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Review

Research Progress on the Construction of Artificial Pathways for the Biosynthesis of Adipic Acid by Engineered Microbes

by
Yuchen Ning
,
Huan Liu
*,
Renwei Zhang
,
Yuhan Jin
,
Yue Yu
,
Li Deng
* and
Fang Wang
Beijing Bioprocess Key Laboratory, State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, China
*
Authors to whom correspondence should be addressed.
Fermentation 2022, 8(8), 393; https://doi.org/10.3390/fermentation8080393
Submission received: 24 June 2022 / Revised: 22 July 2022 / Accepted: 22 July 2022 / Published: 15 August 2022
(This article belongs to the Special Issue Carboxylic Acid Production 2.0)
Browse Figure
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Abstract

:
Adipic acid is an important bulk chemical used in the nylon industry, as well as in food, plasticizers and pharmaceutical fields. It is thus considered one of the most important 12 platform chemicals. The current production of adipic acid relies on non-renewable petrochemical resources and emits large amounts of greenhouse gases. The bio-production of adipic acid from renewable resources via engineered microorganisms is regarded as a green and potential method to replace chemical conversion, and has attracted attention all over the world. Herein we review the current status of research on several artificial pathways for the biosynthesis of adipic acid, especially the reverse degradation pathway, which is a full biosynthetic method and has achieved the highest titer of adipic acid so far. Other artificial pathways including the fatty acid degradation pathway, the muconic acid conversion pathway, the polyketide pathway, the α-ketopimelate pathway and the lysine degradation pathway are also discussed. In addition, the challenges in the bio-production of adipic acid via these artificial pathways are analyzed and the prospects are presented with the intention of providing some significant points for the promotion of adipic acid biosynthesis.

1. Introduction

Environmental pollution is one of the major problems facing the world today, while “white pollution” is the main cause of the greenhouse effect and global environmental warming [1]. The culprit of “white pollution” is the long-term accumulation of hard-to-degrade disposable plastic film products, which damage the ecological environment and restrict sustainable development of society [2]. Biodegradable polybutylene adipate terephthalate (PBAT) as an alternative material is considered to be one of the most important succedaneum to solve the problem of “white pollution” [3]. Adipic acid as an aliphatic dibasic acid is one of the precursors for the synthesis of PBAT [4]. Meanwhile, adipic acid also plays a crucial role in the manufacture of other chemical materials such as nylon 66, polyurethane foam, and artificial leather [5]. Nylon 66 as a common polymeric material in life can be used in automotive parts, electrical and electronic devices due to its high strength, good rigidity, impact resistance, oil resistance, and wear resistance [6]. It accounts for approximately 60% of the consumption of engineering plastics and the global nylon 66 production capacity was about 2.82 million tons in 2018 [7]. Therefore, adipic acid has a huge market demand in the production of biodegradable materials as well as engineering plastics. In addition, adipic acid can be also used in food processing, leather tanning, synthesis of medicinal materials, as well as in the production of various types of ester products such as plasticizers, advanced lubricants, acidifying agents, etc. [5,8,9].
It is thus urgent to develop a method for the efficient production of adipic acid due to its wide application and huge market demand in multiple fields. At present, the production of adipic acid mainly depends on chemical methods using the hazardous compound benzene as substrate, which is oxidized and reduced to generate ketone–alcohol oil, and then catalyzed to produce adipic acid [10,11,12]. However, these chemical production methods have a lot of disadvantages such as complex reaction conditions, high consumption of energy, low conversion rates [13]. Especially, the chemical methods caused serious environmental pollution, which is contrary to the requirements of green chemistry. Therefore, the development of a green-efficient route for adipic acid production has drawn attention worldwide. The microbial conversion method using renewable biomass as feedstock has been considered as a promising method due to its advantages of environmentally friendly and green sustainability [14]. Many high-value chemicals have been successfully produced using biosynthesis methods [15,16,17,18,19,20,21]. Hence, in recent years the microbial method has also been investigated to produce adipic acid.
As no natural microorganisms were discovered to produce adipic acid, several artificial pathways were designed for the biosynthesis of adipic acid including the reverse degradation pathway, fatty acid degradation pathway, and indirect muconic acid conversion pathway (Figure 1). In this review, the research progress of these pathways are summarized to provide a comprehensive understanding of the current production process and bottlenecks in the production of adipic acid. Especially, the studies on the reverse degradation pathway of adipic acid are detailed with introduction due to its high yield and industrialization potential. Finally, we discuss some potential pathways for adipic acid production in the hope of overcoming the present bottleneck and further promoting the industrial production of adipic acid in the future.

