Mechanism of Cytochrome P450 17A1-Catalyzed Hydroxylase and Lyase Reactions

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Mechanism of Cytochrome P450 17A1-Catalyzed Hydroxylase and Lyase Reactions. / Bonomo, Silvia; Jørgensen, Flemming Steen; Olsen, Lars.

In: Journal of Chemical Information and Modeling, Vol. 57, No. 5, 22.05.2017, p. 1123-1133.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Bonomo, S, Jørgensen, FS & Olsen, L 2017, 'Mechanism of Cytochrome P450 17A1-Catalyzed Hydroxylase and Lyase Reactions', Journal of Chemical Information and Modeling, vol. 57, no. 5, pp. 1123-1133. https://doi.org/10.1021/acs.jcim.6b00759

APA

Bonomo, S., Jørgensen, F. S., & Olsen, L. (2017). Mechanism of Cytochrome P450 17A1-Catalyzed Hydroxylase and Lyase Reactions. Journal of Chemical Information and Modeling, 57(5), 1123-1133. https://doi.org/10.1021/acs.jcim.6b00759

Vancouver

Bonomo S, Jørgensen FS, Olsen L. Mechanism of Cytochrome P450 17A1-Catalyzed Hydroxylase and Lyase Reactions. Journal of Chemical Information and Modeling. 2017 May 22;57(5):1123-1133. https://doi.org/10.1021/acs.jcim.6b00759

Author

Bonomo, Silvia ; Jørgensen, Flemming Steen ; Olsen, Lars. / Mechanism of Cytochrome P450 17A1-Catalyzed Hydroxylase and Lyase Reactions. In: Journal of Chemical Information and Modeling. 2017 ; Vol. 57, No. 5. pp. 1123-1133.

Bibtex

@article{f9997edc8bc747299a097fd2f76f05e8,
title = "Mechanism of Cytochrome P450 17A1-Catalyzed Hydroxylase and Lyase Reactions",
abstract = "Cytochrome P450 17A1 (CYP17A1) catalyzes C17 hydroxylation of pregnenolone and progesterone and the subsequent C17-C20 bond cleavage (lyase reaction) to form androgen precursors. Compound I (Cpd I) and peroxo anion (POA) are the heme-reactive species underlying the two reactions. We have characterized the reaction path for both the hydroxylase and lyase reactions using density functional theory (DFT) calculations and the enzyme-substrate interactions by molecular dynamics (MD) simulations. Activation barriers for positions subject to hydroxylase reaction have values close to each other and span from 54 to 60 kJ·mol-1 with a small preference for 17α hydroxylation, in agreement with experimental observations. For the lyase reaction, two different types of mechanisms, concerted and stepwise, with identical activation energies (87 kJ·mol-1) were identified. Embedding the DFT-optimized transition states (TSs) for the two reactions into the active site of CYP17A1 showed that the TS for the C17 hydroxylation needs to be distorted by 13 kJ·mol-1, whereas the TS for the 17,20 lyase reaction easily can be accommodated in the protein. Finally, differences in the hydrogen-bond pattern of the substrates were detected both in the CYP17A1-Cpd I and CYP17A1-POA complexes, with the former found to be more pivotal for the hydroxylation site than the latter, suggesting a possible explanation for the slower conversion of CYP17A1 for 17α-hydroxyprogesterone over 17α-hydroxypregnenolone. The results support the concept that the selectivity of the steroidogenic CYPs is ruled by direct interactions with the enzyme, in contrast to the selectivity of drug-metabolizing CYPs, where the reactivity of the substrates dominates.",
keywords = "Journal Article",
author = "Silvia Bonomo and J{\o}rgensen, {Flemming Steen} and Lars Olsen",
year = "2017",
month = "5",
day = "22",
doi = "10.1021/acs.jcim.6b00759",
language = "English",
volume = "57",
pages = "1123--1133",
journal = "Journal of Chemical Information and Modeling",
issn = "1549-9596",
publisher = "American Chemical Society",
number = "5",

