Complete biosynthesis of the potential medicine icaritin by engineered Saccharomyces cerevisiae and Escherichia coli

Wang, Pingping; Li, Chaojing; Li, Xiaodong; Huang, Wen‐Jun; Wang, Yan; Wang, Jiali; Zhang, Yanjun; Yang, Xiaoman; Yan, Xiaojun; Wang, Ying; Zhou, Zhihua

doi:10.1016/j.scib.2021.03.002

Cited by 41 publications

(33 citation statements)

References 42 publications

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“…In order to solve this problem, GmOMT2 could be relocated into the mitochondria (higher pH than cytoplasm) of S. cerevisiae. The synthesis of icaritin from glucose in microorganisms was also achieved for the first time, and the yield was 7.2 mg/L [57]. However, this regulation mechanism is still under elucidation for GmOMT2.…”

Section: Microbial Mono-culture For Flavonoid Synthesismentioning

confidence: 96%

“…The initial precursors of the phenylpropanoid pathway are L-phenylalanine or L-tyrosine, which are generally produced through the shikimate and aerogenate pathways [7]. The primary metabolite glucose produces phosphoenolpyruvate (PEP) and erythrose 4-phosphate (E4P) through the glycolytic pathway and pentose phosphate pathway, respectively, and they react to produce shikimic acid [57]. After a series of enzymatic reactions, shikimic acid can produce chorismate, prephenate, and finally L-phenylalanine and L-tyrosine [7] (Figure 2).…”

Section: Biosynthesis Of Flavonoids In Plantsmentioning

confidence: 99%

“…E. coli is usually the host of choice because it has several advantages, including a high growth rate, established high cell density culture technology, and extensive investigations in genetic engineering [59]. As a GRAS (generally regarded as safe) strain, S. cerevisiae is often used as a product host, and it has a complete intracellular membrane system and is superior to E. coli in terms of the expression of membrane proteins [57]. In the process of de novo synthesis of anthocyanins by S. cerevisiae, a higher titer of eriodictyol was obtained, which was 152 mg/L [60].…”

Section: Microbial Mono-culture For Flavonoid Synthesismentioning

confidence: 99%

“…Apart from selecting suitable microbial hosts for heterologous expression of pathway enzymes, other strategies had been adopted. For example, when icariin was generated in S. cerevisiae, the pathway enzyme methyltransferase GmOMT2 would lose its activity due to the low pH in the cytoplasm if it was expressed in the cytoplasm [57]. In order to solve this problem, GmOMT2 could be relocated into the mitochondria (higher pH than cytoplasm) of S. cerevisiae.…”

Section: Microbial Mono-culture For Flavonoid Synthesismentioning

confidence: 99%

“…Notably, the co-culture of S. cerevisiae and S. cerevisiae strains separately containing AlCHS and Al4CL could produce not only naringenin but also resveratrol [86]. An artificial icaritin biosynthetic pathway was initially designed to generate icaritin in microbes this year [57]. During the biosynthesis of icariin, the role of methyltransferase GmOMT2 was very important.…”

Section: Microbial Mono-culture For Flavonoid Synthesismentioning

confidence: 99%

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Metabolic Engineering of Microbial Cell Factories for Biosynthesis of Flavonoids: A Review

Lou

Hu²,

et al. 2021

Molecules

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Flavonoids belong to a class of plant secondary metabolites that have a polyphenol structure. Flavonoids show extensive biological activity, such as antioxidative, anti-inflammatory, anti-mutagenic, anti-cancer, and antibacterial properties, so they are widely used in the food, pharmaceutical, and nutraceutical industries. However, traditional sources of flavonoids are no longer sufficient to meet current demands. In recent years, with the clarification of the biosynthetic pathway of flavonoids and the development of synthetic biology, it has become possible to use synthetic metabolic engineering methods with microorganisms as hosts to produce flavonoids. This article mainly reviews the biosynthetic pathways of flavonoids and the development of microbial expression systems for the production of flavonoids in order to provide a useful reference for further research on synthetic metabolic engineering of flavonoids. Meanwhile, the application of co-culture systems in the biosynthesis of flavonoids is emphasized in this review.