2. Biosynthesis of Adipic Acid via the Reverse Degradation Pathway

2.1. The Artificial Design of the Reverse Degradation Pathway

Adipic acid is an intermediate metabolite in the metabolic pathway of some microbial long-chain dicarboxylic acids in nature. Thykaer et al. elucidated the adipic acid metabolic pathway in Penicillium chrysogenum by metabolic network analysis and found that adipic acid could be degraded into succinyl-CoA and acetyl-CoA [22]. The reverse degradation pathway was thus proposed to synthesize adipic acid on this basis. In 2014, Yu et al. first constructed the reverse degradation pathway for the biosynthesis of adipic acid in E. coli [15]. There were five steps involved in the reverse degradation pathway (Figure 1). First of all, succinyl-CoA and acetyl-CoA as the precursors were condensed to form 3-oxoadipyl-CoA by thiolase. Endogenous thiolase (PaaJ) from E. coli was selected as the first enzyme, because it could catalyze the thiolysis of 3-oxoadipyl-CoA into acetyl-CoA and succinate-CoA and also had the capability to catalyze the reverse reaction [23]. Afterwards, three enzymes were selected: 3-hydroxybutyryl-CoA dehydrogenase (Hbd) and crotonyl-CoA hydratase (Crt) from Clostridium butyricum, trans-enoyl Coenzyme A reductase (Ter) from Euglena. These three enzymes had broad substrate selectivity and could catalyze a series of similar reactions such as conversion of acetoacetyl-CoA to butyryl-CoA, 3-carbonylvaleryl-CoA to valeryl-CoA, and 3-carbonylhexanoyl-CoA to hexanoyl-CoA [24]. Therefore, they were possibly able to catalyze the conversion of 3-oxoadipyl-CoA to adipyl-CoA. Finally, phosphobutyryl transferase (Ptb) and butyryl kinase (Buk1) from Clostridium butyricum were selected, which were responsible for the conversion of butyryl-CoA to butyrate in Clostridium butyricum [25]. These screening enzymes were then overexpressed in E. coli and purified to perform multi-enzyme reactions using acetyl-CoA and succinyl-CoA as the substrates to verify their functions in vitro. After analyzing the composition of the intermediates and final products by mass spectrometry, the target product adipic acid was successfully formed. It was indicated that these selected enzymes were functional and could realize the biosynthesis of adipic acid using acetyl-CoA and succinyl-CoA in vitro. Finally, these enzymes were co-overexpressed in E. coli to form an adipic acid produced engineered strain and 31 μg/L adipic acid was obtained using glucose as the substrate. Even though the titer was low, the feasibility of this pathway for adipic acid production in vivo was implied. On this basis, the pathway was further optimized by comparing the impact of combinations of different sources of enzymes. It was shown that the production of adipic acid increased to 120 μg/L when Ter was replaced by the butyryl-CoA dehydrogenase (Bcd) from Clostridium acetobutylicum and Hbd and Crt were replaced by the 3-hydroxyacyl-CoA reductase (PaaH1) and the putative enoyl-CoA hydratase (ECH) from Ralstonia eutropha, respectively, which demonstrated that the combined optimization of the enzymes in the pathway had significant effects on the accumulation of adipic acid. Thereafter, the modified reverse degradation pathway was introduced into the succinate-produced engineered E. coli, which modified several enzymes: (1) knocking out the glucose phosphotransferase system (ptsG) to increase the accumulation of phosphoenolpyruvate as the precursor of succinate; (2) knocking out the pyruvate oxidase (poxB) and phosphotransacetylase (pta) to block the carbon flux of pyruvate and acetyl-CoA to acetic acid; (3) knocking out succinate dehydrogenase (sdhA) to prevent the consumption of succinate; (4) knocking out the isocitrate lyase regulator (iclR) to activate the glyoxylate bypass that could promote the generation of succinate. Owing to the availability of abundant precursors, the production of adipic acid was increased to 0.64 mg/L. It laid a good foundation for the production of adipic acid by the artificial biosynthesis pathway.
On this basis, much work was conducted to optimize the expression of the enzymes in the pathway to improve the production of adipic acid. For example, Babu et al. proposed screening one enzyme to replace the functions of the enzymes Ptb and Buk1 to enhance the efficiency of the conversion of adipyl-CoA to adipic acid. Acot8 from Mus musculus encoding a peroxisomal acyl-CoA thioesterase was reported to have a similar function with low substrate specificity [26]. This was then combined to be overexpressed with paaJ, paaH, paaZ (encoding thiolase, 3-hydroxyacyl-CoA reductase, 3-oxoadipyl-CoA dehydratase) from E. coli and Bcd (encoding butyryl-CoA dehydrogenase) from C. acetobutylicum [16]. Twelve μg/L adipic acid was produced by the engineered strain (Table 1). Although the titer was still low, it demonstrated the feasibility of acyl-CoA thioesterase in the reverse degradation pathway. Moreover, Kallscheuer et al. screened the enzymes in the last two steps, namely adipyl-CoA dehydrogenase and acyl-CoA thioesterase [18]. Acinetobacter baylyi were found to consume adipic acid as carbon source and the putative adipyl-CoA dehydrogenase DcaA was proposed as playing an important role in the degradation of adipic acid [27]. Meanwhile, acyl-CoA thioesterase TesB from A. baylyi was proven to have broad substrate specificity and exhibited a high amino acid sequence similarity to that from E. coli. Therefore, they were chosen to be co-overexpressed with endogenous paaJ, paaH, paaZ in E. coli BL21 (DE3) and the titer of adipic acid was increased to 36 mg/L after 30 h incubation (Table 1) [18]. These works demonstrated that the optimization of the enzymes in the pathway could indeed promote adipic acid synthesis, but the yield was still unsatisfactory. The reason speculated was that the efficiency of the pathway was affected by the balance of the expression of multiple enzymes in the reverse degradation pathway; the suitability of the enzymes from different sources would possible influence their efficiency, which limited the flux of precursors to adipic acid.

