Theoretical Characterization of the Step-by-Step Mechanism of Conversion of Leukotriene A4 to Leukotriene B4 Catalysed by the Enzyme Leukotriene A4 Hydrolase
LTA H is a bifunctional zinc metalloenzyme that converts leukotriene A (LTA) into leukotriene B (LTB), one of the most potent chemotactic agents involved in acute and chronic inflammatory diseases. In this reaction, LTA H acts as an epoxide hydrolase with a unique and fascinating mechanism, which in...
| Autores: | , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Idioma: | inglés |
| OAI Identifier: | oai:ddd.uab.cat:257298 |
| Acceso en línea: | https://ddd.uab.cat/record/257298 https://dx.doi.org/urn:doi:10.3390/ijms23063140 |
| Access Level: | acceso abierto |
| Palabra clave: | Leukotriens Leukotriene A4 hydrolase Enzyme catalysis QM/MM calculations Molecular dynamics simulations Proinflammatory lipid mediators |
| Sumario: | LTA H is a bifunctional zinc metalloenzyme that converts leukotriene A (LTA) into leukotriene B (LTB), one of the most potent chemotactic agents involved in acute and chronic inflammatory diseases. In this reaction, LTA H acts as an epoxide hydrolase with a unique and fascinating mechanism, which includes the stereoselective attachment of one water molecule to the carbon backbone of LTA several methylene units away from the epoxide moiety. By combining Molecular Dynamics simulations and Quantum Mechanics/Molecular Mechanics calculations, we obtained a very detailed molecular picture of the different consecutive steps of that mechanism. By means of a rather unusual 1,7-nucleophilic substitution through a clear S 1 mechanism, the epoxide opens and the triene moiety of the substrate twists in such a way that the bond C-C adopts its cis (Z) configuration, thus exposing the R face of C to the addition of a water molecule hydrogen-bonded to ASP375. Thus, the two stereochemical features that are required for the bioactivity of LTB appear to be closely related. The noncovalent π-π stacking interactions between the triene moiety and two tyrosines (TYR267 and, especially, TYR378) that wrap the triene system along the whole reaction explain the preference for the cis configuration inside LTA H. |
|---|