Metabolic engineering of Yarrowia lipolytica for high-level production of scutellarin

Zhang, Ping; Wei, Wenping; Shang, Yanzhe; Ye, Bang‐Ce

doi:10.1016/j.biortech.2023.129421

Cited by 9 publications

(6 citation statements)

References 34 publications

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“…The combined overexpression of YlARO1 ΔIntro , YlARO2 , ARO4 K221L , and ARO7 G139S significantly boosted (2 S )-eriodictyol production to 94.6 mg/L (21.8 mg/L (2 S )-naringenin). This result is consistent with the previous reports in which the overexpression of YlARO1 , along with the introduction of AROG * and TYRA *, effectively enhances the flux of the shikimate pathway. , Therefore, enhancing the metabolic pathway of shikimate was an effective approach to improve the titer of (2 S )-eriodictyol.…”

Section: Resultssupporting

confidence: 92%

“…Plant extraction and chemical synthesis are the primary methods for obtaining (2 S )-eriodictyol, but these approaches suffer from issues such as expensive raw materials, low titer, and environmental pollution . In contrast, the microbial synthesis of (2 S )-eriodictyol has the obvious advantages of high efficiency, low pollution, and low production cost, making it a sustainable alternative method …”

Section: Introductionmentioning

confidence: 99%

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High-Level De Novo Production of (2S)-Eriodictyol in Yarrowia Lipolytica by Metabolic Pathway and NADPH Regeneration Engineering

Yue,

Liu,

Gao

et al. 2024

J. Agric. Food Chem.

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Metrics & MoreArticle Recommendations * sı Supporting Information ABSTRACT: (2S)-Eriodictyol, a polyphenolic flavonoid, has found widespread applications in health supplements and food additives. However, the limited availability of plant-derived (2S)-eriodictyol cannot meet the market demand. Microbial production of (2S)-eriodictyol faces challenges, including the low catalytic efficiency of flavone 3′-hydroxylase/cytochrome P450 reductase (F3′H/CPR), insufficient precursor supplementation, and inadequate NADPH regeneration. This study systematically engineered Yarrowia lipolytica for high-level (2S)-eriodictyol production. In doing this, the expression of F3′H/CPR was balanced, and the supply of precursors was enhanced by relieving feedback inhibition of the shikimate pathway, promoting fatty acid β-oxidation, and increasing the copy number of synthetic pathway genes. These strategies, combined with NADPH regeneration, achieved an (2S)eriodictyol titer of 423.6 mg/L. Finally, in fed-batch fermentation, a remarkable 6.8 g/L (2S)-eriodictyol was obtained, representing the highest de novo microbial titer reported to date and paving the way for industrial production.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

High-Level De Novo Production of (2S)-Eriodictyol in Yarrowia Lipolytica by Metabolic Pathway and NADPH Regeneration Engineering

Yue,

Liu,

Gao

et al. 2024

J. Agric. Food Chem.

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“…Moreover, the genes ZWF1 and GND1 of the pentose phosphate pathway, which may lead to increased cytoplasmic NADPH supply and enhanced xylose fermentation by intermediates feeding, were also overexpressed (Fig. 3 ) [ 22 , 23 ]. Unlike S. cerevisiae for which the growth on xylose was always less efficient than glucose despites great endeavors made on pathway optimization [ 24 , 25 ], our engineered strain yl4XRHK exhibited similar growth rate (0.18 h −1 ) and biomass yield (0.51 g-DCW/g-xylose) on xylose to that of obtained on glucose (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Considering the presence of significant amount of glucose is prevailing in real LC biomass hydrolysates, eliminating glucose repression on xylose utilization holds great advantage. In addition, it has been demonstrated that Zwf1p and Gnd1p in the PPP play an essential role in cytoplasmic NADPH generation in Y. lipolytica [ 35 ], and their overexpression promoted NADPH regeneration in Y. lipolytica which led to increased erythritol [ 36 ] and scutellarin production [ 23 ]. Similarly, overexpressing the genes ZWF1 and GND1 led to increased cytoplasmic NADPH supply enhanced xylose fermentation by maintaining cofactor balance.…”