2.2. The Identification of the Reverse Degradation Pathway in Thermobifida fusca

Since the reverse degradation pathway involved multiple enzymes, the combinational optimization of the enzymes did not significantly improve the production of adipic acid. A similar and natural pathway with better adaptability was needed to be found. In 2015, Deng et al. reported that a natural reverse degradation pathway of adipic acid had been discovered with Thermobifida fusca [28]. Five natural enzymes were involved in the pathway including β-ketothiolase (Tfu_0875), 3-hydroxyacyl-CoA dehydrogenase (Tfu_2399), 3-hydroxyadipyl-CoA dehydrogenase (Tfu_0067), 5-Carboxy-2-pentenoyl-CoA reductase (Tfu_1647), and succinyl-CoA synthetase (Tfu_2576-7). Moreover, they found that natural T. fusca could not accumulate adipic acid efficiently due to the low expression level of Tfu_1647, which was proven to be the rate-limiting step in the pathway using the cell-free system. Tfu_1647 was thus overexpressed in T. fusca and 2.23 g/L adipic acid was produced from 50 g/L glucose (Table 1). It was the first report of adipic acid production by the native-occurring pathway in microorganisms, which was a major advancement in adipic acid synthesis research. Although the production of adipic acid was significantly improved using the engineered T. fusca, several problems were still needed to be solved: (1) how to further promote the production of adipic acid; (2) whether there was another rate-limiting step in the pathway; (3) whether T. fusca was the best host for the expression of the pathway.
Given the issues above and the lack of available genetic tools for T. fusca, Zhao et al. introduced five enzymes from T. fusca into E.coli BL21 (DE3) using three plasmids pRSFDuet-1, pTrc99A, and pCDFDuet and 0.3 mg/L adipic acid was obtained [19]. To further improve the production, multiple strategies were subsequently conducted. First, the fermentation medium was optimized and SOB medium was proven to be the optimal for the engineered E.coli. Second, different combinations of the five enzymes were inserted into three plasmids to screen the group with the best adaptation. Third, the strong promoter pTrc was used to improve the expression level of the rate-limiting enzyme Tfu_1647. Fourth, the competitive pathways were knocked out including L-lactate dehydrogenase (ldhA), succinate coenzyme A ligase (sucD), and acetyl coenzyme A acetyltransferase (atoB) so as to increase the carbon flux in adipic acid production. After these modifications, 2.01 g/L adipic acid was achieved from 4 g/L glucose by the final engineered strain, which was about 6.7 times higher than before. Under the optimal conditions, the fed-batch fermentation was carried out in a stirred-tank reactor. Glucose was used as the initial carbon source for cell growth and glycerol was used as the supplemental feedstock for adipic acid production. It led to the titer reaching 68 g/L which was the highest production of adipic acid using the microbial method achieved so far (Table 1) [5]. Despite the high production, there were still some problems that hindered its industrial application. Especially, IPTG as an expensive inducer was used to control the expression of the enzymes in the process, which increased the cost of production and also had toxic effects on E. coli to some extent. In addition, the study also mentioned that the engineered E. coli was cultivated under a highly aerobic condition, but the degradation of adipic acid was also promoted in the process, which impacted the accumulation of adipic acid. Meanwhile, succinyl-CoA as one of the precursors for the synthesis of adipic acid was generated from citric acid in the oxidative TCA pathway, but two molecules of carbon dioxide were released due to the two decarboxylation steps. This resulted in the loss of central carbon flow and a relatively low theoretical yield of adipic acid (54.07%).
To solve the problems of the IPTG-induced system, Zhou et al. developed an efficient induction-free system for adipic acid production using a strong promoter-5’-UTR complex (PUTR) [30]. The plasmids pHHD01K containing Tfu_0875, Tfu_2399, Tfu_0067, Tfu_1647, and pTrc99A containing Tfu_2576-7 were used to express the reverse degradation pathway in E. coli K12 MG1655. Four PUTRs, PUTRinfC-rplT, PUTRlpp, PUTRrplU-rpmA, and PUTRrpsT with different levels of transcriptional and translational expression abilities were selected to replace the IPTG-induced promoter in the plasmids and to investigate the effects on the synthesis of adipic acid, respectively [19,20]. It was shown that PUTRrpsT inserted into pHHD01K and PUTRlpp inserted into pTrc99A were the optimal combination. The rate-limiting enzyme Tfu_1647 achieved a high translation level under the new promoter and 1.41 g/L adipic acid was obtained without the addition of IPTG. To