Removal of lycopene substrate inhibition enables 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…

• SA
  Singapore-MIT Alliance for Research and Technology Centre

  Award: 6916236
• NK
  National Key Research and Development Program of China

  Award: 2018YFA0901800