Behavior of human cytochromes P450 on lipid membranes
Language English Country United States Media print-electronic
Document type Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
PubMed
23987570
DOI
10.1021/jp4059559
Knihovny.cz E-resources
- MeSH
- Aryl Hydrocarbon Hydroxylases chemistry MeSH
- Time Factors MeSH
- Cytochrome P-450 CYP1A2 chemistry MeSH
- Cytochrome P-450 CYP3A chemistry MeSH
- Cytochrome P-450 CYP2A6 MeSH
- Cytochrome P-450 CYP2C9 MeSH
- Phosphatidylcholines chemistry MeSH
- Heme chemistry MeSH
- Catalytic Domain MeSH
- Protein Conformation MeSH
- Humans MeSH
- Lipid Bilayers chemistry MeSH
- Solvents chemistry MeSH
- Molecular Dynamics Simulation MeSH
- Cytochrome P-450 Enzyme System chemistry MeSH
- Water chemistry MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
- Names of Substances
- 1,2-oleoylphosphatidylcholine MeSH Browser
- Aryl Hydrocarbon Hydroxylases MeSH
- CYP1A2 protein, human MeSH Browser
- CYP2C9 protein, human MeSH Browser
- CYP3A4 protein, human MeSH Browser
- Cytochrome P-450 CYP1A2 MeSH
- Cytochrome P-450 CYP3A MeSH
- Cytochrome P-450 CYP2A6 MeSH
- Cytochrome P-450 CYP2C9 MeSH
- Phosphatidylcholines MeSH
- Heme MeSH
- Lipid Bilayers MeSH
- Solvents MeSH
- Cytochrome P-450 Enzyme System MeSH
- Water MeSH
Human cytochromes P450 (CYPs) are membrane-anchored enzymes involved in biotransformation of many marketed drugs. We constructed atomic models of six human CYPs (CYP1A2, 2A6, 2C9, 2D6, 2E1, and 3A4) anchored to a lipid bilayer to investigate the positions and orientations of CYPs on a membrane. We equilibrated the models by molecular dynamics simulations on a 100+ ns time scale. Catalytic domains of all studied CYPs were found to be partially immersed in the lipid bilayer, whereas the N-terminal part and F'/G' loop are deeply immersed. The proximal side of the enzyme faces the cytosol, whereas the distal side, where openings of substrate access and product release channels to the active site are primarily located, points toward the lipid bilayer. Access channels with openings in the vicinity of the B/C and F/G loops are typically positioned below the lipid head groups, whereas the solvent channel points toward the membrane-water interface. We found that the access channel opening positions match the preferred substrate positions, whereas the product release channel exit positions correspond closely with the positions of the products. This may indicate that membrane-anchored CYPs have evolutionarily adapted to facilitate uptake of nonpolar substrates from the membrane and uptake/release of polar substrates or products from/to the membrane-water interface.
References provided by Crossref.org
ChannelsDB 2.0: a comprehensive database of protein tunnels and pores in AlphaFold era
Uncovering of cytochrome P450 anatomy by SecStrAnnotator
The Role of Protein-Protein and Protein-Membrane Interactions on P450 Function