Reprogramming the metabolism of oleaginous yeast for sustainably biosynthesizing the anticarcinogen precursor germacrene A

Due to the diverse structures and broad functions of terpenes, microbial biosynthesis of these compounds has been favored as a sustainable alternative to phytoextraction and chemosynthesis. Here, systematic metabolic engineering strategies were explored in the oleaginous yeast Yarrowia lipolytica fo...

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Published in:Green chemistry : an international journal and green chemistry resource : GC 2023-10, Vol.25 (2), p.7988-7997
Main Authors: Liu, Qi, Zhang, Ge, Su, Liqiu, Liu, Pi, Jia, Shiru, Wang, Qinhong, Dai, Zongjie
Format: Article
Language:English
Subjects:
Bioreactors
Biosynthesis
Cell culture
Chemosynthesis
Fermentation
Flasks
Germacrene
Green chemistry
Lipid metabolism
Lipids
Metabolic engineering
Metabolism
Mevalonate pathway
Microorganisms
Terpenes
Yeast
Yeasts
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Summary:Due to the diverse structures and broad functions of terpenes, microbial biosynthesis of these compounds has been favored as a sustainable alternative to phytoextraction and chemosynthesis. Here, systematic metabolic engineering strategies were explored in the oleaginous yeast Yarrowia lipolytica for hyperproducing sesquiterpene germacrene A which serves as an important intermediate of numerous anticarcinogens. By identifying the most efficient germacrene A synthase to date, reconstructing the endogenous mevalonate pathway and extending the cytosolic acetyl-CoA pool by regulating lipid metabolism, the resulting strain overproduced 2.794 g L −1 germacrene A in shake flasks, which represented a 38-fold improvement over the initial strain. The engineered strain was subsequently capable of producing 39 g L −1 germacrene A at a yield of 0.181 g g −1 glucose during optimized bioreactor fermentation, with this being the highest sesquiterpene production level reported to date for Y. lipolytica . These results demonstrate that reprogramming the metabolism of the host cell by systematic metabolic engineering plays an essential role in diverting its inherent metabolic fluxes for sesquiterpene biosynthesis and these approaches can be extensively applied for synthesizing natural terpenes. The highest titer of the anticancer precursor sesquiterpene germacrene A was observed in oleaginous yeast using multi-layered systematic metabolic engineering strategies.
ISSN:1463-9262
1463-9270
DOI:10.1039/d3gc01661g