Metabolic engineering for plant natural products biosynthesis: new procedures, concrete achievements and remaining limits

Courdavault, Vincent; O’Connor, Sarah E.; Jensen, Michael K.; Papon, Nicolas

doi:10.1039/d0np00092b

Cited by 68 publications

(38 citation statements)

References 43 publications

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“…Such an overall increase of enzyme activity will probably involve the expression of additional proteins involved in the regeneration of some MIA pathway enzyme cofactors such as NADPH [22]. Delocalization of MIA biosynthetic enzymes to new subcellular compartments such as vacuoles or peroxisomes may also represent an interesting option to maximize the metabolic flux or avoid the accumulation of undesired/toxic intermediates [31,51,61]. Finally, controlled fed-batch fermentations of the newly developed yeast strains in bioreactors will probably increase MIA synthesis up to industrial scales.…”

Section: Discussionmentioning

confidence: 99%

Optimization of Tabersonine Methoxylation to Increase Vindoline Precursor Synthesis in Yeast Cell Factories

et al. 2021

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Plant specialized metabolites are widely used in the pharmaceutical industry, including the monoterpene indole alkaloids (MIAs) vinblastine and vincristine, which both display anticancer activity. Both compounds can be obtained through the chemical condensation of their precursors vindoline and catharanthine extracted from leaves of the Madagascar periwinkle. However, the extensive use of these molecules in chemotherapy increases precursor demand and results in recurrent shortages, explaining why the development of alternative production approaches, such microbial cell factories, is mandatory. In this context, the precursor-directed biosynthesis of vindoline from tabersonine in yeast-expressing heterologous biosynthetic genes is of particular interest but has not reached high production scales to date. To circumvent production bottlenecks, the metabolic flux was channeled towards the MIA of interest by modulating the copy number of the first two genes of the vindoline biosynthetic pathway, namely tabersonine 16-hydroxylase and tabersonine-16-O-methyltransferase. Increasing gene copies resulted in an optimized methoxylation of tabersonine and overcame the competition for tabersonine access with the third enzyme of the pathway, tabersonine 3-oxygenase, which exhibits a high substrate promiscuity. Through this approach, we successfully created a yeast strain that produces the fourth biosynthetic intermediate of vindoline without accumulation of other intermediates or undesired side-products. This optimization will probably pave the way towards the future development of yeast cell factories to produce vindoline at an industrial scale.

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Section: Discussionmentioning

confidence: 99%

Optimization of Tabersonine Methoxylation to Increase Vindoline Precursor Synthesis in Yeast Cell Factories

et al. 2021

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“…Despite the success of the plant metabolic engineering approaches presented here, alkaloids that are used in oncology and anesthesia are in high demand, whereas drug shortages have become a growing public health issue. This is caused, not only by global pandemics, natural disasters, and the destruction of natural habits, but also by the fact that these molecules are structurally complex, difficult to synthesize, and their content in plants is very low ( Courdavault et al, 2021 ).…”

Section: Perspectivesmentioning

confidence: 99%

Application of metabolic engineering to enhance the content of alkaloids in medicinal plants

Vásquez

Abascal

Leal

et al. 2022

Metabolic Engineering Communications

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Section: Heterologous Biosynthesismentioning

confidence: 99%

“…Once the host successfully expresses the BGC, the culture is examined by liquid chromatography-mass spectrometry (LC-MS) and other analytical methods to determine whether the target secondary metabolites are produced by the heterologous host. Adapted with permission from ref [71]…”

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Advances in Biosynthesis of Natural Products from Marine Microorganisms

Zhou

Hotta²,

Deng

et al. 2021

Microorganisms

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Natural products play an important role in drug development, among which marine natural products are an underexplored resource. This review summarizes recent developments in marine natural product research, with an emphasis on compound discovery and production methods. Traditionally, novel compounds with useful biological activities have been identified through the chromatographic separation of crude extracts. New genome sequencing and bioinformatics technologies have enabled the identification of natural product biosynthetic gene clusters in marine microbes that are difficult to culture. Subsequently, heterologous expression and combinatorial biosynthesis have been used to produce natural products and their analogs. This review examines recent examples of such new strategies and technologies for the development of marine natural products.

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Metabolic engineering for plant natural products biosynthesis: new procedures, concrete achievements and remaining limits

Abstract: The recent achievements in the transfer of biosynthetic pathways of plant natural products in heterologous organisms offer new perspectives towards the supply of these compounds through metabolic engineering approaches.

Cited by 68 publications

References 43 publications

Optimization of Tabersonine Methoxylation to Increase Vindoline Precursor Synthesis in Yeast Cell Factories

Optimization of Tabersonine Methoxylation to Increase Vindoline Precursor Synthesis in Yeast Cell Factories

Application of metabolic engineering to enhance the content of alkaloids in medicinal plants

Advances in Biosynthesis of Natural Products from Marine Microorganisms

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