Cytochrome P450 (CYP) Gene Superfamily

Abstract

Cytochrome P450, which was first named a ‘pigment in the cell’ having an absorption maximum of 450 nm when reduced and bound to carbon monoxide, was thought to be a single enzyme in the early 1960s. P450 was correlated with drug and steroid metabolism by the late 1960s and recognised eventually to comprise an ancient gene superfamily encoding numerous ubiquitous enzymes that participate in countless essential life processes. More than 12 000 P450 genes are named across all kingdoms of life. Nearly all eukaryotes require sterols in their membranes for essential fluidity and lipid‐packing characteristics. CYP51 is the sterol 14α‐demethylase that makes these sterols; thus, it is fundamental to eukaryotic life. Cytochromes P450 evolved novel functions in chordates leading to the origin of steroid hormones. In conjunction with steroid hormone receptors, these novel regulatory pathways distinguish chordates from other animals. Defects in many of the 57 human functional CYP genes are involved in some inborn errors of metabolism and other clinical diseases.

Key Concepts:

  • Cytochromes P450 (CYPs) are haeme‐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 the ER and ferredoxin (FDX) plus ferredoxin reductase (FDXR) in mitochondria.

  • CYP functions can be divided into oxidation/reduction of endogenous or exogenous compounds (e.g. drugs, chemicals, pollutants, etc.).

  • Endogenous P450 substrates are mainly lipids including steroids, lanosterol, bile acids, vitamin D, retinoic acid, eicosanoids, fatty acids and some haeme breakdown products.

  • In 2010, 13 of 57 human P450s remain as orphans without known substrates.

  • Cytochromes P450 in humans (and most vertebrates) are divided into 18 CYP gene families based on sequence similarity.

  • Polymorphism in CYP genes can alter a person's ability to metabolise drugs (poor, intermediate, efficient or ultra‐rapid metaboliser).

  • CYP2D6 and CYP3A4 are the major drug‐metabolising enzymes in humans. CYP2D6 appears to be the most polymorphic.

  • Alterations in CYP drug metabolism are often responsible for adverse drug reactions – especially when multiple drugs are taken.

  • The triazole antifungal drugs ketoconazole, fluconazole and itraconazole target the fungal CYP51 required for fungal sterol biosynthesis. Drug resistance may occur by mutations in this gene.

Keywords: metabolism of fatty acids; cholesterol; steroids; retinoids; vitamin D derivatives; bile acids; eicosanoids; metabolism of environmental pollutants; drug metabolism; monooxygenases

Figure 1.

Structural alignment of CYP102A1 from Bacillus megaterium against human CYP2A6. The structures are a VAST (Vector Alignment Search Tool) 3D comparison of human CYP2A6 (PDB code 1Z11, MMDB code 34695) in blue and B. megaterium CYP102A1 (Bm3) (PDB code 3KX5, MMDB code 82192) in fuchsia. The P450 part of Bm3 is an E‐like P450 (most like eukaryotic P450s) and the CYP2A6 structure was the best match to it from human among the VAST alignments. There is only 18% amino acid sequence identity.

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Further Reading

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Web Links

Additional links to P450 resources http://drnelson.uthsc.edu/matrix.html

Cytochrome P450 Homepage (http://drnelson.uthsc.edu/CytochromeP450.html)

Human Cytochrome P450 Alleles Nomenclature Committee Website http://www.imm.ki.se/CYPalleles

Human Cytochrome P450 Master Table http://drnelson.uthsc.edu/human.P450.table.html

More than 700 links to human P450 data can be found at the Cytochrome P450 Human Master Table http://drnelson.uthsc.edu/human.P450.table.html

Mouse P450 data is available at the Cytochrome P450 Mouse Master Table http://drnelson.uthsc.edu/mouse.P450.table.html

Rat P450 data is available at the Cytochrome P450 Rat Master Table http://drnelson.uthsc.edu/rat.P450.table.html

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Nelson, David R, and Nebert, Daniel W(Jan 2011) Cytochrome P450 (CYP) Gene Superfamily. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005667.pub2]