Biosynthesis of terpene compounds using the non-model yeast Yarrowia lipolytica: grand challenges and a few perspectives

Worland, Alyssa M; Czajka, Jeffrey J.; Li, Yanran; Wang, Yechun; Tang, Yinjie J.; Su, Wei

doi:10.1016/j.copbio.2020.02.020

Cited by 35 publications

(32 citation statements)

References 55 publications

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“…As a pentacyclic triterpenoid, lupeol has valuable pharmaceutical and nutraceutical properties [3,8,30], but a severely negative impact of lupeol on cell viability was observed even at a relatively low concentration of 60 mg/L [3]. Y. lipolytica is emerging as a fascinating host for terpenoid biosynthesis, but the cytotoxicity of terpenes induced by their antimicrobial activities is still a main factor hampering terpene overproduction in Y. lipolytica [4,5].…”

Section: Discussionmentioning

confidence: 99%

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High production of triterpenoids in Yarrowia lipolytica through manipulation of lipid components

Zhang

Bai

Peng

et al. 2020

Biotechnol Biofuels

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Background: Lupeol exhibits novel physiological and pharmacological activities, such as anticancer and immunityenhancing activities. However, cytotoxicity remains a challenge for triterpenoid overproduction in microbial cell factories. As lipophilic and relatively small molecular compounds, triterpenes are generally secreted into the extracellular space. The effect of increasing triterpene efflux on the synthesis capacity remains unknown. Results: In this study, we developed a strategy to enhance triterpene efflux through manipulation of lipid components in Y. lipolytica by overexpressing the enzyme Δ9-fatty acid desaturase (OLE1) and disturbing phosphatidic acid phosphatase (PAH1) and diacylglycerol kinase (DGK1). By this strategy combined with two-phase fermentation, the highest lupeol production reported to date was achieved, where the titer in the organic phase reached 381.67 mg/L and the total production was 411.72 mg/L in shake flasks, exhibiting a 33.20-fold improvement over the initial strain. Lipid manipulation led to a twofold increase in the unsaturated fatty acid (UFA) content, up to 61-73%, and an exceptionally elongated cell morphology, which might have been caused by enhanced membrane phospholipid biosynthesis flux. Both phenotypes accelerated the export of toxic products to the extracellular space and ultimately stimulated the capacity for triterpenoid synthesis, which was proven by the 5.11-fold higher ratio of extra/intracellular lupeol concentrations, 2.79-fold higher biomass accumulation and 2.56-fold higher lupeol productivity per unit OD in the modified strains. This strategy was also highly efficient for the biosynthesis of other triterpenes and sesquiterpenes, including α-amyrin, β-amyrin, longifolene, longipinene and longicyclene. Conclusions: In conclusion, we successfully created a high-yield lupeol-producing strain via lipid manipulation. We demonstrated that the enhancement of lupeol efflux and synthesis capacity was induced by the increased UFA content and elongated cell morphology. Our study provides a novel strategy to promote the biosynthesis of valuable but toxic products in microbial cell factories.

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Section: Discussionmentioning

confidence: 99%

“…Nevertheless, terpenoids, known for their in vivo antifungal activity, are generally highly toxic to microorganisms, inducing apoptosis and having a negative impact on terpene production [3][4][5][6][7][8]. For instance, lupeol, a typical triterpenoid, caused severe damage to cell viability even at a relatively low concentration of 60 mg/L [3,8].…”

mentioning

confidence: 99%

High production of triterpenoids in Yarrowia lipolytica through manipulation of lipid components

Zhang

Bai

Peng

et al. 2020

Biotechnol Biofuels

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“…The particular need to obtain more human-compatible recombinant glycoproteins for possible use as therapeutic agents has prompted the development of glyco-engineered (aka humanized) Y. lipolytica strains, which will be evoked in Section 3.1.6. In the domain of pharma/food industry, new metabolites of interest that can be produced using GM Y. lipolytica cell factories comprise notably a large range of terpenoids (including various carotenoids) and their derivatives [63][64][65], polyketides (including flavonoids) [64], riboflavin [58] and human milk oligosaccharides [47] (cf. Section 2.3.2).…”

