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

Abstract

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. 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. Thus, a longstanding challenge in the field of biologically mediated catalysis has been to develop enzymes with new catalytic functions. 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. 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 accessing new reactivity from existing enzymes simply by using the excited states of common biological co-factors. This represents a departure from existing light-driven biocatalytic techniques, which are typically explored in the context of co-factor regeneration.

Opportunities and challenges for combining chemo- and biocatalysis

“…Ketoreductase activity was transformed into an initiator of radicals and a source of 'chiral' hydrogen atoms. This occurred on irradiation of the nicotinamide cofactor and led to enantioselective dehalogenation of racemic halolactones 85 . In a second example, the scope of this electron transfer capability was recently expanded to ene-reductases 86 .…”

“…Recently, Jeschek et al demonstrated the power of the streptavidin concept by developing a Hoveyda-Grubbs second-generation Ru catalyst containing metalloenzyme for in vivo metathesis in the periplasm of E. coli 84 . A similar strategy for accessing non-natural enzyme activity, via application of a natural cofactor, was utilized by Hyster 85,86 . Ketoreductase activity was transformed into an initiator of radicals and a source of 'chiral' hydrogen atoms.…”

Photoenzymes and Related Topics: An Update

“…Nicotinamide‐dependent enzymes are not known to act as photoenzymes under natural conditions but can be used as such and thereby mediate novel reactions. As an example, ketoreductase can be transformed from a carbonyl reductase into an enzyme that produces chiral lactones instead of alcohols from racemic lactones (Fig. ).…”

Exploiting Cofactor Versatility to Convert a FAD‐Dependent Baeyer–Villiger Monooxygenase into a Ketoreductase

“…[1] In contrast to traditional organometallic catalysts,they offer attractive alternatives due to their low toxicity and mild reaction conditions.H owever,i nm ost cases, enzymes catalyze only their respective natural reaction types.I nducing additional reactivities,r esulting in enzymatic promiscuity,r emains ag reat challenge. [3][4][5][6] Fore xample,n icotinamide-dependent ketoreductases were employed to catalyze asymmetric dehalogenation by irradiating with light. [3][4][5][6] Fore xample,n icotinamide-dependent ketoreductases were employed to catalyze asymmetric dehalogenation by irradiating with light.…”