Premium
Do mammalian cytochrome P450s show multiple ligand access pathways and ligand channelling?
Author(s) -
Schleinkofer Karin,
Winn Peter J,
Lüdemann Susanne K,
Wade Rebecca C
Publication year - 2005
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/sj.embor.7400420
Subject(s) - cytochrome p450 , biochemistry , enzyme , substrate (aquarium) , cytochrome , ligand (biochemistry) , chemistry , biology , microbiology and biotechnology , receptor , ecology
Understanding substrate binding and product release in cytochrome P450 (CYP) enzymes is important for explaining their key role in drug metabolism, toxicity, xenobiotic degradation and biosynthesis. Here, molecular simulations of substrate and product exit from the buried active site of a mammalian P450, the microsomal CYP2C5, identified a dominant exit channel, termed pathway (pw) 2c. Previous simulations with soluble bacterial P450s showed a different dominant egress channel, pw2a. Combining these, we propose two mechanisms in CYP2C5: (i) a one‐way route by which lipophilic substrates access the enzyme from the membrane by pw2a and hydroxylated products egress along pw2c; and (ii) a two‐way route for access and egress, along pw2c, for soluble compounds. The proposed differences in substrate access and product egress routes between membrane‐bound mammalian P450s and soluble bacterial P450s highlight the adaptability of the P450 fold to the requirements of differing cellular locations and substrate specificity profiles.