Theoretical Characterization of the Step-by-Step Mechanism of Conversion of Leukotriene A4 to Leukotriene B4 Catalysed by the Enzyme Leukotriene A4 Hydrolase
Canyelles-Niño, Miquel (Universitat Autònoma de Barcelona. Departament de Química)
González-Lafont, Àngels (Universitat Autònoma de Barcelona. Departament de Química)
Lluch López, Josep Maria (Universitat Autònoma de Barcelona. Departament de Química)

Date:	2022
Abstract:	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.
Grants:	Agencia Estatal de Investigación PID2020-113764GB-I00
Note:	This study was supported by a grant (PID2020-113764GB-I00) from the Spanish ?Ministerio de Ciencia e Innovaci?n?. We also acknowledge CSUC for computational facilities.
Note:	Funding: This study was supported by a grant (PID2020-113764GB-I00) from the Spanish "Ministerio de Ciencia e Innovación". We also acknowledge CSUC for computational facilities.
Note:	Altres ajuts: Ministerio de Ciencia e Innovaci?n?
Note:	Altres ajuts: MICINN
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Leukotriens ; Leukotriene A4 hydrolase ; Enzyme catalysis ; QM/MM calculations ; Molecular dynamics simulations ; Proinflammatory lipid mediators
Published in:	International journal of molecular sciences, Vol. 23 Núm. 6 (Març 2022) , p. 3140, ISSN 1422-0067

DOI: 10.3390/ijms23063140
PMID: 35328561

23 p, 12.3 MB

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