Synthetic biology-driven microbial production of folates: Advances and perspectives

With the development and application of synthetic biology, significant progress has been made in the production of folate by microbial fermentation using cell factories, especially for using generally regarded as safe (GRAS) microorganism as production host. In this review, the physiological functions and applications of folates were firstly discussed. Second, the current advances of folate-producing GRAS strains development were summarized. Third, the applications of synthetic biology-based metabolic regulatory tools in GRAS strains were introduced, and the progress in the application of these tools for folate production were summarized. Finally, the challenges to folates efficient production and corresponding emerging strategies to overcome them by synthetic biology were discussed, including the construction of biosensors using tetrahydrofolate riboswitches to regulate metabolic pathways, adaptive evolution to overcome the flux limitations of the folate pathway. The combination of new strategies and tools of synthetic biology is expected to further improve the efficiency of microbial folate synthesis.