; Zhou et al., 2016). At the same time, carbon fixation has also been explored in vivo in E. coli (Antonovsky et al., 2016; Gong et al., 2015; Tseng et al., 2018), and even in vitro (Schwander et al., 2016; Yu et al., 2018). Scientists are trying to turn E. coli into an autotrophic microbe so that the greenhouse effect can be mitigated. In CO2 utilization, a big problem is the reducing power needed for carbon reduction. The direct utilization of electricity showed great potential for carbon reduction by providing additional electrons (Choi and Sang, 2016; Li et al., 2012; Rowe et al., 2018). Furthermore, an example of naringenin production from methanol was reported in 2017, which demonstrated the in vivo conversion of methanol into natural product in E. coli for the first time (Whitaker et al., 2017). The Bar-Even group also did a significant amount of work on engineering novel routes for one-

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