Reconstitution of a 10-gene pathway for synthesis of the plant alkaloid dihydrosanguinarine in Saccharomyces cerevisiae

Fossati, Elena; Ekins, Andrew; Narcross, Lauren; Zhu, Yun; Falgueyret, Jean‐Pierre; Beaudoin, Guillaume A.W.; Facchini, Peter J.; Martin, Vincent J. J.

doi:10.1038/ncomms4283

Cited by 156 publications

(135 citation statements)

References 63 publications

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“…This information is not only of fundamental importance in plant metabolic biochemistry, but it also establishes a framework for manipulating natural BIA biosynthetic pathways as an approach toward obtaining rare or novel compounds with desirable pharmacological properties. In particular, several efforts are under way to transfer entire BIA biosynthetic pathways found exclusively in plants to heterologous systems, such as yeast (2,3). The ability to control and modify the substrate specificities and catalytic activities of enzymes obtained from the biosynthetic machinery found in plants will be central to the success of these metabolic engineering objectives.…”

mentioning

confidence: 99%

Structural and Functional Studies of Pavine N-Methyltransferase from Thalictrum flavum Reveal Novel Insights into Substrate Recognition and Catalytic Mechanism

Torres

Hoffarth

Eugenio

et al. 2016

Journal of Biological Chemistry

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mentioning

confidence: 99%

Structural and Functional Studies of Pavine N-Methyltransferase from Thalictrum flavum Reveal Novel Insights into Substrate Recognition and Catalytic Mechanism

Torres

Hoffarth

Eugenio

et al. 2016

Journal of Biological Chemistry

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“…For example, in the sanguinarine pathway, SPS was poorly expressed in S. cerevisiae. [266] In order to solve this problem, its N-terminal transmembrane domain was exchanged into lettuce germacrene A oxidase, greatly enhancing its expression confirmed by western blot. The N-terminal domain of BBE was also truncated to aid in its function (Figure 18b).…”

Section: Enzyme Engineeringmentioning

confidence: 99%

“…For the production of sanguinarine from norlaudanosoline, Fossati et al separated the 10-enzyme pathway into three blocksreticuline production block, S-scoulerine production block, and dihydrosanguinarine production block (Figure 18c). [266] These three blocks were individually tested by feeding the corresponding intermediates, and then incorporated into one yeast strain for constructing the whole biosynthetic pathway. Since it turned out that N-terminus truncated BBE (BBEΔN) was the bottleneck, it was additionally expressed in a high-copy plasmid.…”

Section: Module Based Expression Optimizationmentioning

confidence: 99%

“…Six years later, Fossati et al reported a twofold increase in S-reticuline yield by reducing the number of plasmids from 2 to 1 and altering the plasmid configuration. [266] Next year, de novo biosynthesis of S-reticuline from a simple carbon source in S. cerevisiae was reported. [267] Conversion of L-DOPA from tyrosine was the biggest bottleneck, which has hindered de novo biosynthesis of BIAs in yeast.…”

Section: Introduction Of Heterologous Genesmentioning

confidence: 99%

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Metabolic Engineering of Microorganisms for the Production of Natural Compounds

Park

Yang

et al. 2017

Adv. Biosys.

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Natural products have been attracting much interest around the world for their diverse applications, especially in drug and food industries. Plants have been a major source of many different natural products. However, plants are affected by weather and environmental conditions and their successful extraction is rather limited. Chemical synthesis is inefficient due to the complexity of their chemical structures involving enantioselectivity and regioselectivity. For these reasons, an alternative means of overproducing valuable natural products using microorganisms has emerged. In recent years, various metabolic engineering strategies have been developed for the production of natural products by microorganisms. Here, the strategies taken to produce natural products are reviewed. For convenience, natural products are classified into four main categories: terpenoids, phenylpropanoids, polyketides, and alkaloids. For each product category, the strategies for establishing and rewiring the metabolic network for heterologous natural product biosynthesis, systems approaches undertaken to optimize production hosts, and the strategies for fermentation optimization are reviewed. Taken together, metabolic engineering has enabled microorganisms to serve as a prominent platform for natural compounds production. This article examines both the conventional and novel strategies of metabolic engineering, providing general strategies for complex natural compound production through the development of robust microbial‐cell factories.

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“…[80]. In other studies, S. cerevisiae strains were engineered to produce berberine, dihydrosanguinarine and noscapine from norlaudanosoline via reticuline intermediate, through a 7-, 10-and 14-step pathway involving heterologous expression of plant enzymes, respectively [82][83][84]. Also, the production of codeine and morphine from (R)-reticuline was reported by reconstitution of a seven-gene pathway in S. cerevisiae [85].…”

Section: Representative Studies and Their Strain Improvement Strategymentioning

confidence: 99%

Advances in Metabolic Engineering of Saccharomyces cerevisiae for the Production of Industrially and Clinically Important Chemicals

Turanlı-Yıldız¹,

Hacısalihoğlu²,

Çakar³

2017

Old Yeasts - New Questions

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Sustainable production of chemicals is of increasing importance, due to depletion of petroleum and environmental concerns. In addition to its importance in basic research as a simple, eukaryotic model organism, Saccharomyces cerevisiae has long been exploited in industry because of its physiological properties. And today, the development in genetic engineering toolbox and genome-scale metabolic models of S. cerevisiae has extended its application range to new products and bioprocesses. In addition, evolutionary engineering strategies have been useful in improving cellular properties of S. cerevisiae, such as tolerance to product toxicity and inhibitors. In this chapter, recent metabolic and evolutionary engineering studies that involve S. cerevisiae for the production of bulk chemicals and ine chemicals including lavours and pharmaceuticals are reviewed. It was shown that metabolic engineering particularly allowed the improvement of pharmaceuticals production, which will enable economic and large-scale production of many valuable pharmaceuticals. It is clear that S. cerevisiae will continue to be an important host for future metabolic engineering and metabolic pathway engineering applications to produce a variety of industrially and clinically important chemicals.

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Reconstitution of a 10-gene pathway for synthesis of the plant alkaloid dihydrosanguinarine in Saccharomyces cerevisiae

Cited by 156 publications

References 63 publications

Structural and Functional Studies of Pavine N-Methyltransferase from Thalictrum flavum Reveal Novel Insights into Substrate Recognition and Catalytic Mechanism

Structural and Functional Studies of Pavine N-Methyltransferase from Thalictrum flavum Reveal Novel Insights into Substrate Recognition and Catalytic Mechanism

Metabolic Engineering of Microorganisms for the Production of Natural Compounds

Advances in Metabolic Engineering of Saccharomyces cerevisiae for the Production of Industrially and Clinically Important Chemicals

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