Cytochrome P450 Monooxygenase-Catalyzed Ring Opening of the Bicyclic Amine, Nortropine: An Experimental and DFT Computational Study
| Autor: | Katarzyna Kosieradzka, Jean-Yves Le Questel, Anaïs Fournial, Marcel Delaforge, Renata A. Kwiecień, Piotr Paneth, Jacques Lebreton, Richard J. Robins, Emmanuel Gentil |
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| Rok vydání: | 2012 |
| Předmět: |
Reaction mechanism
Bicyclic molecule 010405 organic chemistry Stereochemistry Chemistry Organic Chemistry Protonation 010402 general chemistry Ring (chemistry) 01 natural sciences Heterolysis Catalysis Transition state 0104 chemical sciences Inorganic Chemistry Computational chemistry Kinetic isotope effect Physical and Theoretical Chemistry Bond cleavage |
| Zdroj: | ChemCatChem. 4:530-539 |
| ISSN: | 1867-3880 |
| DOI: | 10.1002/cctc.201100386 |
| Popis: | An approach combining experimental kinetic isotope effects (KIEs) and quantum chemistry calculations at the DFT level was used to explore the mechanism by which the C?N bond of the bicyclic amine nortropine (2) was cleaved during the catabolism of tropine (1) by Pseudomonas bacteria. The working model is that the ring opening involves the oxidation of nortropine at one bridgehead carbon position by cytochrome P450 monooxygenase, followed by the protonation of the nitrogen, which leads to heterolytic bond cleavage. 15N and 2H heavy-atom KIEs for the reaction were determined both experimentally and theoretically (DFT). Transition states were described for both oxidation and ring cleavage. Calculation of the heavy-atom KIE values indicated a high 2H, a moderate 13C, and a negligible 15N effect for the oxidation and a strong inverse 15N and normal 13C KIEs at N and 1C for the 1C?N bond cleavage. Experimental KIE values for the overall reaction were a strongly inverse 15N and negligible 2H effect, which indicated that the catalytic rate depended on the bond-breaking part of the reaction. Thus, from the experimental and calculated results, it could be proposed that the enzyme-dependent activation of the 1C position to destabilize the structure is a prerequisite for bond cleavage, but the driving force behind the carbonnitrogen bond fission is the simultaneous protonation of the nitrogen of the intermediate species [3] and sp3 to sp2 transition at the 1C position. Thus, a mechanism that satisfactorily fits both the experimental and theoretical results could be proposed. It is unusual in that it indicates that the cytochrome P450 monooxygenase-catalyzed hydrogen abstractionthough essential for the overall reaction to occuris not the kinetically limiting partial reaction. |
| Databáze: | OpenAIRE |
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