Cytochrome P450 ( CYP ) Gene Superfamily

Abstract

Cytochrome P450, named in the 1960s as a ‘chromatic (coloured) pigment in the cell’ having an absorption maximum of 450 nm when reduced and bound to carbon monoxide, was originally thought to be a single enzyme. P450 was correlated with drug and steroid metabolism; eventually, P450 was recognised to comprise an ancient gene superfamily encoding numerous ubiquitous enzymes that participate in countless essential life processes. Almost 55 000 P450 genes have now been named across all kingdoms of life. Nearly all eukaryotes require sterols in their membranes for essential fluidity and lipid‐packing properties; CYP51 (sterol 14α‐demethylase) synthesises these sterols and, therefore, is fundamental to eukaryotic life and most likely the ancestral P450 gene from which all others were derived. Cytochromes P450 evolved novel functions in chordates, leading to the beginning of steroid hormones. In conjunction with steroid hormone receptors, these novel regulatory pathways distinguish chordates from other animals. Among human's 57 functional CYP genes, DNA variants can cause a number of inborn errors of metabolism, other clinical diseases, and important differences in drug response. Key Concepts Cytochromes P450 (CYPs) are haem‐containing membrane proteins in the endoplasmic reticulum (ER) or mitochondrial inner membrane. Most CYPs require a source of electrons from an electron transfer chain to function: NADPH‐cytochrome P450 oxidoreductase (POR) in ER and ferredoxin (FDX) plus ferredoxin reductase (FDXR) in mitochondria. CYP functions can be divided into oxidation/reduction of endogenous compounds and foreign chemicals (e.g. drugs, environmental pollutants). Endogenous P450 substrates include mostly lipids (steroids, lanosterol, bile acids, vitamin D, retinoic acid, eicosanoids and other lipid mediators), fatty acids and haem breakdown products. As of 2017, at least six of 57 human P450s still remain ‘orphans’ without agreed‐upon identifiable substrates. Cytochromes P450 in humans (and most vertebrates) are divided into 18 CYP gene families – based on amino acid sequence similarity. CYP gene polymorphisms can alter a person's ability to metabolise drugs (poor, intermediate, efficient or ultrarapid metabolisers). Human CYP3A4 and CYP2D6 are the two major drug‐metabolising enzymes. Removal of mouse Cyp genes and replacement with their human CYP orthologous genes will lead to a better understanding of P450 metabolism that is relevant to clinical pharmacology. Alterations in CYP drug metabolism are often responsible for adverse drug reactions – especially when multiple drugs are taken. Triazole antifungal drugs (ketoconazole, fluconazole and itraconazole) target the CYP51 required for fungal sterol biosynthesis; mutations in this gene can lead to triazole drug resistance.

Fungal Cytochrome P450s and the P450 Complement (CYPome) of Fusarium graminearum

“…CYP nomenclature is mainly based on amino acid sequence identity; 40% identity or greater places CYPs in the same family and greater than 55% identity places CYPs in the same subfamily [ 7 ]. As mentioned above, CYPs are key enzymes in many fungal processes, and classifiable into multigene families, CYP51–CYP69, CYP501–CYP699, and CYP5001–CYP6999 [ 15 , 22 , 23 ] ( Table 1 ).…”

“…Organisms vary in the number of CYP genes they possess. The reference human genome contains 57 CYP genes and 58 pseudogenes, which are distributed into 18 families [ 7 ]. The function of human CYPs has been extensively studied since 1960, particularly with respect to xenobiotic and drug metabolism [ 8 ].…”

Chance and predictability in evolution: The genomic basis of convergent dietary specializations in an adaptive radiation

“…It is well known that heavy metal‐associated toxicity is largely due to damage to the oxidative tissue caused by the accumulation of reactive oxygen species in the cell (Schieber & Chandel, ). Noticeably, among the upregulated MGE candidates (and those regulated in only one of the specialists), we found members of family 3 of the P450 cytochromes, a group of monooxygenases that constitute the largest and most functionally diverse class of insect detoxification enzymes and that have been implicated in the oxidative detoxification of furanocoumarins, alkaloids, plant secondary metabolites and synthetic insecticides (Nelson & Nebert, ). Additionally, we identified among the candidates several esterases, a group of proteins with a role in heavy metal and pesticide detoxification that have been used as biomarkers of metal exposure in many organisms, including spiders (Wilczek, Babczyńska, Migula, & Wencelis, ).…”

“…Noticeably, among the upregulated MGE candidates (and those regulated in only one of the specialists), we found members of family 3 of the P450 cytochromes, a group of monooxygenases that constitute the largest and most functionally diverse class of insect detoxification enzymes and that have been implicated in the oxidative detoxification of furanocoumarins, alkaloids, plant secondary metabolites and synthetic insecticides (Nelson & Nebert, 2011).…”

The Biosynthesis of Enzymatically Oxidized Lipids

“…Here, we focus on lipid metabolism which involves members of most human CYP families. For an extensive review, the reader is referred to Nelson and Nebert (166).…”