Theoretical Characterization of the Step-by-Step Mechanism of Conversion of Leukotriene A to Leukotriene B Catalysed by the Enzyme Leukotriene A Hydrolase.

LTAH 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, LTAH 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 S1 mechanism, the epoxide opens and the triene moiety of the substrate twists in such a way that the bond C-C adopts its () configuration, thus exposing the 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 configuration inside LTAH.