Advanced Understanding of the Electron Transfer Pathway of Cytochrome P450s

Abstract

Cytochrome P450s are heme‐thiolate enzymes that participate in carbon source assimilation, natural compound biosynthesis and xenobiotic metabolism in all kingdoms of life. P450s can catalyze various reactions by using a wide range of organic compounds, thus exhibiting great potential in biotechnological applications. The catalytic reactions of P450s are driven by electron equivalents that are sourced from pyridine nucleotides and delivered by cognate or matching redox partners (RPs). The electron transfer (ET) route from RPs to P450s involves one or more redox center‐containing domains. As the rate of ET is one of the main determinants of P450 efficacy, an in‐depth understanding of the P450 ET pathway should increase our knowledge of these important enzymes and benefit their further applications. Here, the various P450 RP systems along with current understanding of their ET routes will be reviewed. Notably, state‐of‐the‐art structural studies of the two main types of self‐sufficient P450 will also be summarized.

A Core‐Shell Cascade of Chloroperoxidase and Gold Nanoclusters for Asymmetric Hydroxylation of Ethylbenzene

“…Heme proteins, including a series of monooxygenases, [6,7] peroxygenases [8] and peroxidases, [9,10] are proven effective in direct functionalization of alkyl, aryl, benzyl and allyl C−H bonds. Chloroperoxidase (CPO), a heme‐thiolate peroxidase from Caldariomyces fumago , is of particular interest for catalyzing C−H bonds by halogenation and hydroxylation [9,11,12] because it utilizes H 2 O 2 as both oxygen and electron donor thereby circumventing the concomitant regeneration of flavoproteins and cofactors [13] . In addition to enhancing the intrinsic activity through molecular modification, it is necessary to improve the operational stability of CPO for industrial application.…”

Customized exogenous ferredoxin functions as an efficient electron carrier

“…The structural comparison showed that the TDO contained an extra domain (gray part). In previous research, a "swing domain model" of P450BM3 FMN-binding domain operated the back-and-forth motions, which was governed by a flexible hinge domain (Chen et al, 2020). That implied that TDO-Fdx might swing to a favorable position to carry out the effective electron transfer from FAD to [2Fe-2S] cluster (Figure 2a).…”

“…The reduced Fdx transfers the electron to the active center of the oxygenase to support the activation of dioxygen for biphenyl dihydroxylation. Self-sufficient P450 monooxygenases are highly active and convenient systems without partner reductase (Chen et al, 2020). The crystal structure of the self-sufficient P450 enzyme CYP116B46 has indicated that it contains the cofactor FMN to capture electrons from NADPH and RP Fdx, which has most efficient electron transfer.…”

“…The crystal structure of the self-sufficient P450 enzyme CYP116B46 has indicated that it contains the cofactor FMN to capture electrons from NADPH and RP Fdx, which has most efficient electron transfer. The direction of electron transfer NADPH-FMN-[2Fe-2S] -heme correlates with the domain arrangement, which undoubtedly provides a great help for the screening of redox partners (Zhang et al, 2020). Otherwise, Based on the flavin-based electron bifurcation theory (FBEB), the electron bifurcation phenomenon is formed by the oxidation of NADPH in the oxidoreductase complex (Demmer et al, 2015;Duan et al, 2020;Lubner et al, 2017;Schut et al, 2019;Tokmina-Lukaszewska et al, 2018;Yuly et al, 2019).…”

Modifications of diketopiperazines assembled by cyclodipeptide synthases with cytochrome P450 enzymes

“…In eukaryotes, they are usually bound to membranes, whereas bacterial members appear freely in the cytosol. They contribute a major part in carbon source assimilation, production of secondary metabolites and metabolism of xenobiotics (Chen et al 2021). P 450 s have different sizes, cofactors and electron donors as well as various shapes of substrate binding pockets.…”