Protein subinteractomes of human microsomal cytochromes P450

Microsomal cytochromes P450 (micCYPs) are monooxygenases located in the endoplasmic reticulum and other endomembranes of human cells. micCYPs receive electrons from specific redox partners and perform enzymatic transformations of drugs and different endogenous substrates. The large biodiversity of micCYPs leads to the idea that protein-protein interactions (PPIs) involving micCYPs are not limited to classical redox partners. This review aims to perform a systems biology analysis of the complete set of PPIs for all 33 micCYPs studied, as well as to examine the subinteractome of each micCYP. We have retrieved 287 PPIs from interactomic databases, involving 246 unique protein interactors that share a similar profile of subcellular localization with micCYPs. The number of protein interactors per micCYP unevenly varies from one to 47. Interactors of micCYPs are involved in cellular metabolism, signal transduction, cell-cell junctions, cytoskeleton organization, and intracellular or transmembrane transport. Notably, up to one-third of all interactors belong to the latter group, half of which consists of membrane transporters of compounds, metabolites, and ions (e.g., CACNA2D1, ORAI1, SCN3B, SLC7A2, SLC19A3, and SLC11A2). The CYP2C8 subinteractome is enriched with proteins involved in autophagy; CYP2S1- ERBB2 and EPH-Ephrin signaling; CYP3A4- glucuronidation. Proteins UBC, PGRMC1, and FANCG are the most frequent common interactors across various micCYPs. Nine and 12 interactors of micCYPs are involved in phosphorylation and ubiquitination, respectively; 20 interactors are 'moonlighting' proteins that are represented in the CYP3A4 subinteractome. Furthermore, micCYPs such as CYP2C9, 3A5, 2E1, 2A6, 4F2, and 4A11 may be involved in potentially binary interactions with other micCYPs. The functional implication of these CYP-CYP pairs is likely associated with modulation of their activity. Analysis of transcriptomic data revealed that some micCYP/interactor pairs exhibit tissue-, time-, and disease-specific gene expression patterns. Drugs that are metabolized by micCYPs in some cases can influence the expression of corresponding interactors at the gene or protein levels. These findings suggest that micCYPs may play roles in functions beyond their monooxygenase activity, as indicated by the spectrum of PPIs analyzed.