Redox metabolism for improving whole-cell P450-catalysed terpenoid biosynthesis

The growing preference for producing cytochrome P450-mediated natural products in microbial systems stems from the challenging nature of the organic chemistry approaches. The P450 enzymes are redox-dependent proteins, through which they source electrons from reducing cofactors to drive their activities. Widely researched in biochemistry, most of the previous studies have extensively utilised expensive cell-free assays to reveal mechanistic insights into P450 functionalities in presence of commercial redox partners. However, in the context of microbial bioproduction, the synergic activity of P450- reductase proteins in microbial systems have not been largely investigated. This is mainly due to limited knowledge about their mutual interactions in the context of complex systems. Hence, manipulating the redox potential for natural product synthesis in microbial chassis has been limited. As the potential of redox state as crucial regulator of P450 biocatalysis has been greatly underestimated by the scientific community, in this review, we re-emphasize their pivotal role in modulating the in vivo P450 activity through affecting the product profile and yield. Particularly, we discuss the applications of widely used in vivo redox engineering methodologies for natural product synthesis to provide further suggestions for patterning on P450-based terpenoids production in microbial platforms.