further reduce the carbon flux into by-product pathways, ldhA, atoB, and sucD were knocked out in the genome of E. coli K12 MG1655 to prevent the accumulation of lactic acid, butyric acid, and succinic acid. In addition, pyruvate oxidase and phosphate acetyltransferase were also deleted to reduce the synthesis of acetic acid, while the endogenous acetyl-CoA synthetase was overexpressed to promote the conversion of acetic acid to acetyl-CoA to provide more precursors for the adipic acid synthesis. After these strategies were conducted, the titer of adipic acid was increased to 1.7 g/L without any inducer in a shake flask and it was increased to 57.6 g/L under fed-batch fermentation in a reactor (Table 1). The titer was similar to the result with IPTG as the inducer, but the production cost was controlled due to the avoidance of the inducer, which laid a good foundation for industrial production of adipic acid.
Besides the improvement of the induction system, the problem of the poor carbon source conversion rate was also focused on. To avoid the loss of carbon flow in the generation of succinyl-CoA from citric acid, Hao et al. proposed modifying the reductive TCA pathway for the synthesis of succinyl-CoA without decarboxylation, which achieved a theoretical yield of adipic acid of 81% [31]. They first demonstrated the feasibility of adipic acid production by the reductive TCA pathway. The engineered strain E. coli Mad1415s knocking out ldhA, atoB, and overexpressing the reverse degradation pathway of adipic acid was cultivated under anaerobic conditions. Different intermediates including succinate, fumarate, malate, and oxaloacetate were added into medium to investigate the effect of the reductive TCA pathway on adipic acid production. It was indicated that the synthesis of adipic acid was promoted under anaerobic conditions with the addition of these organic intermediates, especially succinate, leading to a higher titer of adipic acid than the others. Although the feasibility of the reductive TCA pathway for adipic acid production was proven, the pathway was generally activated under anaerobic conditions in microorganisms, which negatively impacted the growth of cells and the formation of acetyl-CoA [32]. Therefore, an oxygen-dependent dynamic regulation system was constructed, in which the fumarate and nitrate reductase (FNR) transcription activator was used to establish the oxygen response biosensor. The activity of FNR was regulated by the transition between 4Fe-4S and 2Fe-2S clusters, while the dimer could be activated under anaerobic conditions, which was used as an activator for gene expression [33]. Coupled with the anaerobic inducible synthetic promoter PfnrF8, the oxygen-dependent dynamic regulation system was used to control the expression of pyruvate carboxylase (PYC), malate dehydrogenase (MDH), and fumarate reductase (FrdABCD). The highest titer of adipic acid reached 0.3 g/L using the engineered strain under anaerobic conditions without the use of inducers. To further improve the synthesis of adipic acid, the strength of the anaerobic promoters was optimized. The transcription activator FNR mainly targeted the DNA sequence TTGA(T/C)NNNN(A/G)TCAA in the upstream region of the promoter PfnrF8 [34]. The distance between the FNR binding site and the −35 region was suspected to be affecting the strength of the promoter. Therefore, it was optimized and promoters with different strengths were developed to control the expression of PYC, MDH, and FrdABCD, which led to a titer of adipic acid up to 0.53 g/L under anaerobic conditions (Table 1). The potential of the reductive TCA pathway for adipic acid production was demonstrated, while the loss of carbon was avoided. However, the titer of adipic acid was low and several issues needed to be further addressed. The first was energy supply in the adipic acid production process. The oxidative TCA cycle was inhibited under the anaerobic conditions impacting the generation of NADPH/NADH/ATP, which is important for the synthesis of adipic acid and cell growth. Subsequently, the low biomass was the second issue. Finally, the anaerobic conditions would cause a high production cost and might hinder the scale-up production of adipic acid. In addition, Zhang et al. [29] introduced the reverse degradation pathway into S. cerevisiae by co-expressing Tfu_0875, Tfu_2399, Tfu_0067, Tfu_1647, Tfu_2576, and Tfu_2576 in order to explore the adipic acid synthesis capability in yeast chassis (Table 1). Although only 3.83 mg/L and 10.09 mg/L adipic acid was finally produced by the engineered S. cerevisiae in a shake flask and with fed-batch fermentation, respectively, it demonstrated the functional viability of the reverse degradation pathway in yeast chassis, which laid the foundation for the investigation of an optimum host for adipic acid production.

