The Final Catalytic Step of Cytochrome P450 Aromatase: A Density Functional Theory Study.
B3LYP density functional theory calculations are used to unravel the mysterious third step of aromatase catalysis. The feasibility of mechanisms in which the reduced ferrous dioxygen intermediate mediates androgen aromatization is explored and determined to be unlikely. However, proton-assisted homo...
| Published in: | Journal of the American Chemical Society Vol. 127; no. 14; pp. 5224 - 5238 |
|---|---|
| Main Authors: | , , |
| Format: | Article |
| Published: |
American Chemical Society
4/13/2005
|
| Subjects: | |
| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=hlh&AN=16753776&site=ehost-live header: @attributes: shortDbName: hlh uiTerm: 16753776 longDbName: Humanities International Complete uiTag: AN controlInfo: bkinfo: jinfo: jid: 00027863 ACS jtl: Journal of the American Chemical Society issn: 00027863 maglogo: N pubinfo: dt: 4/13/2005 vid: 127 iid: 14 pid: 997 pub: American Chemical Society artinfo: ui: 16753776 10.1021/ja044716w ppf: 5224 ppct: 14 formats: tig: atl: The Final Catalytic Step of Cytochrome P450 Aromatase: A Density Functional Theory Study. aug: au: Hackett, John C Brueggemeier, Robert W. Hadad, Christopher M. affil: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, Ohio 43210, and the Department of Chemistry, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210. su: Cytochrome P-450 Density functionals Surface chemistry Cytochromes Molecular dynamics Dehydrogenases sug: subj: Cytochrome P-450 Density functionals Surface chemistry Cytochromes Molecular dynamics Dehydrogenases ab: B3LYP density functional theory calculations are used to unravel the mysterious third step of aromatase catalysis. The feasibility of mechanisms in which the reduced ferrous dioxygen intermediate mediates androgen aromatization is explored and determined to be unlikely. However, proton-assisted homolysis of the peroxo hemiacetal intermediate to produce P450 compound I and the C19 gem-diol likely proceeds with a low energetic barrier. Mechanisms for the aromatization and deformylation sequence which are initiated by 1β-hydrogen atom abstraction by P450 compound I are considered. 1β-Hydrogen atom abstraction from substrates in the presence of the 2,3-enol encounters strikingly low barriers (5.3-7.8 kcal/mol), whereas barriers for this same process rise to 17.0-27.1 kcal/mol in the keto tautomer. Transition states for 1β-hydrogen atom abstraction from enolized substrates in the presence of the 1 9-gem-diol decayed directly to the experimentally observed products. If the C19 aldehyde remains unhydrated, aromatization occurs with concomitant decarbonylation and therefore does not support dehydration of the C19 aldehyde prior to the final catalytic step. On the doublet surface, the transition state connects to a potentially labile 1(10) dehydrogenated product, which may undergo rapid aromatization, as well as formic acid. Ab initio molecular dynamics confirmed that the 1β-hydrogen atom abstraction and deformylation or decarbonylation occur in a nonsynchronous, coordinated manner. These calculations support a dehydrogenase behavior of aromatase in the final catalytic step, which can be summarized by 1β-hydrogen atom abstraction followed by gem-diol deprotonation. pubtype: Academic Journal doctype: Article src: R language: English refInfo: copyright: @attributes: flag: Y dt: @attributes: year: 2005 holdings: @attributes: islocal: N |
|---|