Файл:P450cycle.svg

1: The substrate binds to the active site of the enzyme, in close proximity to the heme group, on the side opposite to the peptide chain. The bound substrate induces a change in the conformation of the active site, displacing a water molecule from the distal axial coordination position of the heme iron^{[#cite_note-P450Mechanism-1 [1]]} changing the state of the heme iron from low-spin to high-spin^{[#cite_note-HiResCam-2 [2]]}. This gives rise to a change in the spectral properties of the enzyme, with an increase in absorbance at 390~nm and a decrease at 420~nm. This can be measured by difference spectrometry and is referred to as the "type~I" difference spectrum (see inset graph in figure). Some substrates cause an opposite change in spectral properties, a "reverse type~I" spectrum, by processes that are as yet unclear. Inhibitors and certain substrates that bind directly to the heme iron give rise to the type~II difference spectrum, with a maximum at 430~nm and a minimum at 390~nm (see inset graph in figure). If no reducing equivalents are available, this complex remains stable, allowing the degree of binding to be determined from absorbance measurements in vitro^{[#cite_note-p450struc-3 [3]]}

2: The change in the electronic state of the active site favours the transfer

of an electron from NAD(P)H^{[#cite_note-P450pot-4 [4]]}. This takes place via the electron transfer chain, as described above, reducing the ferric heme iron to the ferrous state.

3: Molecular oxygen binds covalently to the distal axial coordination

position of the heme iron. The cysteine ligand is a better electron donor than histidine, with the oxygen consequently being activated to a greater extent than in other heme proteins. However, this sometimes allows the bond to dissociate, the so-called "decoupling reaction", releasing a reactive superoxide radical, interrupting the catalytic cycle^{[#cite_note-P450Mechanism-1 [1]]}.

4: A second electron is transferred via the electron-transport system,

reducing the dioxygen adduct to a negatively charged peroxo group. This is a short-lived intermediate state.

5: The peroxo group formed in step 4 is rapidly protonated twice by local

transfer from surrounding amino-acid side chains, releasing one mole of water, and forming a highly reactive iron(V)-oxo species^{[#cite_note-P450Mechanism-1 [1]]}.

6: Depending on the substrate and enzyme involved, P450 enzymes can

catalyse any of a wide variety of reactions. A hypothetical hydroxylation is shown in this illustration. After the product has been released from the active site, the enzyme returns to its original state, with a water molecule returning to occupy the distal coordination position of the iron nucleus. S An alternative route for mono-oxygenation is via the "peroxide shunt": interaction with single-oxygen donors such as peroxides and hypochlorites can lead directly to the formation of the iron-oxo intermediate, allowing the catalytic cycle to be completed without going through steps 3, 4 and 5^{[#cite_note-p450struc-3 [3]]}. A hypothetical peroxide "XOOH" is shown in the diagram.

C: If carbon monoxide (CO) binds to reduced P450, the catalytic cycle is

interrupted. This reaction yields the classic CO difference spectrum with a maximum at 450 nm.

1. ↑ [#cite_ref-P450Mechanism_1-0 a] [#cite_ref-P450Mechanism_1-1 b] [#cite_ref-P450Mechanism_1-2 c] Bernard Meunier, Samuël P. de Visser and Sason Shaik (2004). "Mechanism of Oxidation Reactions Catalyzed by Cytochrome P450 Enzymes". Chemical Reviews 104 (9): 3947 - 3980.
2. [#cite_ref-HiResCam_2-0 ↑] Thomas L. Poulos, Barry C. Finzel and Andrew J. Howard (1987). "High-resolution crystal structure of cytochrome P450_cam". Journal of Molecular Biology 195 (3): 687-700.
3. ↑ [#cite_ref-p450struc_3-0 a] [#cite_ref-p450struc_3-1 b] P.R. Ortiz de Montellano (Ed.) (1995) Cytochrome P450 : structure, mechanism, and biochemistry, 2nd ed., Category:New York: Plenum
4. [#cite_ref-P450pot_4-0 ↑] S. G. Sligar, D. L. Cinti, G. G. Gibson and J. B. Schenkman (1979). "Spin state control of the hepatic cytochrome P450 redox potential". Biochemical and Biophysical Research Communications 90 (3): 925-932.

Slashme at English Wikipedia

When using this image in external works, it may be cited as follows:

• Richfield, David. "Medical gallery of David Richfield 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.009. ISSN 2001-8762.