3. Other Feasible Artificial Pathways for Adipic Acid Production

3.1. The Fatty Acid Degradation Pathway

As a kind of short-chain organic acid with two carboxyl groups, it was suspected that adipic acid could be converted from fatty acid. In yeast, fatty acids are mainly metabolized via the β-oxidation pathway and ω-oxidation pathway. In the β-oxidation pathway, the backbones of fatty acids are shortened by releasing a molecule of acetyl-CoA in each cycle until the fatty acids are completely converted to acetyl-CoA. In the ω-oxidation pathway, fatty acids cannot be entirely degraded but are converted to the corresponding dicarboxylic acids via terminal oxidation. Therefore, fatty acids could convert to adipic acid though the combination of the β-oxidation and ω-oxidation pathways (Figure 1). Beardslee et al. explored the feasibility of adipic acid production from the fatty acid degradation pathway [35]. Acyl-CoA oxidase (POX) as the first enzyme in the β-oxidation pathway was considered as the rate-limiting step. There were two POX isozymes in yeast with different substrate chain-length specificity. POX4 could function on the fatty acid or dicarboxylic acid with broad chain-length specificity (4–20 carbons), while POX5 only catalyzed the dicarboxylic acid with less than six carbons [36]. POX4 was hence knocked out to promote the degradation of the fatty acid or dicarboxylic acid containing more than six carbons, while the 6-carbon adipic acid was accumulated. When coconut oil was used as the feedstock, more than 50 g/L adipic acid was produced by the engineered yeast. Afterwards, Ju et al. conducted a similar work with Candida tropicalis KCTC 7212 by deleting POX4 and overexpressing POX5 [37], while 12.1 g/L adipic acid was produced after optimizing the fermentation process using C12-lauric acid methyl ester as the substrate (Table 2). These works demonstrated the feasibility and potential of the biological production of adipic acid from the fatty acid degradation pathway. Nevertheless, there have been relatively few studies on this subject and the many limitations need to be further explored, such as the development of more available host, implementation of more genetic modification to improve production, application of more sustainable alternative feedstocks to reduce production cost and so on.

3.2. The Muconic Acid Conversion Pathway

Muconic acid as an intermediate in the metabolism of aromatic compounds has been identified in many microorganisms [40]. The bio-production of muconic acid has been thoroughly studied and glucose as well as aromatic compounds are the two main feedstocks for the production of muconic acid [41]. The shikimate pathway is the commonly studied pathway for muconic acid synthesis. Glucose is first metabolized to form erythritose 4-phosphate and phosphoenolpyruvic acid, which are then condensed and catalyzed to form 3-dehydroshikimate (DHS), an important intermediate of the shikimate pathway. DHS is then converted to catechol and subsequently transformed to muconic acid. Based on the various intermediate of the shikimate pathway, various branch pathways have been explored and have resulted in achieving a high productivity of muconic acid [42]. Due to having a similar chemical structure to adipic acid, muconic acid was proposed to be converted to adipic acid via elimination of the unsaturated double bond. Therefore, a combined chemical–biological method was developed at the beginning, in which muconic acid was produced by microorganisms and then the double bond in muconic acid was eliminated by chemical hydrogenation. In 1994, Frost et al. first reported the semi-biosynthetic method for the synthesis of muconic acid using glucose as a carbon source in E. coli and about 2.4 g/L and 38.6 g/L muconic acid was produced in a shake flask and bioreactor, respectively. It was subsequently converted to adipic acid via chemical hydrogenation and the yield reached 90% [43,44]. This provided a sustainable method for the production of adipic acid. More and more investigations were then conducted to improve the production of muconic acid using engineered microorganisms, which demonstrated it to be the only viable route for the biological–chemical synthesis of adipic acid over the past 20 years [10,38,45,46]. However, with deep evaluation of the method, it was found that the chemical conversion of muconic acid led to high energy consumption and high production cost, which impacted the efficiency of the method. Hence, a complete biological method needed to be established by identifying the key enzyme to realize the bio-hydrogenation of muconic acid (Figure 1). Enoate reductase was reported to have broad substrate specificity and could reduce C=C bonds of unsaturated chemicals using NAD(P)H as the cofactor [38,46]. Joo et al. screened the enoate reductase from different microorganisms and showed that the enzyme from Clostridium acetobutylicum could hydrogenate muconic acid [46]. On this basis, Sun et al. overexpressed the enzyme in the engineered E. coli to convert muconic acid to adipic acid. They found that the enoate reductase was sensitive to oxygen, which contradicted the aerobic environment that the cell growth depended on. To solve the dilemma, Vitreoscilla hemoglobin was co-expressed to enhance the oxygen transmission and a co-culture system was developed, which finally led to 27.6 mg/L adipic acid produced under microaerobic conditions (Table 2) [38]. It demonstrated that the bio-hydrogenation route had been successfully constructed with E. coli, but the efficiency was low. Even though the same work was carried out in yeast to enhance the activity of the enoate reductase, the conversion rate was still poor [45]. Therefore, the catalytic efficiency of the enoate reductase has remained the bottleneck in this pathway and more strategies need to be employed to improve the issue, including understanding the expression and catalytic mechanism of enoate reductase, screening an enoate reductase with high oxygen tolerance using directed evolutionary techniques, and rational design of the enzyme in combination with computer simulation techniques.

