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

Original Research

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.

Keywords

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

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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Copyright information

© 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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