From Tradition to Innovation: The Transition of P450 Enzyme Catalysis via Light-Driven Electron Transfer

Cytochrome P450s are heme-thiolate enzymes that play a pivotal role in pharmaceutical and biosynthetic applications due to their proficiency in the oxyfunctionalization of unactivated carbon atoms. Although extensive engineering efforts were dedicated to their application for novel non-natural substrates and reactions, their industrial potential is currently limited due to NAD(P)H dependence and complex redox partner requirements. Light-driven catalysis has emerged as a promising alternative, alleviating the need for cumbersome cofactor recycling, thereby facilitating economical and environmentally friendly biosynthesis. This review systematically explores the transition from conventional NADPH-driven P450 systems to innovative light-driven approaches. We analyze the photocatalytic principles underpinning this shift, discussing the catalytic mechanism of P450 enzymes and strategies for regenerating cofactors using light. A major focus is placed on direct electron transfer mechanisms between photosensitizers and P450 enzymes followed by a critical discussion of their current limitations, with particular emphasis on the pivotal challenge of enhancing the coupling efficiency of photocatalytic electron. Therefore, this review aims to further explore intricate catalytic mechanisms powered by light, including the strategic design of electron transfer pathways in two types of semiartificial systems, as well as advanced characterization techniques for probing the interactions between photosensitizers and P450 enzymes. Finally, strategies for system optimization to improve the overall stability and applicability are also outlined, underscoring the importance of continuous innovation in reactor design and operational efficiency for biomanufacturing. This transformative shift heralds a promising era in biocatalysis, in which light-driven systems offer unprecedented opportunities for eco-friendly chemistry.