APPLICATIONS OF TECHNOLOGY:
High-value products using methylmalonyl-CoA as substrate:
- Erythromycin (antibiotic) and spinosyn (insecticide)
- Germicidin, which has significant inhibitory activity on hexokinase which is expressed at a high level in cancer cells
- Novel recyclable materials
- Flavors and fragrances
- Commodity or specialty chemicals
- Improved titer, rate, and yield (TRY) of polyketide biosynthesis
Polyketides produced by fungi, bacteria, and plants are clinically relevant due to their antibiotic, anticancer, antifungal, antiparasitic, and immunosuppressive properties. One host engineering strategy is to maximize malonyl-CoA production, a precursor for polyketide synthesis. Another crucial polyketide precursor is methylmalonyl-CoA, however it is not widespread in bacterial hosts.
Corynebacterium glutamicum, is a promising bacterial host for production of valuable polyketides. However, increasing methylmalonyl-CoA production through propionate addition inhibits the growth of C. glutamicum.
Researchers at Berkeley Lab and the Joint BioEnergy Institute have determined the metabolic basis of propionate induced growth inhibition in C. glutamicum. When genes that enabled catabolism of propionyl-CoA and methylmalonyl-CoA were deleted, and genes encoding methylmalonyl-CoA-dependent polyketide synthases were integrated, growth inhibition was alleviated.
Using adaptive laboratory evolution (ALE) in the presence of propionate, the researchers increased the titer of germicidin, a pyrone-derived polyketide, over 18-fold, and thoroughly eliminated growth inhibition in propionate medium. Further, several different polyketide synthase systems were expressed in C. glutamicum, and in all cases polyketide production was correlated with faster growth in propionate.
Additional research will confirm that the system is generalizable to additional species.
- Robert Haushalter
- Chunjun Zhan
- Jay Keasling
FOR MORE INFORMATION:
Zhan, C., Lee, N., Lan, G. et al. Improved polyketide production in C. glutamicum by preventing propionate-induced growth inhibition. Nat Metab 5, 1127–1140 (2023). https://doi.org/10.1038/s42255-023-00830-x
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