Biosynthesis of catharanthine in engineered Pichia pastoris

Gao, Jucan; Zuo, Yimeng; Xiao, Feng; Wang, Yiling; Li, Dongfang; Xu, Junhao; Ye, Cuifang; Feng, Linjuan; Jiang, Leijie; Liu, Tengfei; Gao, Di; Ma, Bin; Huang, Lei; Xu, Zhinan; Lian, Jiazhang

doi:10.1038/s44160-022-00205-2

Cited by 45 publications

(26 citation statements)

References 61 publications

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“…Furthermore, it shows a higher expression level of heterologous protein than S. cerevisiae. For example, recombinant proteins expressed under the control of the yeast alcohol oxidase 1 (AOX1) promoter can contribute more than 30% of the total proteins in P. pastoris 23 . A recent study has shown that a cytochrome P450 enzyme, which catalyzes the conversion of scoulerine (a product downstream of reticuline) to cheilanthifoline, exhibits a higher conversion rate in P. pastoris cells (70%) than S. cerevisiae cells (20%) 24 .…”

Section: Yeast For the Heterologous Production Of Npsmentioning

confidence: 99%

A roadmap to establish a comprehensive platform for sustainable manufacturing of natural products in yeast

Naseri

2023

Nat Commun

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Secondary natural products (NPs) are a rich source for drug discovery. However, the low abundance of NPs makes their extraction from nature inefficient, while chemical synthesis is challenging and unsustainable. Saccharomyces cerevisiae and Pichia pastoris are excellent manufacturing systems for the production of NPs. This Perspective discusses a comprehensive platform for sustainable production of NPs in the two yeasts through system-associated optimization at four levels: genetics, temporal controllers, productivity screening, and scalability. Additionally, it is pointed out critical metabolic building blocks in NP bioengineering can be identified through connecting multilevel data of the optimized system using deep learning.

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Section: Yeast For the Heterologous Production Of Npsmentioning

confidence: 99%

A roadmap to establish a comprehensive platform for sustainable manufacturing of natural products in yeast

Naseri

2023

Nat Commun

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“…Ideally, metabolic engineering strategies could be employed to elevate paclitaxel levels in Taxus cell cultures or to refactor its production in heterologous hosts (such as Saccharomyces cerevisiae ). Recent successful instances include vinblastine [ 5 , 6 , 7 ], another anticancer drug with a highly complex biosynthetic pathway involving 31 plant-derived enzymatic steps, which has been de novo biosynthesized in microorganisms. However, the prerequisite for implementing metabolic engineering strategies lies in the comprehensive elucidation of the paclitaxel biosynthetic pathway.…”

Section: Introductionmentioning

confidence: 99%

Intricate Metabolic Network for Paclitaxel Biosynthesis

Gou,

Jiang,

Lian

2024

BioDesign Res

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Paclitaxel is a renowned broad-spectrum anticancer drug. With the establishment of a chromosome-level high-quality reference genome map of Taxus , recent research on paclitaxel biosynthesis has flourished. The oxetane ring is a distinctive chemical moiety of paclitaxel, and three recent studies have proposed different enzymes involved in its formation, reflecting divergent opinions on whether the pathway proceeds via acetylation followed by epoxidation or vice versa. Subsequently, researchers have elucidated gene clusters responsible for the biosynthesis of the key intermediate baccatin III. Despite varying reports, two studies successfully achieved heterologous biosynthesis of baccatin III by transient expression in tobacco. Taxadiene 5α-hydroxylase (T5αH), the first cytochrome P450 in the pathway, exhibited varied product profiles upon heterologous expression systems, contrasting with observations in native Taxus species, probably due to differences in partner proteins or cellular microenvironments. Further elucidation of biosynthesis mechanisms, including the reaction order and the promiscuity of key enzymes, is anticipated through collaborative efforts among botanists, chemists, and synthetic biologists.

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“…As for biosynthesis, using native strains for production is typically hindered by the complexity of metabolites, difficulties in separation, and challenges such as a long fermentation period and complex genetic manipulation [ 7 ]. In recent years, with the development of synthetic biology, constructing cell factories for producing valuable terpenoid compounds has emerged as a more efficient alternative, including carotenoids and squalene used as healthcare products [ 8 – 10 ], vincristine and artemisinin as natural pharmaceuticals [ 11 – 13 ], and limonene employed in fragrances [ 14 ]. Using synthetic biology approaches for heterologous biosynthesis of ophiobolins represents an attractive option.…”

Section: Introductionmentioning

confidence: 99%

De novo production of bioactive sesterterpenoid ophiobolins in Saccharomyces cerevisiae cell factories

Zhang,

Wu,

Sun

et al. 2024

Microb Cell Fact

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Background Sesterterpenoids are rare species among the terpenoids family. Ophiobolins are sesterterpenes with a 5-8-5 tricyclic skeleton. The oxidized ophiobolins exhibit significant cytotoxic activity and potential medicinal value. There is an urgent need for large amounts of ophiobolins supplication for drug development. The synthetic biology approach has been successfully employed in lots of terpene compound production and inspired us to develop a cell factory for ophiobolin biosynthesis. Results We developed a systematic metabolic engineering strategy to construct an ophiobolin biosynthesis chassis based on Saccharomyces cerevisiae. The whole-cell biotransformation methods were further combined with metabolic engineering to enhance the expression of key ophiobolin biosynthetic genes and improve the supply of precursors and cofactors. A high yield of 5.1 g/L of ophiobolin F was reached using ethanol and fatty acids as substrates. To accumulate oxidized ophiobolins, we optimized the sources and expression conditions for P450-CPR and alleviated the toxicity of bioactive compounds to cells through PDR engineering. We unexpectedly obtained a novel ophiobolin intermediate with potent cytotoxicity, 5-hydroxy-21-formyl-ophiobolin F, and the known bioactive compound ophiobolin U. Finally, we achieved the ophiobolin U titer of 128.9 mg/L. Conclusions We established efficient cell factories based on S. cerevisiae, enabling de novo biosynthesis of the ophiobolin skeleton ophiobolin F and oxidized ophiobolins derivatives. This work has filled the gap in the heterologous biosynthesis of sesterterpenoids in S. cerevisiae and provided valuable solutions for new drug development based on sesterterpenoids.

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Biosynthesis of catharanthine in engineered Pichia pastoris

Cited by 45 publications

References 61 publications

A roadmap to establish a comprehensive platform for sustainable manufacturing of natural products in yeast

A roadmap to establish a comprehensive platform for sustainable manufacturing of natural products in yeast

Intricate Metabolic Network for Paclitaxel Biosynthesis

De novo production of bioactive sesterterpenoid ophiobolins in Saccharomyces cerevisiae cell factories

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