Promoter Engineering and Two-Phase Whole-Cell Catalysis Improve the Biosynthesis of Naringenin in E. coli

Naringenin and its analogues are important flavonoids with various health benefits such as anti-inflammatory, antibacterial, and anticancer activities. Biosynthesis of naringenin using microbial cell factories is often hampered by the pool of intracellular malonyl-CoA and its inherent toxicity to host cells. Here, we investigated promoter engineering and two-phase whole-cell catalysis for improving the production of naringenin. A total of 357 T7-derived promoters were obtained and utilized to fine-tune acetyl-CoA carboxylase expression for enhanced intracellular malonyl-CoA in Escherichia coli, resulting in increased bioproduction by 62.0% compared to the original strain. Furthermore, through two-phase whole-cell catalysis using selected isopropyl myristate, the naringenin titer increased to 3001.7 mg L^–1. Additionally, naringenin and its analogue homoeriodictyol showed significant anticancer activity against ID8, MC38, HepG2, B16–F10, and MDA-MB-231 cancer cells. This study provides an efficient strategy for naringenin biosynthesis and implies the potential of naringenin analogues for further drug development.