Section: Discussionmentioning

confidence: 99%

Installing xylose assimilation and cellodextrin phosphorolysis pathways in obese Yarrowia lipolytica facilitates cost-effective lipid production from lignocellulosic hydrolysates

Zhang,

Li,

Zhu

et al. 2023

Biotechnol Biofuels

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Background Yarrowia lipolytica, one of the most charming chassis cells in synthetic biology, is unable to use xylose and cellodextrins. Results Herein, we present work to tackle for the first time the engineering of Y. lipolytica to produce lipids from cellodextrins and xylose by employing rational and combinatorial strategies. This includes constructing a cellodextrin-phosphorolytic Y. lipolytica by overexpressing Neurospora crassa cellodextrin transporter, Clostridium thermocellum cellobiose/cellodextrin phosphorylase and Saccharomyces cerevisiae phosphoglucomutase. The effect of glucose repression on xylose consumption was relieved by installing a xylose uptake facilitator combined with enhanced PPP pathway and increased cytoplasmic NADPH supply. Further enhancing lipid production and interrupting its consumption conferred the obese phenotype to the engineered yeast. The strain is able to co-ferment glucose, xylose and cellodextrins efficiently, achieving a similar μmax of 0.19 h−1, a qs of 0.34 g-s/g-DCW/h and a YX/S of 0.54 DCW-g/g-s on these substrates, and an accumulation of up to 40% of lipids on the sugar mixture and on wheat straw hydrolysate. Conclusions Therefore, engineering Y. lipolytica capable of assimilating xylose and cellodextrins is a vital step towards a simultaneous saccharification and fermentation (SSF) process of LC biomass, allowing improved substrate conversion rate and reduced production cost due to low demand of external glucosidase.

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“…cerevisiae also has disadvantages, including the Crabtree effect (which generates ethanol at the expense of most available acetyl-CoA) and limited secretion systems. , Consequently, Yarrowia lipolytica has served as a popular and promising host for advanced biomanufacturing due to its cumulated advantages (Table ). − …”

Section: Introductionmentioning

confidence: 99%

Building Yarrowia lipolytica Cell Factories for Advanced Biomanufacturing: Challenges and Solutions

Sun,

Gao,

Lin

et al. 2023

J. Agric. Food Chem.

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Microbial cell factories have shown great potential for industrial production with the benefit of being environmentally friendly and sustainable. Yarrowia lipolytica is a promising and superior non-model host for biomanufacturing due to its cumulated advantages compared to model microorganisms, such as high fluxes of metabolic precursors (acetyl-CoA and malonyl-CoA) and its naturally hydrophobic microenvironment. However, although diverse compounds have been synthesized in Y. lipolytica cell factories, most of the relevant studies have not reached the level of industrialization and commercialization due to a number of remaining challenges, including unbalanced metabolic flux, conflict between cell growth and product synthesis, and cytotoxic effects. Here, various metabolic engineering strategies for solving the challenges are summarized, which is developing fast and extremely conducive to rational design and reconstruction of robust Y. lipolytica cell factories for advanced biomanufacturing. Finally, future engineering efforts for enhancing the production efficiency of this platform strain are highlighted.

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Metabolic engineering of Yarrowia lipolytica for high-level production of scutellarin

Cited by 9 publications

References 34 publications

High-Level De Novo Production of (2S)-Eriodictyol in Yarrowia Lipolytica by Metabolic Pathway and NADPH Regeneration Engineering

High-Level De Novo Production of (2S)-Eriodictyol in Yarrowia Lipolytica by Metabolic Pathway and NADPH Regeneration Engineering

Installing xylose assimilation and cellodextrin phosphorolysis pathways in obese Yarrowia lipolytica facilitates cost-effective lipid production from lignocellulosic hydrolysates

Building Yarrowia lipolytica Cell Factories for Advanced Biomanufacturing: Challenges and Solutions

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