De novo biosynthesis of diverse plant-derived styrylpyrones in Saccharomyces cerevisiae

Wu, Yinan; Chen, Maple N.; Li, Sijin

doi:10.1016/j.mec.2022.e00195

Cited by 8 publications

(8 citation statements)

References 46 publications

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“…In 2019, Pluskal et al (2019) characterized two CHS-like genes encode functional SPSs from P. methysticum, namely PmSPS1 and PmSPS2. Complete biosynthesis of plant styrylpyrones was achieved in yeast (Wu et al, 2022). Firstly, a styrylpyroneproducing strain containing PmSPS1 and kava O-methyltransferase 1 (PmKOMT1) enable diverse plant styrylpyrones production from fed substrates (e.g., p-coumaric acid and cinnamic acid).…”

Section: Styrylpyrone Synthasementioning

confidence: 99%

Engineered biosynthesis of plant polyketides by type III polyketide synthases in microorganisms

Liu

2022

Front. Bioeng. Biotechnol.

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Plant specialized metabolites occupy unique therapeutic niches in human medicine. A large family of plant specialized metabolites, namely plant polyketides, exhibit diverse and remarkable pharmaceutical properties and thereby great biomanufacturing potential. A growing body of studies has focused on plant polyketide synthesis using plant type III polyketide synthases (PKSs), such as flavonoids, stilbenes, benzalacetones, curcuminoids, chromones, acridones, xanthones, and pyrones. Microbial expression of plant type III PKSs and related biosynthetic pathways in workhorse microorganisms, such as Saccharomyces cerevisiae, Escherichia coli, and Yarrowia lipolytica, have led to the complete biosynthesis of multiple plant polyketides, such as flavonoids and stilbenes, from simple carbohydrates using different metabolic engineering approaches. Additionally, advanced biosynthesis techniques led to the biosynthesis of novel and complex plant polyketides synthesized by diversified type III PKSs. This review will summarize efforts in the past 10 years in type III PKS-catalyzed natural product biosynthesis in microorganisms, especially the complete biosynthesis strategies and achievements.

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Section: Styrylpyrone Synthasementioning

confidence: 99%

Engineered biosynthesis of plant polyketides by type III polyketide synthases in microorganisms

Liu

2022

Front. Bioeng. Biotechnol.

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“…1) with a total of 12 heterologous enzymes. Module I overproduces L-tyrosine by the optimization of the yeast endogenous aromatic acid biosynthetic pathway, which has been constructed in previous work 40 . Yeast endogenous transketolase 1 (TKL1), phospho-2-dehydro-3deoxyheptonate aldolase variant (ARO4 Q166K ), and chorismite mutase variant (ARO7 T226I ) were overexpressed in this strain with an antibiotic hygromycin resistant marker (HygR), namely ySL14 40 .…”

Section: Resultsmentioning

confidence: 99%

“…Module I overproduces L-tyrosine by the optimization of the yeast endogenous aromatic acid biosynthetic pathway, which has been constructed in previous work 40 . Yeast endogenous transketolase 1 (TKL1), phospho-2-dehydro-3deoxyheptonate aldolase variant (ARO4 Q166K ), and chorismite mutase variant (ARO7 T226I ) were overexpressed in this strain with an antibiotic hygromycin resistant marker (HygR), namely ySL14 40 . Module II leads to the formation of the BIA scaffold norcoclaurine, which contains four enzymes including tyrosine hydroxylase (TyrH), cytochrome P450 reductase (CPR), dihydroxyphenylalanine decarboxylase (DoDC), and norcoclaurine synthase (NCS).…”

Section: Resultsmentioning

confidence: 99%

De novo biosynthesis of berberine and halogenated benzylisoquinoline alkaloids in Saccharomyces cerevisiae

