Structural Chemistry

, Volume 26, Issue 1, pp 279–300 | Cite as

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

  • Balázs Krámos
  • Julianna OláhEmail author
Original Research


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.


Deformylation Androstenedione QM/MM Reaction mechanism C–C bond fission 



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).

Supplementary material

11224_2014_545_MOESM1_ESM.doc (2.7 mb)
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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© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Inorganic and Analytical ChemistryBudapest University of Technology and EconomicsBudapestHungary

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