Section: Potential Applications Of Genetically Modified Strains: Bioproducts and Biofuelsmentioning

confidence: 99%

“…Bioprocess engineering steps will not be detailed in this review, since they have been addressed more appropriately in several previous publications who highlighted, from different examples, the importance of various external factors (temperature, pH, nutrients and oxygen availability) on Y. lipolytica growth and productivity, together with the stress that industrial conditions can exert on yeast cells [63,172,[272][273][274]. As seen in Section 2.2, this yeast benefits from a robust tolerance to a large pH range, to high salt levels and to organic solvents, all valuable assets in easing bioprocess optimization.…”

Section: Adaptative Evolution Strategies and Bioprocess Engineeringmentioning

confidence: 99%

Yarrowia lipolytica strains and their biotechnological applications: how natural biodiversity and metabolic engineering could contribute to cell factories improvement

Madzak

2021

Preprint

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Among non-conventional yeasts of industrial interest, the dimorphic oleaginous yeast Yarrowia lipolytica appears as one of the most attractive for a large range of white biotechnology applications, from heterologous proteins secretion to cell factories process development. The past, present and potential applications of wild type, traditionally improved or genetically modified Yarrowia lipolytica strains will be resumed, together with the wide array of molecular tools now available to genetically engineer and metabolically remodel this yeast. The present review will also provide a detailed description of Yarrowia lipolytica strains and highlight the natural biodiversity of this yeast, a subject little touched upon in most previous reviews. This work intends to fill this gap by retracing the genealogy of the main Yarrowia lipolytica strains of industrial interest, by illustrating the search for new genetic backgrounds and by providing data about the main publicly available strains in yeast collections worldwide. At last, it will focus on exemplifying how advances in engineering tools can leverage a better biotechnological exploitation of the natural biodiversity of Yarrowia lipolytica and of other yeasts from the Yarrowia clade.

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“…Y. lipolytica is an industrial oleaginous strain and is usually used for high-yield lipid production, up to 70% w/w dry cell weight [ 88 ]. The high efficiency of acetyl-CoA synthesis and robust lipid storage make Y. lipolytica a favorable host for the hydrophobic steroid production [ 88 – 90 ]. P. pastoris can be cultured with methanol and grow at a relatively low pH, making the fermentation process less prone to microorganism contamination [ 91 ].…”

Section: Future Perspectivementioning

confidence: 99%

Yeast as a promising heterologous host for steroid bioproduction

2020

Journal of Industrial Microbiology and Biotechnology

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With the rapid development of synthetic biology and metabolic engineering technologies, yeast has been generally considered as promising hosts for the bioproduction of secondary metabolites. Sterols are essential components of cell membrane, and are the precursors for the biosynthesis of steroid hormones, signaling molecules, and defense molecules in the higher eukaryotes, which are of pharmaceutical and agricultural significance. In this mini-review, we summarize the recent engineering efforts of using yeast to synthesize various steroids, and discuss the structural diversity that the current steroidproducing yeast can achieve, the challenge and the potential of using yeast as the bioproduction platform of various steroids from higher eukaryotes.

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Biosynthesis of terpene compounds using the non-model yeast Yarrowia lipolytica: grand challenges and a few perspectives

Cited by 35 publications

References 55 publications

High production of triterpenoids in Yarrowia lipolytica through manipulation of lipid components

High production of triterpenoids in Yarrowia lipolytica through manipulation of lipid components

Yarrowia lipolytica strains and their biotechnological applications: how natural biodiversity and metabolic engineering could contribute to cell factories improvement

Yeast as a promising heterologous host for steroid bioproduction

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