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The mechanism of human aromatase (CYP 19A1) revisited: DFT and QM/MM calculations support a compound I-mediated pathway for the aromatization process

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Abstract

Human aromatase is responsible for the last step of estrogen biosynthesis, for the aromatization of ring A of androstenedione or testosterone. In this work, the mechanism of aromatization was studied using gas phase and hybrid QM/MM calculations. It is shown that human aromatase can efficiently catalyze the aromatization process via a compound I (or compound II)-mediated pathway. The nature of the oxidant is very sensitive to the polarizing environment of the enzyme, as the oxidant has a compound I nature in the gas phase calculations, which is modulated by the enzyme environment to become a mixed compound I and compound II character. The electronic structure of the obtained QM-only and QM/MM stationary points is thoroughly discussed.

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Acknowledgments

The authors thank Prof. Jeremy Harvey (University of Bristol. UK) for useful discussions, Dóra K. Menyhárd for proof-reading of the manuscript, and the financial support of the New Széchenyi Plan (TÁMOP-4.2.2/B-10/1-2010-0009) and of OTKA Grant No. 108721. JO acknowledges receipt of an EU Marie Curie ERG Fellowship (Project “Oestrometab”). Part of this work was supported by the COST Action CM1305 (ECOSTBio).

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  1. Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Szent Gellért tér 4, Budapest, 1111, Hungary

    Balázs Krámos & Julianna Oláh

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  1. Balázs Krámos
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Correspondence to Julianna Oláh.

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SUPPORTING INFORMATION. Selected geometrical parameters and fragment charges for QM-only optimized structures using various basis sets, and details of all reactants, TS, and product complexes obtained in QM/MM calculations. Furthermore, total energies and Cartesian coordinates of all QM-only structures, geometries of the QM region of the QM/MM structures belonging to profile 1, and MM parameters for the 19-oxo-ASD are also provided in the SI together with tables and figures indicated in the text. (DOC 2789 kb)

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Krámos, B., Oláh, J. The mechanism of human aromatase (CYP 19A1) revisited: DFT and QM/MM calculations support a compound I-mediated pathway for the aromatization process. Struct Chem 26, 279–300 (2015). https://doi.org/10.1007/s11224-014-0545-9

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