Accessing non-natural reactivity by irradiating nicotinamide-dependent enzymes with light

hotoexcitation of a catalytic enzyme enzyme’s co-factor is shown to change the reactivity of the enzyme, enabling it to carry out a non-natural enantioselective dehalogenation of lactone molecules. New activity for nicotinamide-dependent enzymes Enzymatic catalysis offers high selectivity and efficiency for specific chemical reactions in complex environments, but these reactions are limited to those found in nature. Todd Hyster and colleagues report a new method for altering the catalytic behaviour of an enzyme, using the photoexcited state of its cofactor. Nicotinamide-dependent ketoreductases are transformed from a hydride source into a radical initiator and chiral hydrogen atom source. Using the new reactivity of the ketoreductase, the authors carry out enantioselective dehalogenation of lactones by irradiation with visible light, a challenging transformation by traditional small-molecule catalysis. Enzymes are ideal for use in asymmetric catalysis by the chemical industry, because their chemical compositions can be tailored to a specific substrate and selectivity pattern while providing efficiencies and selectivities that surpass those of classical synthetic methods 1 . However, enzymes are limited to reactions that are found in nature and, as such, facilitate fewer types of transformation than do other forms of catalysis 2 . Thus, a longstanding challenge in the field of biologically mediated catalysis has been to develop enzymes with new catalytic functions 3 . Here we describe a method for achieving catalytic promiscuity that uses the photoexcited state of nicotinamide co-factors (molecules that assist enzyme-mediated catalysis). Under irradiation with visible light, the nicotinamide-dependent enzyme known as ketoreductase can be transformed from a carbonyl reductase into an initiator of radical species and a chiral source of hydrogen atoms. We demonstrate this new reactivity through a highly enantioselective radical dehalogenation of lactones—a challenging transformation for small-molecule catalysts 4 , 5 , 6 , 7 . Mechanistic experiments support the theory that a radical species acts as an intermediate in this reaction, with NADH and NADPH (the reduced forms of nicotinamide adenine nucleotide and nicotinamide adenine dinucleotide phosphate, respectively) serving as both a photoreductant and the source of hydrogen atoms. To our knowledge, this method represents the first example of photo-induced enzyme promiscuity, and highlights the potential for