メチル化レスベラトロールの改変された大腸菌における生産性向上とその抗がん活性

Nguyen Quang Huy^1,2, Quyen My Linh¹, Nguyen Thi An Hoa²

¹National Key Laboratory of Enzyme and Protein Technology, University of Science, Vietnam National University, Hanoi (VNU), 334 Nguyen Trai, Thanh Xuan, Hanoi, 10000 Vietnam.

|December 26, 2025

Abstract:

Resveratrol, a prominent member of the plant-derived stilbenoid family, exhibits diverse biological and pharmaceutical activities. Its methylated derivatives possess enhanced attributes compared to the parent compound, such as improved stability and bioavailability. Although resveratrol analogs are widely used in healthcare and industrial applications, their current production relies predominantly on plant extraction, which often leads to low yields and inconsistent product quality. Microbial biosynthesis offers a promising alternative to chemical synthesis and plant-based extraction. Furthermore, gene expression regulation of engineered microbes allows cells to respond to their environment and maintain proper cellular function, which results in improved target products. In this study, we developed synthetic gene clusters comprising O-methyltransferase from Streptomyces avermitilis (SaOMT2) and S-adenosylmethionine (SAM) synthase from Escherichia coli (E. coli) (EcMetK), resulting in the engineered E. coli biosynthesis of methylated resveratrol. The engineered C2 strain, in which both genes were individually regulated by T7 promoters and ribosome binding site (RBS), demonstrated a 6.1-fold increase in 4'-O-methylresveratrol production compared to the control strain C0 harboring SaOMT2. Optimization of culture conditions, including medium composition and substrate concentration, further enhanced bioconversion efficiency. The bioproductivity of 4'-O-methylresveratrol production was obtained as 476.72 µM (~ 115.485 mg/L) at 36 h in a 5-L fermentor. Importantly, 4'-O-methylresveratrol exhibited stronger anticancer activity than resveratrol, with significant cytotoxic effects observed against A549 (lung carcinoma) and HepG2 (liver carcinoma) cell lines. To our knowledge, this is the first report demonstrating the anticancer potential of 4'-O-methylresveratrol produced via microbial biosynthesis.

Supplementary Information:

The online version contains supplementary material available at 10.1007/s13205-025-04449-5.

キーワード:

4'-O-メチルレスベラトロール抗がん活性大腸菌メチルトランスフェラーゼレスベラトロール

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