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Section: Microbial Mono-culture For Flavonoid Synthesismentioning

confidence: 96%

Section: Biosynthesis Of Flavonoids In Plantsmentioning

confidence: 99%

Section: Microbial Mono-culture For Flavonoid Synthesismentioning

confidence: 99%

Section: Microbial Mono-culture For Flavonoid Synthesismentioning

confidence: 99%

Section: Microbial Mono-culture For Flavonoid Synthesismentioning

confidence: 99%

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Metabolic Engineering of Microbial Cell Factories for Biosynthesis of Flavonoids: A Review

Lou

Hu²,

et al. 2021

Molecules

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Construction of ajmalicine and sanguinarine de novo biosynthetic pathways using stable integration sites in yeast

Liu

Gou

Zhang

et al. 2022

Biotech & Bioengineering

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Yeast cell factories have been increasingly employed for producing plant‐derived natural products. Unfortunately, the stability of plant natural product biosynthetic pathway genes, particularly when driven by the same sets of promoters and terminators, remains one of the biggest concerns for synthetic biology. Here we profile genomic loci flanked by essential genes as stable integration sites in a genome‐wide manner, for stable maintenance of multigene biosynthetic pathways in yeast. We demonstrate the application of our yeast integration platform in the construction of sanguinarine (24 expression cassettes) and ajmalicine (29 expression cassettes) de novo biosynthetic pathways for the first time. Moreover, we establish stable yeast cell factories that can produce 119.2 mg L−1 heteroyohimbine alkaloids (containing 61.4 mg L−1 ajmalicine) in shake flasks, representing the highest titer of monoterpene indole alkaloids (MIAs) ever reported and promising the complete biosynthesis of other high‐value MIAs (such as vinblastine) for biotechnological applications.

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New insights into the anticancer therapeutic potential of icaritin and its synthetic derivatives

Reyes‐Hernández,

Figueroa‐González,

Quintas‐Granados

et al. 2024

Drug Development Research

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Icaritin is a natural prenylated flavonoid derived from the Chinese herb Epimedium. The compound has shown antitumor effects in various cancers, especially hepatocellular carcinoma (HCC). Icaritin exerts its anticancer activity by modulating multiple signaling pathways, such as IL‐6/JAK/STAT3, ER‐α36, and NF‐κB, affecting the tumor microenvironment and immune system. Several clinical trials have evaluated the safety and efficacy of icaritin in advanced HCC patients with poor prognoses, who are unsuitable for conventional therapies. The results have demonstrated that icaritin can improve survival, delay progression, and produce clinical benefits in these patients, with a favorable safety profile and minimal adverse events. Moreover, icaritin can enhance the antitumor immune response by regulating the function and phenotype of various immune cells, such as CD8+ T cells, MDSCs, neutrophils, and macrophages. These findings suggest that icaritin is a promising candidate for immunotherapy in HCC and other cancers. However, further studies are needed to elucidate the molecular mechanisms and optimal dosing regimens of icaritin and its potential synergistic effects with other agents. Therefore, this comprehensive review of the scientific literature aims to summarize advances in the knowledge of icaritin in preclinical and clinical studies as well as the pharmacokinetic, metabolism, toxicity, and mechanisms action to recognize the main challenge, gaps, and opportunities to develop a medication that cancer patients can use. Thus, our main objective was to clarify the current state of icaritin for use as an anticancer drug.

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Complete biosynthesis of the potential medicine icaritin by engineered Saccharomyces cerevisiae and Escherichia coli

Cited by 41 publications

References 42 publications

Metabolic Engineering of Microbial Cell Factories for Biosynthesis of Flavonoids: A Review

Metabolic Engineering of Microbial Cell Factories for Biosynthesis of Flavonoids: A Review

Construction of ajmalicine and sanguinarine de novo biosynthetic pathways using stable integration sites in yeast

New insights into the anticancer therapeutic potential of icaritin and its synthetic derivatives

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