Do mammalian cytochrome P450s exhibit multiple ligand access pathways and ligand channelling?

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Do mammalian cytochrome P450s exhibit multiple ligand access pathways and ligand channelling? / Schleinkofer, K; Sudarko, S; Winn, Peter; Luedemann, SJ; Wade, RC.

In: EMBO Reports, Vol. 6, No. 6, 01.06.2005, p. 584-589.

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Schleinkofer, K ; Sudarko, S ; Winn, Peter ; Luedemann, SJ ; Wade, RC. / Do mammalian cytochrome P450s exhibit multiple ligand access pathways and ligand channelling?. In: EMBO Reports. 2005 ; Vol. 6, No. 6. pp. 584-589.

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@article{6f72348cc7ad4327a9ccfa970c5e4eeb,
title = "Do mammalian cytochrome P450s exhibit multiple ligand access pathways and ligand channelling?",
abstract = "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.",
author = "K Schleinkofer and S Sudarko and Peter Winn and SJ Luedemann and RC Wade",
year = "2005",
month = jun
day = "1",
doi = "10.1038/sj.embor.7400420",
language = "English",
volume = "6",
pages = "584--589",
journal = "EMBO Reports",
issn = "1469-221X",
publisher = "EMBO Press",
number = "6",

}

RIS

TY - JOUR

T1 - Do mammalian cytochrome P450s exhibit multiple ligand access pathways and ligand channelling?

AU - Schleinkofer, K

AU - Sudarko, S

AU - Winn, Peter

AU - Luedemann, SJ

AU - Wade, RC

PY - 2005/6/1

Y1 - 2005/6/1

N2 - 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.

AB - 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.

U2 - 10.1038/sj.embor.7400420

DO - 10.1038/sj.embor.7400420

M3 - Article

C2 - 16028306

VL - 6

SP - 584

EP - 589

JO - EMBO Reports

JF - EMBO Reports

SN - 1469-221X

IS - 6

ER -