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Removal of lycopene substrate inhibition enables high carotenoid productivity in Yarrowia lipolytica

文献类型： 外文期刊

作者： Ma, Yongshuo 1 ; Liu, Nian 1 ; Greisen, Per 4 ; Li, Jingbo 1 ; Qiao, Kangjian 1 ; Huang, Sanwen 2 ; Stephanopoulos, Gregory 1 ;

作者机构： 1.MIT, Dept Chem Engn, Cambridge, MA 02142 USA

2.Chinese Acad Agr Sci, Agr Genom Inst Shenzhen, Shenzhen Branch,Genome Anal Lab Minist Agr & Rura, Guangdong Lab Lingnan Modern Agr, Shenzhen 518120, Peoples R China

3.Bristol Myers Squibb, 400 Dexter Ave N, Seattle, WA 98109 USA

4.Novo Nordisk AS, Global Res, DK-2760 Malov, Denmark

期刊名称：NATURE COMMUNICATIONS （ 影响因子：17.694； 五年影响因子：17.763 ）

ISSN：

年卷期： 2022 年 13 卷 1 期

页码：

收录情况： SCI

摘要： Substrate inhibition has not been widely studied in the context of synthetic biology and metabolic engineering. Here, the authors report removal of lycopene substrate inhibition by two different strategies and enable high carotenoid productivity in Yarrowia lipolytica. Substrate inhibition of enzymes can be a major obstacle to the production of valuable chemicals in engineered microorganisms. Here, we show substrate inhibition of lycopene cyclase as the main limitation in carotenoid biosynthesis in Yarrowia lipolytica. To overcome this bottleneck, we exploit two independent approaches. Structure-guided protein engineering yields a variant, Y27R, characterized by complete loss of substrate inhibition without reduction of enzymatic activity. Alternatively, establishing a geranylgeranyl pyrophosphate synthase-mediated flux flow restrictor also prevents the onset of substrate inhibition by diverting metabolic flux away from the inhibitory metabolite while maintaining sufficient flux towards product formation. Both approaches result in high levels of near-exclusive beta-carotene production. Ultimately, we construct strains capable of producing 39.5 g/L beta-carotene at a productivity of 0.165 g/L/h in bioreactor fermentations (a 1441-fold improvement over the initial strain). Our findings provide effective approaches for removing substrate inhibition in engineering pathways for efficient synthesis of natural products.

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