Escolar Documentos
Profissional Documentos
Cultura Documentos
pubs.acs.org/acscatalysis
Estrogen Formation via HAbstraction from the OH Bond of gemDiol by Compound I in the Reaction of CYP19A1: Mechanistic
Scenario Derived from Multiscale QM/MM Calculations
Kai Xu, Yong Wang,*, and Hajime Hirao*,
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, Singapore 637371
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Lanzhou Institute of Chemical
Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, China
S Supporting Information
*
ABSTRACT: Recent experiments suggested that, contrary to traditional belief, the third
step of aromatase-catalyzed estrogen formation should be eected by compound I (Cpd
I), rather than by ferric peroxide. We performed QM/MM calculations to address the
question of how Cpd I drives the aromatization process. Surprisingly, the calculations
show that the reaction begins with hydrogen abstraction from the OH bond of a gemdiol substrate, which is followed by barrierless homolytic CC bond cleavage and then
1-H-abstraction. Proton-coupled electron transfer enables the cleavage of the strong
OH bond. Another product, carboxylic acid, can be formed from either the gem-diol or
aldehyde.
KEYWORDS: aromatase, Cpd I, QM/MM, H-abstraction, PCET
4175
DOI: 10.1021/acscatal.5b00510
ACS Catal. 2015, 5, 41754179
Letter
ACS Catalysis
Figure 1. (a) Energy proles (kcal/mol) for the reactions of gem-diol with Cpd I. (b) Transition-state geometries. Key bond distances are shown in
.
DOI: 10.1021/acscatal.5b00510
ACS Catal. 2015, 5, 41754179
Letter
ACS Catalysis
DOI: 10.1021/acscatal.5b00510
ACS Catal. 2015, 5, 41754179
Letter
ACS Catalysis
Figure 3. (a) Energy proles (kcal/mol) for the reactions of aldehyde with Cpd I. (b) Transition-state geometries. Key bond distances are shown in
.
DOI: 10.1021/acscatal.5b00510
ACS Catal. 2015, 5, 41754179
Letter
ACS Catalysis
(19) Chung, L. W.; Hirao, H.; Li, X.; Morokuma, K. Wiley Interdiscip.
Rev.: Comput. Mol. Sci. 2012, 2, 327350.
(20) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci,
B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.
P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M. J.; Heyd, J.; Brothers, E. N.;
Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A. P.; Burant, J. C.; Iyengar, S. S.;
Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.; Knox, J. E.;
Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A.
D.; Farkas, O .; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J.
Gaussian 09, Rev. D.01; Gaussian, Inc.: Wallingford, CT, USA, 2009.
(21) Becke, A. D. J. Chem. Phys. 1993, 98, 56485652.
(22) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B: Condens. Matter
Mater. Phys. 1988, 37, 785789.
(23) Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980, 58, 1200
1211.
(24) Hehre, W. J.; Radom, L.; Schleyer, P. V. R.; Pople, J. A. Ab Initio
Molecular Orbital Theory; Wiley: New York, 1986; Vol. 67.
(25) Duan, Y.; Wu, C.; Chowdhury, S.; Lee, M. C.; Xiong, G.; Zhang,
W.; Yang, R.; Cieplak, P.; Luo, R.; Lee, T.; Caldwell, J.; Kollman, J.;
Wang, J. J. Comput. Chem. 2003, 24, 19992012.
(26) Wang, J.; Wolf, R. M.; Caldwell, J. W.; Kollman, P. A.; Case, D.
A. J. Comput. Chem. 2004, 25, 11571174.
(27) Pettersen, E. F.; Goddard, T. D.; Huang, C. C.; Couch, G. S.;
Greenblatt, D. M.; Meng, E. C.; Ferrin, T. E. J. Comput. Chem. 2004,
25, 16051612.
(28) Portmann, S.; Luthi, H. P. Chimia 2000, 54, 766770.
(29) Korzekwa, K. R.; Trager, W. F.; Mancewicz, J.; Osawa, Y. J.
Steroid Biochem. Mol. Biol. 1993, 44, 367373.
(30) Hackett, J. C.; Brueggemeier, R. W.; Hadad, C. M. J. Am. Chem.
Soc. 2005, 127, 52245237.
(31) Kramos, B.; Olah, J. Struct. Chem. 2015, 26, 279300.
(32) Blanksby, S. J.; Ellison, G. B. Acc. Chem. Res. 2003, 36, 255263.
(33) Usharani, D.; Lacy, D. C.; Borovik, A. S.; Shaik, S. J. Am. Chem.
Soc. 2013, 135, 1709017104.
(34) Hirao, H.; Chuanprasit, P. Chem. Phys. Lett. 2015, 621, 188
192.
(35) Hirao, H.; Ng, W. K. H.; Moeljadi, A. M. P.; Bureekaew, S. ACS
Catal. 2015, 32873291.
(36) Wang, D.; Farquhar, E. R.; Stubna, A.; Munck, E.; Que, L., Jr.
Nat. Chem. 2009, 1, 145150.
(37) Wang, Y.; Yang, C.; Wang, H.; Han, K.; Shaik, S. ChemBioChem
2007, 8, 277281.
(38) Schyman, P.; Lai, W.; Chen, H.; Wang, Y.; Shaik, S. J. Am. Chem.
Soc. 2011, 133, 79777984.
(39) Hirao, H.; Thellamurege, N.; Chuanprasit, P.; Xu, K. Int. J. Mol.
Sci. 2013, 14, 2469224705.
(40) Wang, Y.; Wang, H.; Wang, Y.; Yang, C.; Yang, L.; Han, K. J.
Phys. Chem. B 2006, 110, 61546159.
(41) Liu, X.; Wang, Y.; Han, K. JBIC, J. Biol. Inorg. Chem. 2007, 12,
10731081.
(42) Denisov, I. G.; Makris, T. M.; Sligar, S. G.; Schlichting, I. Chem.
Rev. 2005, 105, 22532277.
ASSOCIATED CONTENT
S Supporting Information
*
AUTHOR INFORMATION
Corresponding Authors
*E-mail: wangyong@licp.cas.cn.
*E-mail: hirao@ntu.edu.sg.
Notes
ACKNOWLEDGMENTS
H.H. is grateful for nancial support in the form of a Nanyang
Assistant Professorship and also thanks the High-Performance
Computing Centre at Nanyang Technological University for
computer resources. W.Y. gratefully acknowledges research
support from the National Natural Science Foundation of
China (NFSC) (Grants 21003116 and 21173211).
REFERENCES
DOI: 10.1021/acscatal.5b00510
ACS Catal. 2015, 5, 41754179