Recent Advances in P450 Enzyme Engineering for the Production of Natural Products

Natural products exhibit a wide range of biological activities and are the crucial resources for drug development and compound modification. Cytochrome P450 enzymes (P450s, CYP) are a class of multifunctional and stereoselective biocatalysts that utilize heme as a cofactor and can be employed in the biosynthesis of natural products. With the development of biotechnology, P450s have been widely applied in the synthesis of natural products. However, several challenges still exist during the catalytic process, including the difficulties in the soluble expression of P450s, the insufficient supply of cofactor heme, the limited substrate selectivity, and the low efficiency of electron transfer. This concept systematically summarizes recent advances in P450 enzyme engineering for the synthesis of natural products. It covers the engineering strategies to improve heme supply and enhance the catalytic efficiency for various P450 enzymes and their applications in synthesizing steroids, flavonoids, alkaloids, and terpenoids. This concept provides a foundation for overcoming catalytic bottlenecks and promoting the green biomanufacturing of high‐value natural products.