Expanding the Chemical Palette of Industrial Microbes: Metabolic Engineering for Type III PKS‐Derived Polyketides

Palmer, Claire M.; Alper, Hal S.

doi:10.1002/biot.201700463

Cited by 37 publications

(15 citation statements)

References 125 publications

(308 reference statements)

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“…The alternative pathway relies upon direct conversion of tyrosine into p -coumaric acid via a tyrosine ammonia lyase (TAL) [40]. After either approach, the resulting p -coumaric acid is then converted into its corresponding coenzyme A ester, coumaroyl-CoA, through the activity of a 4-coumarate:CoA ligase (4CL) [41].…”

Section: Naringeninmentioning

confidence: 99%

Metabolic engineering of microbial cell factories for production of nutraceuticals

2019

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Metabolic engineering allows for the rewiring of basic metabolism to overproduce both native and non-native metabolites. Among these biomolecules, nutraceuticals have received considerable interest due to their health-promoting or disease-preventing properties. Likewise, microbial engineering efforts to produce these value-added nutraceuticals overcome traditional limitations of low yield from extractions and complex chemical syntheses. This review covers current strategies of metabolic engineering employed for the production of a few key nutraceuticals with selecting polyunsaturated fatty acids, polyphenolic compounds, carotenoids and non-proteinogenic amino acids as exemplary molecules. We focus on the use of both mono-culture and co-culture strategies to produce these molecules of interest. In each of these cases, metabolic engineering efforts are enabling rapid production of these molecules.

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Section: Naringeninmentioning

confidence: 99%

Metabolic engineering of microbial cell factories for production of nutraceuticals

2019

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“…However, plants usually contain complex styrylpyrone mixtures, which are difficult to separate into larger amounts of desired individual compounds. In contrast, the functional combination of plant-specific biosynthetic pathways into microorganisms allows for the production of individual styrylpyrones as a single compound, which can be synthesized in large amounts and isolated more easily ( Facchini et al, 2012 ; Wang et al, 2016 ; Noda and Kondo, 2017 ; Palmer and Alper, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Construction of an Artificial Biosynthetic Pathway for the Styrylpyrone Compound 11-Methoxy-Bisnoryangonin Produced in Engineered Escherichia coli

et al. 2021

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A cDNA clone (named pnpks), which shows high homology to the known chalcone synthase (CHS)-like type III PKS, was obtained from the leaves of Piper nigrum. The PnPKS protein with ferulic acid catalyzed lactonization instead of chalcone or stilbene formation. The new product was characterized as a styrylpyrone, 11-methoxy-bisnoryangonin, which is the lactonization compound of a linear triketide formed as the reaction product of PnPKS protein with ferulic acid. These results show that pnpks encodes a styrylpyrone synthase (SPS)-like PKS that catalyzes two-chain elongation with feruloyl CoA-linked starter substrates. Although these styrylpyrone compounds are promising for use in human healthcare, they are mainly obtained by extraction from raw plant or mushroom sources. For de novo synthesis of 11-methoxy-bisnoryangonin in the heterologous host Escherichia coli from a simple sugar as a starter, the artificial biosynthetic pathway contained five genes: optal, sam5, com, and 4cl2nt, along with the pnpks gene. The engineered L-tyrosine overproducing E. coli ∆COS1 strain, in which five biosynthetic genes were cloned into two vectors, pET-opT5M and pET22-4P, was cultured for 24 h in a minimal glucose medium containing ampicillin and kanamycin. As a result, 11-methoxy-bisnoryangonin production of up to 52.8 mg/L was achieved, which is approximately 8.5-fold higher than that in the parental E. coli strain harboring a plasmid for 11-methoxy-bisnoryangonin biosynthesis. As a potential styrylpyrone compound, 11-methoxy-bisnoryangonin, was successfully produced in E. coli from a simple glucose medium, and its production titer was also increased using engineered strains. This study provides a useful reference for establishing the biological manufacture of styrylpyrone compounds.

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“…Therefore, malonyl-CoA is the key precursor of diverse fatty-acid-derived compounds, including biofuels [36]. Malonyl-CoA is also a precursor for the microbial synthesis of many pharmaceutically interesting polyketides and natural products, such as phenylpropanoids [37]. Fatty acids are a promising resource for the biosynthesis of malonyl-CoA via carboxylation of acetyl-CoA, which can be efficiently obtained from the β-oxidation of fatty acids.…”

Section: Discussionmentioning

confidence: 99%

Efficient bioconversion of raspberry ketone in Escherichia coli using fatty acids feedstocks

et al. 2021

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Background Phenylpropanoid including raspberry ketone, is a kind of important natural plant product and widely used in pharmaceuticals, chemicals, cosmetics, and healthcare products. Bioproduction of phenylpropanoid in Escherichia coli and other microbial cell factories is an attractive approach considering the low phenylpropanoid contents in plants. However, it is usually difficult to produce high titer phenylpropanoid production when fermentation using glucose as carbon source. Developing novel bioprocess using alternative sources might provide a solution to this problem. In this study, typical phenylpropanoid raspberry ketone was used as the target product to develop a biosynthesis pathway for phenylpropanoid production from fatty acids, a promising alternative low-cost feedstock. Results A raspberry ketone biosynthesis module was developed and optimized by introducing 4-coumarate-CoA ligase (4CL), benzalacetone synthase (BAS), and raspberry ketone reductase (RZS) in Escherichia coli strains CR1–CR4. Then strain CR5 was developed by introducing raspberry ketone biosynthesis module into a fatty acids-utilization chassis FA09 to achieve production of raspberry ketone from fatty acids feedstock. However, the production of raspberry ketone was still limited by the low biomass and unable to substantiate whole-cell bioconversion process. Thus, a process by coordinately using fatty-acids and glycerol was developed. In addition, we systematically screened and optimized fatty acids-response promoters. The optimized promoter Pfrd3 was then successfully used for the efficient expression of key enzymes of raspberry ketone biosynthesis module during bioconversion from fatty acids. The final engineered strain CR8 could efficiently produce raspberry ketone repeatedly using bioconversion from fatty acids feedstock strategy, and was able to produce raspberry ketone to a concentration of 180.94 mg/L from soybean oil in a 1-L fermentation process. Conclusion Metabolically engineered Escherichia coli strains were successfully developed for raspberry ketone production from fatty acids using several strategies, including optimization of bioconversion process and fine-tuning key enzyme expression. This study provides an essential reference to establish the low-cost biological manufacture of phenylpropanoids compounds.

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Expanding the Chemical Palette of Industrial Microbes: Metabolic Engineering for Type III PKS‐Derived Polyketides

Cited by 37 publications

References 125 publications

Metabolic engineering of microbial cell factories for production of nutraceuticals

Metabolic engineering of microbial cell factories for production of nutraceuticals

Construction of an Artificial Biosynthetic Pathway for the Styrylpyrone Compound 11-Methoxy-Bisnoryangonin Produced in Engineered Escherichia coli

Efficient bioconversion of raspberry ketone in Escherichia coli using fatty acids feedstocks

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