Title : Concurrent cooperativity and substrate inhibition in the epoxidation of carbamazepine by cytochrome P450 3A4 active site mutants inspired by molecular dynamics simulations.

Pub. Date : 2015 Jan 27

PMID : 25545162






12 Functional Relationships(s)
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1 Concurrent cooperativity and substrate inhibition in the epoxidation of carbamazepine by cytochrome P450 3A4 active site mutants inspired by molecular dynamics simulations. Carbamazepine cytochrome P450 family 3 subfamily A member 4 Homo sapiens
2 Cytochrome P450 3A4 (CYP3A4) is the major human P450 responsible for the metabolism of carbamazepine (CBZ). Carbamazepine cytochrome P450 family 3 subfamily A member 4 Homo sapiens
3 Cytochrome P450 3A4 (CYP3A4) is the major human P450 responsible for the metabolism of carbamazepine (CBZ). Carbamazepine cytochrome P450 family 3 subfamily A member 4 Homo sapiens
4 Cytochrome P450 3A4 (CYP3A4) is the major human P450 responsible for the metabolism of carbamazepine (CBZ). Carbamazepine cytochrome P450 family 3 subfamily A member 4 Homo sapiens
5 Cytochrome P450 3A4 (CYP3A4) is the major human P450 responsible for the metabolism of carbamazepine (CBZ). Carbamazepine cytochrome P450 family 3 subfamily A member 4 Homo sapiens
6 To explore the mechanisms of interactions of CYP3A4 with this anticonvulsive drug, we carried out multiple molecular dynamics (MD) simulations, starting with the complex of CYP3A4 manually docked with CBZ. Carbamazepine cytochrome P450 family 3 subfamily A member 4 Homo sapiens
7 On the basis of these simulations, we engineered CYP3A4 mutants I369F, I369L, A370V, and A370L, in which the productive binding orientation was expected to be stabilized, thus leading to increased turnover of CBZ to the 10,11-epoxide product. Carbamazepine cytochrome P450 family 3 subfamily A member 4 Homo sapiens
8 Evaluation of the kinetics profiles of CBZ epoxidation demonstrate that CYP3A4-containing bacterial membranes (bactosomes) as well as purified CYP3A4 (wild-type and mutants I369L/F) exhibit substrate inhibition in reconstituted systems. Carbamazepine cytochrome P450 family 3 subfamily A member 4 Homo sapiens
9 MD simulations with two to four CBZ molecules provide evidence that the substrate-binding pocket of CYP3A4 can accommodate more than one molecule of CBZ. Carbamazepine cytochrome P450 family 3 subfamily A member 4 Homo sapiens
10 MD simulations with two to four CBZ molecules provide evidence that the substrate-binding pocket of CYP3A4 can accommodate more than one molecule of CBZ. Carbamazepine cytochrome P450 family 3 subfamily A member 4 Homo sapiens
11 Analysis of the kinetics profiles of CBZ metabolism with a model that combines the formalism of the Hill equation with an allowance for substrate inhibition demonstrates that the mechanism of interactions of CBZ with CYP3A4 involves multiple substrate-binding events (most likely three). Carbamazepine cytochrome P450 family 3 subfamily A member 4 Homo sapiens
12 Analysis of the kinetics profiles of CBZ metabolism with a model that combines the formalism of the Hill equation with an allowance for substrate inhibition demonstrates that the mechanism of interactions of CBZ with CYP3A4 involves multiple substrate-binding events (most likely three). Carbamazepine cytochrome P450 family 3 subfamily A member 4 Homo sapiens