Combinatorial optimization of resveratrol production in engineered E. coli.

Resveratrol, a plant-derived polyphenolic compound with various health activities, is widely used in nutraceutical and food additives. Herein, combinatorial optimization of resveratrol biosynthetic pathway and intracellular environment of E. coli was carried out. Screening pathway genes from various species and exploring their expression pattern, we constructed initial resveratrol-producing strain. Further targeting at availability of malonyl-CoA through expressing ACC of Corynebacterium glutamicum and antisense inhibiting native fabD significantly increased resveratrol biosynthesis. Transport engineering for resveratrol secretion and molecular chaperones helping for folding heterologous enzymes were employed to improve the intracellular environments in remarkable degrees. By introducing PcTAL of Phanerochaete chrysosporium and tuning expression model of PcTAL, At4CL, and VvSTS, an engineered E. coli produced 57.77 mg/L of resveratrol from L-tyrosine. After integrating above strategies, resveratrol titer reached to 238.71 mg/L from L-tyrosine. The combinatorial optimization in this study provides a promising strategy to produce valuable natural products in heterologous expression systems.