Cytochrome P450

Molecular structure of cytochrome P450eryF (PDB: 1EGY)

The cytochromes P450 (CYP) are heme proteins with enzymatic activity ( oxidoreductases ) that occur in practically all forms of life. In animals, they were found in all organs, especially in the liver. 57 different CYPs have been found in humans. CYPs react almost exclusively as monooxygenases (one-oxygen atom carriers). The most important type of reaction is the hydroxylation of non-activated CH bonds:

${\displaystyle \mathrm {R{-}H+2e^{-}+2H^{+}+O_{2}\longrightarrow R{-}OH+H_{2}O} }$

NADH / NADPH (16 cases), flavins or flavoproteins (26 cases) or iron-sulfur proteins such as ferredoxin (5 cases) are used as reducing agents .

CYPs make an important contribution to the metabolism of water-insoluble substances through oxidation . This makes them more soluble in water and can be eliminated from the body more quickly ( biotransformation ). Both endogenous and exogenous substances (e.g. drugs) function as substrates. In addition, CYPs are involved in important steps in the synthesis of steroid hormones , prostaglandins , retinoids and vitamin D ₃ (e.g. through the CYP27B1 ).

history

In the absence of any knowledge of their function, the cytochromes P450 (P = pigment) were named after the unusual position of the Soret band of the complex with carbon monoxide at 450 nm, which was first observed by Martin Klingenberg in 1958 while working with "cytochrome b5". A first function in steroid metabolism was established in 1963 by Estabrook, Cooper and Rosenthal.

structure

Cytochrome P450 enzymes are proteins that usually consist of around 500 amino acids . The active center of the enzyme on which the catalysis takes place is an iron (III) ion, the equatorial coordination points of which are occupied by the four nitrogen atoms of a protoporphyrin IX . This heme b is linked to the protein backbone through the coordination of a cysteinator residue in one of the two axial positions of the iron center. The second axial position is occupied by a weakly bound water ligand when the enzyme is at rest.

Cytochrome P450 enzymes are usually part of a two- or three-part protein system; the redox partners are responsible for the transfer of electrons from the cofactor NAD (P) H to P450. Two-component systems predominate in eukaryotes , with a NADPH cytochrome P450 oxidoreductase (CPR) partner. In the three-component systems in prokaryotes and mitochondria , an iron-sulfur protein (ferredoxin) is usually added in addition to a flavoprotein .

Types

A separate nomenclature creates an order of the numerous subtypes of cytochrome P450. The representatives in the human body are: CYP1A1 , CYP1A2 , CYP1B1 , CYP2A6 , CYP2A7 , CYP2A13 , CYP2B6 , CYP2C8 , CYP2C9 , CYP2C18 , CYP2C19 , CYP2D6 , CYP2E1 , CYP2F1 , CYP2J2 , CYP2R1 , CYP2S1 , CYP2U1 , CYP2W1 , CYP3A4 , CYP3A5 , CYP3A7 , CYP3A43 , CYP4A11 , CYP4A22 , CYP4B1 , CYP4F2 , CYP4F3 , CYP4F8 , CYP4F11 , CYP4F12 , CYP4F22 , CYP4V2 , CYP4X1 , CYP4Z2 , CYP5A1 , CYP7A1 , CYP7B1 , CYP8A1 , CYP8B1 , CYP11A1 , CYP11B1 , CYP11B2 , CYP17A1 , CYP19A1 , CYP20A1 , CYP21A1 , CYP21A2 , CYP24A1 , CYP26A1 , CYP26B1 , CYP26C1 , CYP27A1 , CYP27B1 , CYP27C1 , CYP39A1 , CYP46A1 , CYP51A1 .

Mechanism of action in outline

The most widely used proposal for the Groves cytochrome P450 reaction cycle. The existence of the iron oxide species is controversial.

The catalytic cycle begins with the binding of a substrate molecule near the active site. This displaces the unstable water ligand. Now the active center is reduced once and then molecular oxygen is attached to the iron center. After taking up another electron and two protons, the bond of the dioxygen is split. One of the oxygen atoms is released as a water molecule, the other is transferred to the substrate. Finally, the oxidized substrate is displaced by entering water and the state of rest is restored. The reduction equivalents are provided by NADPH and a flavoprotein (e.g. NADPH cytochrome P450 reductase). In three-component systems, an iron-sulfur protein usually takes part in the electron transfer. Instead of the native system O ₂ / NADPH, hydrogen peroxide can also be used to generate the active species (see S in Fig.). The disadvantage here is that the enzyme is quickly damaged and thus loses its activity.

A disorder can lead to a cytochrome POR deficiency .

See also

• Drug interaction

literature

• Hasler JA: Human Cytochromes P450 . In: Mol Aspects Med.. . 20, 1999, pp. 1-137. doi : 10.1016 / S0098-2997 (99) 00005-9 .
• Sono M, Roach MP, Coulter ED, Dawson JH: Heme-Containing Oxygenases . In: Chem Rev.. . 96, No. 7, November 1996, pp. 2841-2888. PMID 11848843 .
• Solomon EI, Brunold TC, Davis MI, et al. : Geometric and electronic structure / function correlations in non-heme iron enzymes . In: Chem Rev.. . 100, No. 1, January 2000, pp. 235-350. PMID 11749238 .
• Guengerich FP: Reactions and significance of cytochrome P-450 enzymes . In: J. Biol. Chem. . 266, No. 16, June 1991, pp. 10019-22. PMID 2037557 .
• KJ McLean, M. Sabri, et al. a .: Biodiversity of cytochrome P450 redox systems. In: Biochem. Soc. Trans. Volume 33, Pt 4 August 2005, pp. 796-801, doi: 10.1042 / BST0330796 . PMID 16042601 . (Review).
• IG Denisov, AY Shih, SG Sligar: Structural differences between soluble and membrane bound cytochrome P450s. In: Journal of Inorganic Biochemistry . Volume 108, March 2012, pp. 150-158, doi: 10.1016 / j.jinorgbio.2011.11.026 . PMID 22244217 .

Individual evidence

1. ↑ UniProt search result CYP450 (human) by EC number
2. ↑ Estabrook RW: A passion for P450s (remembrances of the early history of research on cytochrome P450) . In: Drug Metab. Dispos. . 31, No. 12, December 2003, pp. 1461-73. doi : 10.1124 / dmd.31.12.1461 . PMID 14625342 .
3. ↑ ^{a b} Interpro: IPR001128: Cytochrome P450

Web links

Commons : Cytochrome P450  - Collection of images, videos and audio files

• The cytochrome P450 superfamily on KEGG
• PROSITE entry
• Cytochrome P450 Database Drug cytochrome interactions (Engl.)
• List of metabolized drugs, enzyme inducers, and enzyme inhibitors for each isoenzyme
• Jennifer McDowall / Interpro: Protein Of The Month: Cytochrome P450. (engl.)
• Video of the group of Nicholas Turner, University of Manchester: Expanding the toolbox of cytochrome P450s through enzyme engineering (Engl.)

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !