Enolization as an alternative proton delivery pathway in human aromatase (P450 19A1)

Balázs Krámos, Julianna Oláh

Research output: Contribution to journalArticle

10 Citations (Scopus)


Human aromatase catalyzes the last step of estrogen biosynthesis, the aromatization of ring A of androstenedione (ASD) and testosterone leading to estrone and estradiol. The enolization of the substrate molecule has been suggested to play an essential role in this process. In this work using quantum mechanical and hybrid QM/MM calculations, the reaction mechanism of enolization was investigated. It is shown that the energetically unfavorable enolization of andostenedione occurs in a coupled process with the energetically favorable protonation of the ferrous superoxo complex (traditionally called ferric peroxo complex) via a low barrier of about 5 kcal/mol. This mechanism implies an alternative way for protonation of the ferrous superoxo complex to form compound 0, which occurs via the Asp309-water-ASD proton delivery pathway instead of the Asp-water-Thr pathway suggested for other P450 enzymes. It is also shown that Thr310, which is known experimentally to be important for catalysis, plays a key role in the conversion of compound 0 to compound I.

Original languageEnglish
Pages (from-to)390-405
Number of pages16
JournalJournal of Physical Chemistry B
Issue number2
Publication statusPublished - Jan 16 2014

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

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