}

RIS

TY - JOUR

T1 - Mechanism of Cytochrome P450 17A1-Catalyzed Hydroxylase and Lyase Reactions

AU - Bonomo, Silvia

AU - Jørgensen, Flemming Steen

AU - Olsen, Lars

PY - 2017/5/22

Y1 - 2017/5/22

N2 - Cytochrome P450 17A1 (CYP17A1) catalyzes C17 hydroxylation of pregnenolone and progesterone and the subsequent C17-C20 bond cleavage (lyase reaction) to form androgen precursors. Compound I (Cpd I) and peroxo anion (POA) are the heme-reactive species underlying the two reactions. We have characterized the reaction path for both the hydroxylase and lyase reactions using density functional theory (DFT) calculations and the enzyme-substrate interactions by molecular dynamics (MD) simulations. Activation barriers for positions subject to hydroxylase reaction have values close to each other and span from 54 to 60 kJ·mol-1 with a small preference for 17α hydroxylation, in agreement with experimental observations. For the lyase reaction, two different types of mechanisms, concerted and stepwise, with identical activation energies (87 kJ·mol-1) were identified. Embedding the DFT-optimized transition states (TSs) for the two reactions into the active site of CYP17A1 showed that the TS for the C17 hydroxylation needs to be distorted by 13 kJ·mol-1, whereas the TS for the 17,20 lyase reaction easily can be accommodated in the protein. Finally, differences in the hydrogen-bond pattern of the substrates were detected both in the CYP17A1-Cpd I and CYP17A1-POA complexes, with the former found to be more pivotal for the hydroxylation site than the latter, suggesting a possible explanation for the slower conversion of CYP17A1 for 17α-hydroxyprogesterone over 17α-hydroxypregnenolone. The results support the concept that the selectivity of the steroidogenic CYPs is ruled by direct interactions with the enzyme, in contrast to the selectivity of drug-metabolizing CYPs, where the reactivity of the substrates dominates.

AB - Cytochrome P450 17A1 (CYP17A1) catalyzes C17 hydroxylation of pregnenolone and progesterone and the subsequent C17-C20 bond cleavage (lyase reaction) to form androgen precursors. Compound I (Cpd I) and peroxo anion (POA) are the heme-reactive species underlying the two reactions. We have characterized the reaction path for both the hydroxylase and lyase reactions using density functional theory (DFT) calculations and the enzyme-substrate interactions by molecular dynamics (MD) simulations. Activation barriers for positions subject to hydroxylase reaction have values close to each other and span from 54 to 60 kJ·mol-1 with a small preference for 17α hydroxylation, in agreement with experimental observations. For the lyase reaction, two different types of mechanisms, concerted and stepwise, with identical activation energies (87 kJ·mol-1) were identified. Embedding the DFT-optimized transition states (TSs) for the two reactions into the active site of CYP17A1 showed that the TS for the C17 hydroxylation needs to be distorted by 13 kJ·mol-1, whereas the TS for the 17,20 lyase reaction easily can be accommodated in the protein. Finally, differences in the hydrogen-bond pattern of the substrates were detected both in the CYP17A1-Cpd I and CYP17A1-POA complexes, with the former found to be more pivotal for the hydroxylation site than the latter, suggesting a possible explanation for the slower conversion of CYP17A1 for 17α-hydroxyprogesterone over 17α-hydroxypregnenolone. The results support the concept that the selectivity of the steroidogenic CYPs is ruled by direct interactions with the enzyme, in contrast to the selectivity of drug-metabolizing CYPs, where the reactivity of the substrates dominates.

KW - Journal Article

U2 - 10.1021/acs.jcim.6b00759

DO - 10.1021/acs.jcim.6b00759

M3 - Journal article

VL - 57

SP - 1123

EP - 1133

JO - Journal of Chemical Information and Modeling

JF - Journal of Chemical Information and Modeling

SN - 1549-9596

IS - 5

ER -

ID: 187579776