Application of a ligand-based theoretical approach to derive conversion paths and ligand conformations in CYP11B2-mediated aldosterone formation.
| Title: | Application of a ligand-based theoretical approach to derive conversion paths and ligand conformations in CYP11B2-mediated aldosterone formation. |
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| Authors: | Roumen L; Biomodeling and Bioinformatics, Eindhoven University of Technology, Eindhoven, The Netherlands. luc.roumen@gmail.com; Van Hoof B; Pieterse K; Hilbers PA; Custers EM; Plate R; De Gooyer M; Beugels IP; Emmen JM; Leysen D; Smits JF; Ottenheijm HC; Hermans JJ |
| Source: | Journal of computational chemistry [J Comput Chem] 2011 Aug; Vol. 32 (11), pp. 2441-8. Date of Electronic Publication: 2011 May 19. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Wiley Country of Publication: United States NLM ID: 9878362 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-987X (Electronic) Linking ISSN: 01928651 NLM ISO Abbreviation: J Comput Chem Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: New York : Wiley |
| MeSH Terms: | Ligands* ; Quantum Theory*; Aldosterone/*biosynthesis ; Aldosterone/*chemistry ; Cytochrome P-450 CYP11B2/*chemistry; Iron/chemistry ; Oxygen/chemistry ; Molecular Structure |
| Abstract: | The biosynthesis of the mineralocorticoid hormone aldosterone involves a multistep hydroxylation of 11-deoxycorticosterone at the 11- and 18-positions, resulting in the formation of corticosterone and 18-hydroxycorticosterone, the final precursor of aldosterone. Two members of the cytochrome P450 11B family, CYP11B1 and CYP11B2, are known to catalyze these 11- and 18-hydroxylations, however, only CYP11B2 can oxidize 18-hydroxycorticosterone to aldosterone. It is unknown what sequence of hydroxylations leads to the formation of 18-hydroxycorticosterone. In this study we have investigated which of the possible conversion paths towards formation of 18-hydroxycorticosterone and aldosterone are most likely from the ligand perspective. Therefore, we combined quantum mechanical investigations on the steroid conformations of 11-deoxycorticosterone and its ensuing reaction intermediates with Fukui indices calculations to predict the reactivity of their carbon atoms for an attack by the iron-oxygen species. Both F(-) and F(0) were calculated to account for different mechanisms of substrate conversion. We show which particular initial conformations of 11-deoxycorticosterone and which conversion paths are likely to result in the successful synthesis of aldosterone, and thereby may be representative for the mechanism of aldosterone biosynthesis by CYP11B2. Moreover, we found that the most likely path for aldosterone synthesis coincides with the substrate conformation proposed in an earlier publication. To summarize, we show that on a theoretical and strictly ligand-directed basis only a limited number of reaction paths in the conversion of 11-deoxycorticosterone to aldosterone is possible. Despite its theoretical nature, this knowledge may help to understand the catalytic function of CYP11B1 and CYP11B2.; (Copyright © 2011 Wiley Periodicals, Inc.) |
| Substance Nomenclature: | 0 (Ligands); 4964P6T9RB (Aldosterone); E1UOL152H7 (Iron); EC 1.14.15.4 (Cytochrome P-450 CYP11B2); S88TT14065 (Oxygen) |
| Entry Date(s): | Date Created: 20110521 Date Completed: 20110923 Latest Revision: 20141120 |
| Update Code: | 20260130 |
| DOI: | 10.1002/jcc.21827 |
| PMID: | 21598279 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't