Expanding P450 catalytic reaction space through evolution and engineering

•Discovering enzymes for new reactions is important but challenging.•Cytochrome P450 enzymes catalyze many different chemical reactions in nature.•P450s can be engineered to catalyze reactions first discovered by synthetic chemists.•Engineering enhances the activity and selectivity of P450s in non-natural reactions. Advances in protein and metabolic engineering have led to wider use of enzymes to synthesize important molecules. However, many desirable transformations are not catalyzed by any known enzyme, driving interest in understanding how new enzymes can be created. The cytochrome P450 enzyme family, whose members participate in xenobiotic metabolism and natural products biosynthesis, catalyzes an impressive range of difficult chemical reactions that continues to grow as new enzymes are characterized. Recent work has revealed that P450-derived enzymes can also catalyze useful reactions previously accessible only to synthetic chemistry. The evolution and engineering of these enzymes provides an excellent case study for how to genetically encode new chemistry and expand biology's reaction space.