Science 364, 1166–1169 (2019)

During chemical synthesis, radical reactions can be facilitated by irradiation with light (photoexcitation). Biegasiewicz et al. have now found that this effect can also be extended to enzymes, demonstrating that irradiation with visible light enables certain flavin-dependent ene-reductases (EREDs) to cyclize α-chloroacetamides into γ-lactams. EREDs generally have large, substrate-promiscuous active sites, allowing them to accept a range of substrates while still providing a suitable scaffold to ensure stereoselectivity. Kinetic and spectroscopic data suggest that a complex between the substrate and the flavin hydroquinone in the enzyme active site promotes the initial electron-transfer step. Variation of the substrates and ERED homologs, occasionally with minimal mutagenesis, also affords different ring sizes and cyclization modes, some of which are difficult to access through small-molecule synthetic approaches. This method of using photoexcitation to promote alternative radical reactions in EREDs is likely also applicable to other classes of oxidoreductases and expands the toolbox of available biocatalytic reactions for forming new carbon–carbon bonds.