2024-03-29T12:51:37Zhttps://repositori.uji.es/oai/requestoai:repositori.uji.es:10234/1602712022-02-02T18:25:47Zcom_10234_7013com_10234_9col_10234_8638
00925njm 22002777a 4500
dc
Viciano Gonzalo, Ignacio
author
Castillo, Raquel
author
Martí Forés, Sergio
author
2015-09
CYP19A1 aromatase is a member of the Cytochrome P450 family of hemeproteins, and is the enzyme responsible for the final step of the androgens conversion into the corresponding estrogens, via a three-step oxidative process. For this reason, the inhibition of this enzyme plays an important role in the treatment of hormone-dependent breast cancer. The first catalytic subcycle, corresponding to the hydroxilation of androstenedione, has been proposed to occur through a first hydrogen abstraction and a subsequent oxygen rebound step. In present work, we have studied the mechanism of the first catalytic subcycle by means of hybrid quantum mechanics/molecular mechanics methods. The inclusion of the protein flexibility has been achieved by means of Free Energy Perturbation techniques, giving rise to a free energy of activation for the hydrogen abstraction step of 13.5 kcal/mol. The subsequent oxygen rebound step, characterized by a small free energy barrier (1.5 kcal/mol), leads to the hydroxylated products through a highly exergonic reaction. In addition, an analysis of the primary deuterium kinetic isotopic effects, calculated for the hydrogen abstraction step, reveals values (∼10) overpassing the semiclassical limit for the C[BOND]H, indicating the presence of a substantial tunnel effect. Finally, a decomposition analysis of the interaction energy for the substrate and cofactor in the active site is also discussed. According to our results, the role of the enzymatic environment consists of a transition state stabilization by means of dispersive and polarization effects.
Viciano, Ignacio, Raquel Castillo, and Sergio Martí. "QM/MM modeling of the hydroxylation of the androstenedione substrate catalyzed by cytochrome P450 aromatase (CYP19A1)." Journal of computational chemistry 36.23 (2015): 1736-1747.
http://hdl.handle.net/10234/160271
http://dx.doi.org/10.1002/jcc.23967
cytochrome P450
compound I
aromatase
hydrogen abstraction
androstenedione
CYP19A1
quantum mechanics/molecular mechanics
QM/MM modeling of the hydroxylation of the androstenedione substrate catalyzed by cytochrome P450 aromatase (CYP19A1)