Metabolic engineering of Yarrowia lipolytica for improving squalene production

Tang, Wenyan; Wang, Dongping; Tian, Yun; Fan, Xiaojun; Wang, Chong; Lu, Xiangyang; Li, Pei-Wang; Ji, Xiao‐Jun; Liu, Huhu

doi:10.1016/j.biortech.2020.124652

Cited by 57 publications

(48 citation statements)

References 48 publications

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“…Y. lipolytica has been previously engineered for the production of various high‐value terpenoids including β‐farnesene, [ 30 ] β‐carotene, [ 16 ] lycopene, [ 26 ] astaxanthin, [ 31 ] betulinic acid, [ 32 ] (‐)‐α‐bisabolol [ 33 ] and so on. [ 34 ] Experimental results such as β‐carotene have reached a titer of 6.5 g L ‐1 (the highest reported so far) after 122 h, [ 24 ] indicate that Y. lipolytica can be engineered using synthetic biology and metabolic engineering to produce terpenoids on an industrial level.…”

Section: Discussionmentioning

confidence: 99%

Engineering the oleaginous yeast Yarrowia lipolytica for β‐farnesene overproduction

Shi

Zhu³

et al. 2021

Biotechnology Journal

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β‐farnesene is a sesquiterpenoid with various industrial applications which is now commercially produced by a Saccharomyces cerevisiae strain obtained by random mutagenesis and genetic engineering. We rationally designed a genetically defined Yarrowia lipolytica through recovery of L‐leucine biosynthetic route, gene dosage optimization of β‐farnesene synthase and disruption of the competition pathway. The resulting β‐farnesene titer was improved from 8 to 345 mg L‐1. Finally, the strategy for decreasing the lipid accumulation by individually and iteratively knocking out four acyltransferases encoding genes was adopted. The result displayed that β‐farnesene titer in the engineered strain CIBT6304 in which acyltransferases (DGA1 and DGA2) were deleted increased by 45% and reached 539 mg L‐1 (88 mg g‐1 DCW). Using fed‐batch fermentation, CIBT6304 could produce the highest β‐farnesene titer (22.8 g L‐1) among the genetically defined strains. This study will provide the foundation of engineering Y. lipolytica to produce other terpenoids more cost‐efficiently.

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Section: Discussionmentioning

confidence: 99%

Engineering the oleaginous yeast Yarrowia lipolytica for β‐farnesene overproduction

Shi

Zhu³

et al. 2021

Biotechnology Journal

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“… Knock out PAH1 [ 33 ] Aedicagenic-28-O-glucoside 27.1 mg/L Knock out PAH1 [ 33 ] Artemisinic acid N.A. Knock out PAH1 [ 33 ] Squalene 634 mg/L Overexpression of INO2 [ 35 ] Ginsenoside 12.1 mg/L Overexpression of INO2 [ 35 ] Lipid droplet Y. Lipolytica Lycopene 16 mg/g Strengthen the isoprenoid biosynthesis pathway and block the β-oxidation pathway [ 47 ] Squalene 731.18 mg/L Co-overexpression of tHMG1 and DGA1 [ 53 ] S. cerevisiae Squalene 445.6 mg/L Co-overexpression of tHMG1 and DGA1 [ 54 ] Lycopene 2.37 g/L (73.3 mg/g) Strengthen the TAG pathway and modulate TAG fatty acyl composition [ 49 ] Ginsenoside …”

Section: Compartmentalization Strategies For Effective Synthesis Of T...mentioning

confidence: 99%

Compartmentalization and transporter engineering strategies for terpenoid synthesis

Jin

Xia²,

Liu

et al. 2022

Microb Cell Fact

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Microbial cell factories for terpenoid synthesis form a less expensive and more environment-friendly approach than chemical synthesis and extraction, and are thus being regarded as mainstream research recently. Organelle compartmentalization for terpenoid synthesis has received much attention from researchers owing to the diverse physiochemical characteristics of organelles. In this review, we first systematically summarized various compartmentalization strategies utilized in terpenoid production, mainly plant terpenoids, which can provide catalytic reactions with sufficient intermediates and a suitable environment, while bypassing competing metabolic pathways. In addition, because of the limited storage capacity of cells, strategies used for the expansion of specific organelle membranes were discussed. Next, transporter engineering strategies to overcome the cytotoxic effects of terpenoid accumulation were analyzed. Finally, we discussed the future perspectives of compartmentalization and transporter engineering strategies, with the hope of providing theoretical guidance for designing and constructing cell factories for the purpose of terpenoid production.

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“…Similar examples were also observed in increasing campesterol and squalene synthesis by improving the lipid content in engineered Y. lipolytica. 93,114 However, it should be noted that although lipids provide a space for the accumulation of hydrophobic terpenoids, excessive lipid synthesis must deplete the acetyl-CoA pools, which can in turn limit terpenoid production. The second strategy is contrary to the first one.…”

Section: Enhancing the Precursor Flux By Regulating Thementioning

confidence: 99%

Advanced Strategies for the Synthesis of Terpenoids in Yarrowia lipolytica

Wang

et al. 2021

J. Agric. Food Chem.

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Terpenoids are an important class of secondary metabolites that play an important role in food, agriculture, and other fields. Microorganisms are rapidly emerging as a promising source for the production of terpenoids. As an oleaginous yeast, Yarrowia lipolytica contains a high lipid content which indicates that it must produce high amounts of acetyl-CoA, a necessary precursor for the biosynthesis of terpenoids. Y. lipolytica has a complete eukaryotic mevalonic acid (MVA) pathway but it has not yet seen commercial use due to its low productivity. Several metabolic engineering strategies have been developed to improve the terpenoids production of Y. lipolytica, including developing the orthogonal pathway for terpenoid synthesis, increasing the catalytic efficiency of terpenoids synthases, enhancing the supply of acetyl-CoA and NADPH, expressing rate-limiting genes, and modifying the branched pathway. Moreover, most of the acetyl-CoA is used to produce lipid, so it is an effective strategy to strike a balance of precursor distribution by rewiring the lipid biosynthesis pathway. Lastly, the latest developed non-homologous end-joining strategy for improving terpenoid production is introduced. This review summarizes the status and metabolic engineering strategies of terpenoids biosynthesis in Y. lipolytica and proposes new insights to move the field forward.

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Metabolic engineering of Yarrowia lipolytica for improving squalene production

Cited by 57 publications

References 48 publications

Engineering the oleaginous yeast Yarrowia lipolytica for β‐farnesene overproduction

Engineering the oleaginous yeast Yarrowia lipolytica for β‐farnesene overproduction

Compartmentalization and transporter engineering strategies for terpenoid synthesis

Advanced Strategies for the Synthesis of Terpenoids in Yarrowia lipolytica

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