3.3. Some Potential Pathways for Adipic Acid Production

Besides the pathways above, there have been several potential synthesis pathways for adipic acid, including the polyketide pathway, the α-ketopimelate (AKP) pathway, and the lysine degradation pathway. Although few works have focused on these pathway, great feasibility and potential in theory has been demonstrated.
The polyketide pathway has been commonly engineered for the production of various polyketones [47]. Polyketide synthases (PKSs), a multifunctional enzyme system, are the critical enzymes in the pathway, which are divided into three types according to their structural domains and functions [48]. Olano et al. first identified the borrelidin PKS in Streptomyces parvulus, which was a kind of type-I PKS containing 31 individual domains organized into a loading module and six extender modules [49]. Afterwards, Hagen et al. analyzed and modified the structural domains of the borrelidin PKS by introducing the dehydratase and enoyl reductase into the extender modules [39,50]. The pure enzyme was then obtained by expressing the engineered borrelidin PKS in E. coli, which was proven to successfully catalyze the synthesis of adipic acid in vitro using succinyl-CoA and malonyl-CoA as the intial unit (Figure 1). Despite the low production (~0.3 mg/L, Table 2), it indicated the potential value of PKSs in the production of adipic acid and other commercial chemicals.
Different to the polyketide pathway, the AKP pathway and the lysine degradation pathway did not depend on succinyl-CoA and malonyl-CoA as precursor. α-ketopimelate (AKP) was a compound known to be present in archaea as an intermediate in the biosynthesis of coenzyme B. In the AKP pathway, α-ketoglutaric acid and acetyl-CoA were used as the precursors (Figure 1). Similar to the reverse adipic acid degradation pathway, α-ketoadipic acid was generated in the first step by the condensation of the two precursors under the catalysis of four enzymes (AksA, AksD, AksE, AksF) [51,52,53]. The chemicals α-ketopimelate and α-ketosuberate were also formed via chain-elongation reactions due to the broad substrate specificity of the four enzymes [53,54]. In the previous work, the AKP pathway was combined and modified with the reverse adipic acid degradation pathway to produce nylon-6, while adipic acid as the by-product accumulated as more than 300 mg/L (Table 2) [6]. It presented the potential capability of the AKP pathway for the production of adipic acid. However, more work should be conducted, especially in screening for enzymes with good specificity, to contribute to the controlled chain length of the intermediates and promote the efficient accumulation of adipic acid.
In the lysine degradation pathway, lysine as the substrate was converted to adipic acid semialdehyde via the removal of the two amino groups (Figure 1). Adipic acid was then produced from adipic acid semialdehyde by the catalysis of dehydrogenase [55,56]. Although the process seemed simple, serious challenges were associated with this pathway: (1) three enzymes in the pathway were not known to be present; (2) the economic feasibility of the process was not reasonable due to the cost of lysine as feedstock. Karlsson et al. proposed to change the order of the steps in the pathway. First, the terminal amino group of lysine was removed and oxidized to form 2-aminoadipic. Second, the α-amino group was removed to form hex-2-enedioic acid, which was then converted to adipic acid via hydrogenation. The authors screened and designed the enzymes in the alternative pathway via computer simulation techniques and successfully reduced the number of unknown enzymes to one instead of three [57]. However, the lysine degradation pathway is not completely clear so far and more works should further focus on enzyme screening and pathway construction. Meanwhile, lysine directly used as starting material is really expensive, but the process would be more economics feasible if the pathway was constructed with lysine-producing organisms. The highest titer of lysine reached 120 g/L with productivity of 4.0 g/L h with Corynebacterium glutamicum in the previous work [58,59,60]. This might provide an available chassis for the investigation of adipic acid production via the lysine degradation pathway.

4. Conclusions

Adipic acid is in high demand as an important nylon precursor substance. However, there are no native microorganisms for adipic acid production and it is difficult to produce industrially by environmentally friendly biological methods. With the development of new technologies in the field of metabolic engineering and synthetic biology, more research has been carried out and various pathways explored to produce adipic acid including the reverse degradation pathway, the fatty acid degradation pathway, and the muconic acid conversion pathway. The reverse degradation pathway is considered the most promising way, and achieved the highest titer of adipic acid (68 g/L) so far. Nevertheless, there are still some issues affecting the industrial production process of adipic acid such as low substrate conversion, low product yield, poor energy availability, etc. Some new strategies need to be developed to address these issues in future work.
First, the low activity of the enzymes and the poor efficiency of the pathways have been the main limiting factors in the synthesis of adipic acid. Expressing and screening the enzymes from various sources has been the common method to improve the efficiency of the pathways. However, the activity of the heterologous enzymes is usually low due to the differences in expression and translation mechanisms. With the development of bioinformatics, a feasible way has been found to solve this problem via reasonable modification of the enzymes based on computer simulation design, which has provided excellent opportunities for obtaining highly efficient enzymes coupled with the application of high-throughput screening technology.
Second, the investigation of potential synthesis pathways as well as the multi-pathway combined modifications might also offer the possibility to address the poor efficiency. The consumption of cofactor NADPH/NADH in the synthesis of adipic acid resulted in the imbalance of intracellular redox potential. The exploitation of a synthesis pathway with low energy requirement or combined modification of the redox power regeneration pathways could reduce the metabolism stress of cells and be possibly beneficial for the production of adipic acid.
Third, the synthesis of adipic acid with the present pathways has mainly depended on the intermediate metabolites in the TCA cycle, which compete with the metabolic demands of cell growth. Moreover, the formation of metabolites in the TCA cycle concomitantly lost two molecules of carbon, which led to a low theoretical yield of adipic acid. Modification of the reductive TCA cycle is an alternative way to generate the precursors for adipic acid synthesis, which could avoid the loss of carbons and have a higher carbon conversion rate.
Finally, E. coli is currently the most widely used host for adipic acid pathway construction. There are however still some weaknesses using E. coli as chassis including poor acid resistance, the incomplete protein expression system, low precursor synthesis flux, and so on. Therefore, the exploitation of a more preferable host is also an essential way to improve the efficiency of adipic acid synthesis. Some work has been reported to introduce the reverse degradation pathway into S. cerevisiae. Although the titer of adipic acid was low, it has laid a good foundation for further investigation. It is believed that there will be new breakthroughs in the synthesis of bio-based adipic acid with the development of more techniques and further research.

