A Dehydrogenase Dual Hydrogen Abstraction Mechanism Promotes Estrogen Biosynthesis: Can We Expand the Functional Annotation of the Aromatase Enzyme?

Chemistry : a European Journal
Angelo SpinelloAlessandra Magistrato

Abstract

Cytochrome P450 (CYP450) enzymes are involved in the metabolism of exogenous compounds and in the synthesis of signaling molecules. Among the latter, human aromatase (HA) promotes estrogen biosynthesis, which is a key pharmacological target against breast cancers. After decades of debate, interest in gaining a comprehensive picture of HA catalysis has been renewed by the recent discovery that compound I (Cpd I) is the reactive species of the peculiar aromatization step. Herein, for the first time, a complete atomic-level picture of all controversial steps of estrogen biosynthesis is presented. By performing cumulative quantum-classical molecular dynamics and metadynamics simulations of about 180 ps, it is revealed that the most likely enzymatic path relies on three factors: 1) androstenedione enolization and compound 0 (Cpd 0) formation through a proton network mediated by Asp309; 2) subsequent formation of Cpd I, upon rearrangement of the Asp309 side chain and the establishment of a proton network involving Asp309 and Thr310; and 3) after two hydroxylation reactions, 19,19-gem-diol is converted into estrone by Cpd I, through an uncommon dehydrogenase-like dual hydrogen abstraction mechanism. As a result, HA performs estrogen b...Continue Reading

References

Mar 15, 1978·Biochemical and Biophysical Research Communications·J T Groves, G A McClusky
Apr 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·P A ColeC H Robinson
Nov 1, 1969·Biochemistry·J FishmanD Dixon
Mar 1, 1982·The Biochemical Journal·M AkhtarJ N Wright
Jul 1, 1996·Chemical Research in Toxicology·G BellucciP G Gervasi
Sep 15, 1988·Physical Review A: General Physics·A D Becke
Jul 15, 1996·Physical Review. B, Condensed Matter·S GoedeckerJ Hutter
Jun 21, 2001·Chemical Research in Toxicology·F P Guengerich
Nov 7, 1996·Chemical Reviews·Masanori SonoJohn H. Dawson
Aug 28, 2002·Natural Product Reports·Paul R Ortiz de Montellano, James J De Voss
Mar 27, 2003·Journal of the American Chemical Society·Srabani Taraphder, Gerhard Hummer
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Sep 9, 2004·Chemical Reviews·Bernard MeunierSason Shaik
Apr 7, 2005·Journal of the American Chemical Society·John C HackettChristopher M Hadad
Jun 9, 2005·Chemical Reviews·Ilia G DenisovIlme Schlichting
Jun 9, 2005·Chemical Reviews·Sason ShaikWalter Thiel
Oct 8, 2005·Journal of Computational Chemistry·David Van Der SpoelHerman J C Berendsen
Feb 7, 2006·Journal of Molecular Graphics & Modelling·Junmei WangDavid A Case
Mar 7, 2006·Journal of Inorganic Biochemistry·John T Groves
Jul 21, 2006·The Journal of Physical Chemistry. B·Devesh KumarSason Shaik
Oct 5, 2006·Journal of the American Chemical Society·Jingjing ZhengSason Shaik
Jan 11, 2007·The Journal of Chemical Physics·Giovanni BussiMichele Parrinello
Sep 25, 2007·The Journal of Chemical Physics·Joost VandeVondele, Jürg Hutter
Mar 21, 2008·Journal of Computational Chemistry·Sunhwan JoWonpil Im
Aug 5, 2009·Biophysical Journal·Lauren WickstromCarlos Simmerling
Apr 14, 2010·The Journal of Biological Chemistry·Christal D Sohl, F Peter Guengerich
Apr 22, 2010·Proteins·Kresten Lindorff-LarsenDavid E Shaw
Nov 6, 2010·Endocrine Reviews·Walter L Miller, Richard J Auchus
Oct 15, 2011·Journal of Computational Chemistry·Kiumars ShahrokhThomas E Cheatham
Jul 25, 2012·BMC Research Notes·Alan W Sousa da Silva, Wim F Vranken
Mar 14, 2013·Journal of Computational Chemistry·Eric D GlendeningFrank Weinhold
Dec 29, 2013·The Journal of Physical Chemistry. B·Balázs Krámos, Julianna Oláh
May 8, 2014·Journal of Chemical Theory and Computation·Callum J DicksonRoss C Walker
Jul 10, 2014·Biomolecules·Pietro Vidossich, Alessandra Magistrato

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Citations

Apr 3, 2019·Future Medicinal Chemistry·Jacopo SgrignaniAlessandra Magistrato
Jul 25, 2019·Expert Opinion on Drug Discovery·Angelo SpinelloAlessandra Magistrato
Aug 9, 2020·International Journal of Environmental Research and Public Health·Chao ZhangGiovanna Di Nardo
Jan 28, 2020·The Journal of Physical Chemistry Letters·Ida RitaccoAlessandra Magistrato
Apr 21, 2021·Expert Opinion on Drug Discovery·Giulia PalermoAlessandra Magistrato
Mar 20, 2021·ChemMedChem·Angelo SpinelloAlessandra Magistrato
May 22, 2020·ACS Medicinal Chemistry Letters·Jessica CaciollaAlessandra Magistrato
Dec 27, 2018·Journal of Chemical Information and Modeling·Angelo SpinelloAlessandra Magistrato
Apr 30, 2019·Journal of Chemical Information and Modeling·Ida RitaccoAlessandra Magistrato
Aug 20, 2020·Journal of the American Chemical Society·Savvas LoukaSam P de Visser

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