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

Yongshuo Ma, Nian Liu, Per Greisen, Jingbo Li, Kangjian Qiao, Sanwen Huang () and Gregory Stephanopoulos ()
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Yongshuo Ma: Massachusetts Institute of Technology
Nian Liu: Massachusetts Institute of Technology
Per Greisen: Global Research, Novo Nordisk A/S
Jingbo Li: Massachusetts Institute of Technology
Kangjian Qiao: Massachusetts Institute of Technology
Sanwen Huang: Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences
Gregory Stephanopoulos: Massachusetts Institute of Technology

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract 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 β-carotene production. Ultimately, we construct strains capable of producing 39.5 g/L β-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.

Date: 2022
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DOI: 10.1038/s41467-022-28277-w

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