Microbial Whole-Cell Biocatalysis for Phloretin Production from Naringenin

Phloretin, a dihydrochalcone with pharmaceutical and nutraceutical applications, is traditionally extracted from plants with limited efficiency. In this study, we report a bioconversion pathway for phloretin production from naringenin in Lactobacillus plantarum. The biosynthetic route was established by screening heterologous iron–sulfur cluster-containing enoate reductases and coexpressing flavin reductases and formate dehydrogenases, which provided dual NADH–FAD cofactor regeneration. Promoter engineering, along with the targeted overexpression of iron uptake genes and optimized iron concentrations, increased the phloretin titer. Structure-guided semirational design of enoate reductase identified the D656R mutant, and a phloretin titer of 70.53 mg/L was achieved, representing the first report of flavonoid biosynthesis in L. plantarum. This work offers L. plantarum as a promising host for the production of phloretin and its derivatives.