Author Contributions

H.L. and L.D. conceived the topic; H.L. and Y.N. wrote original draft; Y.N., R.Z., Y.J. and Y.Y. searched references and accessed information; L.D. and F.W. carried out review and editing, supervision, funding acquisition, conceptualization, project administration. All authors have read and agreed to the published version of the manuscript.

Funding

This research was financially supported by the National Natural Science Foundation of China (21978017, 21978019, 21978020, and 22078013).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Fermentation 08 00393 g001 550
Figure 1. Overview of the artificial designed pathways for the production of adipic acid (OAA, oxaloacetate; CIT, citrate; Mal, malate; Succ, succinate; Suc-CoA, succinyl-CoA; α-KG, α-ketoglutarate; EntC, isochorismate synthase; PchB, isochorismate pyruvate lyase; NahG, salicylate 1-monoxygenase; CatA, catechol 1,2-dioxygenase; ER, enoate reductase; HCS, homocitrate synthase; HA, homoaconitase; HICDH, homoisocitrate dehydrogenase; KivD, α-keto acid decarboxylase; GabD, succinate semialdehyde dehydrogenase; Homo-Cit, homocitrate; Homo-Aco, homoaconitate; Homo-Iso, homoisocitrate; ApSa, adipate semialdehyde; paaJ, β-ketoadipyl-CoA thiolase; Hbd, 3-hydroxy-acyl-CoA reductase; Ech, enoyl-CoA hydratase; Ter, trans-enoyl-CoA reductase; Buk1, butyryl kinase; 3-OA-CoA, 3-Oxo-adipyl-CoA; 3-HA-CoA, 3-Hydroxyadipyl-CoA; 2,3-DHA-CoA, 5-Carboxy-2-pentencyl-CoA; 6-amino-HEA, 6-aminohex-2-enoic acid; 6-amino-CA, 6-aminocaproic acid).
Figure 1. Overview of the artificial designed pathways for the production of adipic acid (OAA, oxaloacetate; CIT, citrate; Mal, malate; Succ, succinate; Suc-CoA, succinyl-CoA; α-KG, α-ketoglutarate; EntC, isochorismate synthase; PchB, isochorismate pyruvate lyase; NahG, salicylate 1-monoxygenase; CatA, catechol 1,2-dioxygenase; ER, enoate reductase; HCS, homocitrate synthase; HA, homoaconitase; HICDH, homoisocitrate dehydrogenase; KivD, α-keto acid decarboxylase; GabD, succinate semialdehyde dehydrogenase; Homo-Cit, homocitrate; Homo-Aco, homoaconitate; Homo-Iso, homoisocitrate; ApSa, adipate semialdehyde; paaJ, β-ketoadipyl-CoA thiolase; Hbd, 3-hydroxy-acyl-CoA reductase; Ech, enoyl-CoA hydratase; Ter, trans-enoyl-CoA reductase; Buk1, butyryl kinase; 3-OA-CoA, 3-Oxo-adipyl-CoA; 3-HA-CoA, 3-Hydroxyadipyl-CoA; 2,3-DHA-CoA, 5-Carboxy-2-pentencyl-CoA; 6-amino-HEA, 6-aminohex-2-enoic acid; 6-amino-CA, 6-aminocaproic acid).
Fermentation 08 00393 g001
Table
Table 1. The comparison of adipic acid production by modification of the reverse degradation pathway.
Table 1. The comparison of adipic acid production by modification of the reverse degradation pathway.
StrainsPhenotypeSubstratesProduction of Adipic AcidReference
E. ColiPTrc-paaJ (β-ketoadipyl-CoA thiolase from E. coli), PCMV-Hbd (3-hydroxybutyryl-CoA dehydrogenase from C. acetobutylicum), PCMV-Crt (crotonase from C. acetobutylicum), PTrc-Ter (trans-enoyl-CoA reductase from E. gracilis), PCMV-Ptb (phosphate butyryltransferase from C. acetobutylicum), PCMV-Buk1(butyryl kinase from C. acetobutylicum); ▲ptsG (Glucose phosphotransferase system),▲poxB (py-ruvate oxidase), ▲pta (phosphotransacetylase), ▲sdhA (succinate dehydrogenase), ▲iclR (isocitrate lyase regulator)glucose0.64 mg/L[15]
