Theoretical Study of the Mechanism of Exemestane Hydroxylation Catalyzed by Human Aromatase Enzyme
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Theoretical Study of the Mechanism of Exemestane Hydroxylation Catalyzed by Human Aromatase EnzymeData de publicació
2016-03Editor
ACSCita bibliogràfica
VICIANO, Ignacio; MARTÍ, Sergio. Theoretical Study of the Mechanism of Exemestane Hydroxylation Catalyzed by Human Aromatase Enzyme. The Journal of Physical Chemistry B, 2016, vol. 120, no 13, p. 3331-3343.Tipus de document
info:eu-repo/semantics/articleVersió de l'editorial
http://pubs.acs.org/doi/abs/10.1021/acs.jpcb.6b01014Versió
info:eu-repo/semantics/submittedVersionParaules clau / Matèries
Resum
Human aromatase (CYP19A1) aromatizes the androgens to form estrogens via a three-step oxidative process. The
estrogens are necessary in humans, mainly in women, because of the role they play in sexual and reproductive ... [+]
Human aromatase (CYP19A1) aromatizes the androgens to form estrogens via a three-step oxidative process. The
estrogens are necessary in humans, mainly in women, because of the role they play in sexual and reproductive development.
However, these also are involved in the development and growth of hormone-dependent breast cancer. Therefore, inhibition of
the enzyme aromatase, by means of drugs known as aromatase inhibitors, is the frontline therapy for these types of cancers.
Exemestane is a suicidal third-generation inhibitor of aromatase, currently used in breast cancer treatment. In this study, the
hydroxylation of exemestane catalyzed by aromatase has been studied by means of hybrid QM/MM methods. The Free Energy
Perturbation calculations provided a free energy of activation for the hydrogen abstraction step (rate-limiting step) of 17 kcal/
mol. The results reveal that the hydroxylation of exemestane is not the inhibition stage, suggesting a possible competitive
mechanism between the inhibitor and the natural substrate androstenedione in the
first catalytic subcycle of the enzyme.
Furthermore, the analysis of the interaction energy for the substrate and the cofactor in the active site shows that the role of the
enzymatic environment during this reaction consists of a transition state stabilization by means of electrostatic effects. [-]
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J. Phys. Chem. B, 2016, 120 (13)Drets d'accés
© 2016 American Chemical Society
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