Cytochrome P450

The cytochrome P450 ( CYP) are heme proteins with enzymatic activity ( oxidoreductases ) which occur in virtually all forms of life. In animals, they were detected in all organs, especially the liver. In humans, 60 different CYPs were found. CYPs react almost exclusively as monooxygenases (one oxygen atom - transfer agent ). The most important type of reaction is the hydroxylation of non-activated CH bonds:

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

CYPs play an important role in the metabolism of water-insoluble substances by oxidation. They will thus become more water soluble and can be excreted rapidly from the body ( biotransformation ). Suitable substrates, both endogenous and exogenous substances (eg, drugs). In addition, CYPs are involved in key steps in the synthesis of steroid hormones, prostaglandins, retinoids and vitamin D3 ( for example, by CYP27B1 ).

History

The cytochromes P450 ( P = pigment) have been appointed in the absence of any knowledge about their function by the unusual position of the Soret band of the complex with carbon monoxide at 450 nm, which was first observed by Martin Klingenberg 1958 at work with " cytochrome b5 ". A first function in steroid metabolism could be saved in 1963 by Estabrook, Cooper and Rosenthal.

Structure

Cytochrome P450 enzymes are proteins, usually consisting of about 500 amino acids. The active site of the enzyme where catalysis takes place, is an iron (III ) ion, the equatorial coordination sites are occupied by the four nitrogen atoms of protoporphyrin IX. This heme b linked by the coordination of a Cysteinatorestes in one of the two axial positions of the iron center to the protein backbone. The second axial position is occupied in the resting state of the enzyme by a water ligand weakly bound.

Cytochrome P450 enzymes are usually part of a two - or three-part system protein; the redox partners are responsible for the transfer of electrons from the cofactor NAD (P ) H to P450. In eukaryotes Zweikomponentsysteme prevail, with an NADPH - cytochrome P450 oxidoreductase (CPR ) as a partner. The Dreikomponentsystemen in prokaryotes and mitochondria comes next to a flavoprotein still mostly an iron - sulfur protein ( ferredoxin ) was added.

Types

A separate nomenclature establishes 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, CYP7A1, CYP7B1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17A1, CYP19A1, CYP20A1, CYP21A1, CYP21A2, CYP24A1, CYP26A1, CYP26B1, CYP26C1, CYP27A1, CYP27B1, CYP27C1, CYP39A1, CYP46A1, CYP51A1.

Mechanism of action in broad terms

The catalytic cycle begins with the binding of a substrate molecule in the vicinity of the active site. Thus, the labile Wasserligand is displaced. Now the active site is reduced once and then annealed molecular oxygen to the iron center. After receiving another electron and two protons, the binding of dioxygen is cleaved. One of the oxygen atoms is given here as a water molecule, and the other transferred to the substrate. Finally, the oxidized substrate is displaced by incoming water and the rest state is restored. The reducing equivalents may be provided in this case and a flavoprotein NADPH (e.g., NADPH-cytochrome P450 reductase). In three-component systems usually still participates in an iron - sulfur protein in the electron transfer. Can O2/NADPH Instead of the native system and hydrogen peroxide are used to generate the active species (see S in Fig.) The disadvantage here is that the enzyme quickly takes damage and thus loses its activity.