Effect of alpha lipoic acid on leukotriene A4 hydrolase

Leukotriene A(4) hydrolase is a soluble enzyme with epoxide hydrolase and aminopeptidase activities catalysing the conversion of leukotriene A(4) to leukotriene B-4 and the hydrolysis of the peptide proline-glycine-proline. Imbalances in leukotriene B-4 synthesis are related to several pathologic conditions. Currently there are no available drugs capable to modulate the synthesis of leukotriene B-4 or to block its receptors. Here we show the inhibitory profile of alpha lipoic acid on the activity of leukotriene A(4) Hydrolase. Alpha lipoic acid inhibited both activities of the enzyme at concentrations lower than 10 M. The 5-lipoxygenase inhibitor zileuton, or the 5lipoxygenase activating protein inhibitor MK-886, were unable to inhibit the activity of the enzyme. Acute promyelocytic leukaemia HL-60 cells were differentiated to leukotriene A(4) hydrolase expressing neutrophil-like cells. Alpha lipoic acid inhibited the aminopeptidase activity of the cytosolic fraction from neutrophil-like cells but had no effect on the cytosolic fraction from undifferentiated cells. Docking and molecular dynamic approximations revealed that alpha lipoic acid participates in electrostatic interactions with K-565 and R-563, which are key residues for the carboxylate group recognition of endogenous substrates by the enzyme. Alpha lipoic acid is a compound widely used in clinical practice, most of its therapeutic effects are associated with its antioxidants properties, however, antioxidant effect alone is unable to explain all clinical effects observed with alpha lipoic acid. Our results invite to evaluate the significance of the inhibitory effect of alpha lipoic acid on the catalytic activity of leukotriene A(4) hydrolase using in vivo models.