Metal ions program flavonolignan biosynthesis and enable photo-biohybrid production

Abiotic photocatalysis synthesizes major milk thistle flavonolignans. • Metal ions program flavonolignan regioselectivity and productivity in vitro. • Fe 3+ and Al 3+ direct radical coupling toward silychristin synthesis. • Photo-biohybrid process enables de novo flavonolignan production from sugar. • Metal-guided photocatalysis expands flavonolignan chemical diversity. Flavonolignans are pharmacologically important plant natural products whose production has been limited to extraction from natural sources. Their defining transformation, the oxidative coupling of flavonoid and phenylpropanoid precursors, was demonstrated to be enzyme-catalyzed. Here we show that milk thistle flavonolignans can also be assembled through an abiotic, light-driven process in vitro . Photocatalytic coupling of taxifolin and coniferyl alcohol generated the major natural flavonolignans, including silychristins, whose synthesis from native precursors has not previously been reproduced in vitro . Importantly, we identify environmental metal ions as programmable regulators of reaction outcome. Fe 3+ and Al 3+ selectively direct radical coupling toward silychristin formation, whereas Mn 2+ primarily enhances catalytic efficiency. Mechanistic analyses indicate that metal coordination of flavonoid substrates governs regioselective radical attack and molecular architecture of final products. Leveraging this principle, we establish a metal-programmable photocatalytic platform for the synthesis of both natural and new-to-nature flavonolignans. Integration of this abiotic chemistry with engineered Saccharomyces cerevisiae enabled de novo flavonolignan production directly from sugar in a one-pot photo-biohybrid process for the first time, establishing a versatile strategy for the sustainable production and diversification of flavonolignans.