Han

2023

Commun Chem

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Berberine is an extensively used pharmaceutical benzylisoquinoline alkaloid (BIA) derived from plants. Microbial manufacturing has emerged as a promising approach to source valuable BIAs. Here, we demonstrated the complete biosynthesis of berberine in Saccharomyces cerevisiae by engineering 19 genes including 12 heterologous genes from plants and bacteria. Overexpressing bottleneck enzymes, fermentation scale-up, and heating treatment after fermentation increased berberine titer by 643-fold to 1.08 mg L-1. This pathway also showed high efficiency to incorporate halogenated tyrosine for the synthesis of unnatural BIA derivatives that have higher therapeutical potentials. We firstly demonstrate the in vivo biosynthesis of 11-fluoro-tetrahydrocolumbamine via nine enzymatic reactions. The efficiency and promiscuity of our pathway also allow for the simultaneous incorporation of two fluorine-substituted tyrosine derivatives to 8, 3’-di-fluoro-coclaurine. This work highlights the potential of yeast as a versatile microbial biosynthetic platform to strengthen current pharmaceutical supply chain and to advance drug development.

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“…Furthermore, the abundance of intracellular compartments enables the appropriate localization of heterologous enzymes. , The ease of genomic integration into the yeast chromosome allows for stable heterologous pathway expression and PNP production, conferring yeast-based large-scale industrial fermentation with wide compatibility compared to transient plasmid-based pathway construction in other microbes. Many successful examples of valuable PNP biosynthesis by genomically integrated pathways have been reported for a diverse range of compounds including polyketides, , terpenes, , and alkaloids. − …”

Section: Introductionmentioning

confidence: 99%

“…8,9 The ease of genomic integration into the yeast chromosome allows for stable heterologous pathway expression and PNP production, conferring yeastbased large-scale industrial fermentation with wide compatibility compared to transient plasmid-based pathway construction in other microbes. Many successful examples of valuable PNP biosynthesis by genomically integrated pathways have been reported for a diverse range of compounds including polyketides, 10,11 terpenes, 12,13 and alkaloids. 14 Novel and complicated PNP biosynthetic pathways are being discovered at an unprecedented rate, yet the techniques and ability to reconstruct these pathways in microbial systems lag far behind.…”

Section: Introductionmentioning

confidence: 99%

MULTI-SCULPT: Multiplex Integration via Selective, CRISPR-Mediated, Ultralong Pathway Transformation in Yeast for Plant Natural Product Synthesis

Gong

Han

2022

ACS Synth. Biol.

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Yeast has been a versatile model host for complex and valuable natural product biosynthesis via the reconstruction of heterologous biosynthetic pathways. Recent advances in natural product pathway elucidation have uncovered many large and complicated plant pathways that contain 10–30 genes for the biosynthesis of structurally complex, valuable natural products. However, the ability to reconstruct ultralong pathways efficiently in yeast does not match the increasing demand for valuable plant natural product biomanufacturing. Here, we developed a one-pot, multigene pathway integration method in yeast, named MULTI-SCULPT for multiplex integration via selective, CRISPR-mediated, ultralong pathway transformation. Leveraging multilocus genomic disruption via CRISPR/Cas9, newly developed native and synthetic genetic parts, and fine-tuned gene integration and characterization methods, we managed to integrate 21 DNA inserts that contain a 12-gene plant isoflavone biosynthetic pathway into yeast with a 90–100% success rate in 12 days. This method enables fast and efficient ultralong biosynthetic pathway integration and can allow for the fast iterative integration of even longer pathways in the future. Ultimately, this method will accelerate combinatorial optimization of elucidated plant natural product pathways and accelerate putative pathway characterization heterologously.

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De novo biosynthesis of diverse plant-derived styrylpyrones in Saccharomyces cerevisiae

Cited by 8 publications

References 46 publications

Engineered biosynthesis of plant polyketides by type III polyketide synthases in microorganisms

Engineered biosynthesis of plant polyketides by type III polyketide synthases in microorganisms

De novo biosynthesis of berberine and halogenated benzylisoquinoline alkaloids in Saccharomyces cerevisiae

MULTI-SCULPT: Multiplex Integration via Selective, CRISPR-Mediated, Ultralong Pathway Transformation in Yeast for Plant Natural Product Synthesis

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