PT7-paaJ (thiolase from E. coli), PT7-paaH (3-hydroxyacyl-CoA reductase from E. coli), PT7-paaZ (3-oxoadipyl-CoA dehydratase from E. coli), PT7-Bcd (butyryl-CoA dehydrogenase from C. acetobutylicum), PT7-Bcd (peroxisomal acyl-CoA thioesterase from M. musculus)glucose12 ug/L[16]
PT7-paaJ (thiolase from E. coli), PT7-paaH (3-hydroxyacyl-CoA reductase from E. coli), PT7-paaZ (3-oxoadipyl-CoA dehydratase from E. coli), PT7-DcaA (adipyl-CoA dehydrogenase from A. baylyi), PT7-TesB (acyl-CoA thioesterase from A. baylyi)glucose36 mg/L[18]
PT7-Tfu_0875 (β-ketothiolase from T. fusca), PT7-Tfu_2399 (3-hydroxyacyl-CoA dehydrogenase from T. fusca), PTrc-Tfu_0067 (3-hydroxyadipyl-CoA dehydrogenase from T. fusca), PTrc-Tfu_1647 (5-Carboxy-2-pentenoyl-CoA reductase), PT7-Tfu_2576-7 (adipyl-CoA synthetase from T. fusca); ▲ldhA (L-lactate dehydrogenase), ▲sucD (succinate coenzyme A ligase), ▲atoB (acetyl coenzyme A acetyltransferase).glycerin68 g/L[19]
PUTRrpst-Tfu_0875 (β-ketothiolase from T. fusca), PUTRrpst-Tfu_2399 (3-hydroxyacyl-CoA dehydrogenase from T. fusca), PUTRrpst-Tfu_0067 (3-hydroxyadipyl-CoA dehydrogenase from T. fusca), PUTRrpst-Tfu_1647 (5-Carboxy-2-pentenoyl-CoA reductase), PUTRlpp-Tfu_2576-7 (adipyl-CoA synthetase from T. fusca);▲ldhA (L-lactate dehydrogenase), ▲sucD (succinate coenzyme A ligase), ▲atoB (acetyl coenzyme A acetyltransferase)glycerin57.6 g/L[20]
T. fuscaPT7-Tfu_1647 (5-Carboxy-2-pentenoyl-CoA reductase from T. fusca)glucose2.23 g/L[28]
S. cerevisiaePTEF1-Tfu_0875 (β-ketothiolase from T. fusca), PGPD1-Tfu_2399(3-hydroxyacyl-CoA dehydrogenase from T. fusca), PADH1-Tfu_0067 (3-hydroxyadipyl-CoA dehydrogenase from T. fusca), PPGK1-Tfu_1647 (5-Carboxy-2-pentenoyl-CoA reductase), PTDH3-Tfu_2576-7 (adipyl-CoA synthetase from T. fusca); ▲LSC1 (succinyl-CoA ligase)glucose3.83 mg/L[29]
P is the promoter in the genes overexpression process; ▲ means the deletion of the genes.
Table
Table 2. Adipic acid production by the by the modification of potential pathways.
Table 2. Adipic acid production by the by the modification of potential pathways.
PathwaysStrainsProductionReference
α-Ketopimelate (AKP) pathwayE. Coli300 mg/L[6]
Fatty acid degradation pathwayYeast12.1 g/L[37]
Muconic acid conversion pathwayE. Coli27.6 mg/L[38]
Polyketide pathwayE. Coli0.3 mg/L[39]
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Ning, Y.; Liu, H.; Zhang, R.; Jin, Y.; Yu, Y.; Deng, L.; Wang, F. Research Progress on the Construction of Artificial Pathways for the Biosynthesis of Adipic Acid by Engineered Microbes. Fermentation 2022, 8, 393. https://doi.org/10.3390/fermentation8080393

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Ning Y, Liu H, Zhang R, Jin Y, Yu Y, Deng L, Wang F. Research Progress on the Construction of Artificial Pathways for the Biosynthesis of Adipic Acid by Engineered Microbes. Fermentation. 2022; 8(8):393. https://doi.org/10.3390/fermentation8080393

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Ning, Yuchen, Huan Liu, Renwei Zhang, Yuhan Jin, Yue Yu, Li Deng, and Fang Wang. 2022. "Research Progress on the Construction of Artificial Pathways for the Biosynthesis of Adipic Acid by Engineered Microbes" Fermentation 8, no. 8: 393. https://doi.org/10.3390/fermentation8080393

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