Enzyme Redesign Turns Photochemistry Into a Route to Chiral Phosphorus Compounds

Chemists have long struggled to control the handedness of phosphorus-centred radicals, reactive intermediates that could unlock a valuable class of molecules but have stubbornly resisted stereocontrol. Now a team writing in Nature Catalysis reports that a nicotinamide-dependent imine reductase, an enzyme normally associated with reducing imines, has been repurposed into an asymmetric hydrophosphinylation catalyst, using light to generate P-centred radicals and steer them into chiral carbon–phosphorus bonds with high selectivity.

The work addresses a persistent gap in biocatalysis. Although non-natural photoenzymatic catalysis has broadened the range of radical reactions enzymes can perform, P-centred radicals had remained unexplored territory, and enzymes capable of catalysing chiral C–P bond formation are scarce. Phosphorus chirality matters because P-chirogenic organophosphorus compounds appear in pharmaceuticals, agrochemicals and materials, yet accessing them selectively is difficult with conventional synthetic tools.

In the reported system, photoexcited NADP+ initiates single-electron oxidation of secondary phosphine oxides, generating the elusive P-centred radicals inside the enzyme’s chiral active site. The radical then undergoes stereoselective C–P coupling in a redox-neutral manner, meaning no external stoichiometric oxidant or reductant is needed to balance the transformation. The authors describe this pathway, initiated by photoexcited NADP+, as previously unreported.

The products are tertiary phosphine oxides, and the enzyme delivers them in several stereochemical flavours. Using mutants obtained through a focused site-directed evolution strategy, the team prepared series of products bearing C-stereocentres, P-stereocentres, or both simultaneously as C/P-bistereocentres. This stereodivergence is the key advance: by selecting different enzyme variants, the same general reaction can be directed toward different chiral outcomes rather than locked into a single configuration.

Mechanistic studies underpin the claim that the radical pathway is genuine. The published figures describe experiments on the reaction’s mechanism alongside computational studies, supporting the assignment of single-electron oxidation of the substrate by the photoexcited nicotinamide cofactor as the initiating event. Such mechanistic detail matters because it distinguishes this chemistry from classical two-electron hydride transfer chemistry that imine reductases typically perform, and it explains how an enzyme built for reduction can instead host an oxidative radical process.

The significance for synthesis is considerable. Phosphine oxides are workhorses in catalysis and ligand design, and P-chiral variants are prized but hard to make enantioselectively. A biocatalytic route that controls both carbon and phosphorus stereochemistry, and that can be switched between outcomes by protein engineering, offers a modular alternative to multistep chiral synthesis. Because the reaction is redox-neutral and driven by light in the presence of a cofactor the enzyme already uses, it also fits the broader trend of merging photoredox chemistry with enzymatic catalysis.

The study, published on 30 October 2026 in Nature Catalysis, was led by Kaihao Mou and Zehua Tian as co-first authors, with a team including Weihua Xu, Xiuwen Kang, Yuyang Ma, Peixuan Zhuang, Zhenyu Lu, Jingxin Zhang, Yue Guo, Leyan Xu, Chunyang Cao, Zhiguo Wang, Bei Ding and corresponding author Qi Wu. The abstract indicates the work advances enzymatic P–C coupling and achieves divergent stereocontrol over P- and C/P-bistereocentred radical intermediates.

As with any early-stage method report, the headline results come from the authors’ own reaction development and substrate series, and the full text is behind a subscription preview, so independent replication and scope mapping across broader substrate classes will be the next test. The published figures outline reaction development for C-stereogenic products, extension to P-stereogenic and C/P-bistereogenic products, mechanistic experiments and computational analysis, giving a roadmap of how the method was validated. For now, the demonstration that a photoexcited enzyme cofactor can forge chiral bonds to phosphorus marks a notable expansion of what engineered enzymes can be asked to do.

Subject of Research: Photoenzymatic stereodivergent hydrophosphinylation using a repurposed nicotinamide-dependent imine reductase

Article Title: Photoenzymatic stereodivergent hydrophosphinylation enabled by nicotinamide-dependent imine reductases

Article References: Mou, K., Tian, Z., Xu, W., Kang, X., Ma, Y., Zhuang, P., Lu, Z., Zhang, J., Guo, Y., Xu, L., Cao, C., Wang, Z., Ding, B., & Wu, Q. (2026). Photoenzymatic stereodivergent hydrophosphinylation enabled by nicotinamide-dependent imine reductases. Nature Catalysis. https://doi.org/10.1038/s41929-026-01624-6

Image Credits: AI Generated

DOI: 10.1038/s41929-026-01624-6

Keywords: photoenzymatic catalysis, P-centred radicals, imine reductase, phosphine oxides, stereocontrol, site-directed evolution, NADP+, C–P bond formation, biocatalysis, Nature Catalysis, Photoenzymatic, stereodivergent