title: Effect of alpha lipoic acid on leukotriene A4hydrolase.
abstract: Leukotriene A4hydrolase is a soluble enzyme with epoxide hydrolase and aminopeptidase activities catalysing the conversion of leukotriene A4to leukotriene B4and the hydrolysis of the peptide proline-glycine-proline. Imbalances in leukotriene B4synthesis are related to several pathologic conditions. Currently there are no available drugs capable to modulate the synthesis of leukotriene B4or to block its receptors. Here we show the inhibitory profile of alpha lipoic acid on the activity of leukotriene A4Hydrolase. Alpha lipoic acid inhibited both activities of the enzyme at concentrations lower than 10μM. The 5-lipoxygenase inhibitor zileuton, or the 5-lipoxygenase activating protein inhibitor MK-886, were unable to inhibit the activity of the enzyme. Acute promyelocytic leukaemia HL-60 cells were differentiated to leukotriene A4hydrolase 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 A4hydrolase using in vivo models.
authors.affiliation: Laboratorio de Farmacología y Toxicología Molecular, Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Chile; Laboratorio de Simulación Molecular, Departamento de Química Orgánica, Facultad de Química, Pontificia Universidad Católica de Chile, Chile.
authors.forename: María José
authors.initials: MJ
authors.lastname: Torres
authors.affiliation: Laboratorio de Simulación Molecular, Departamento de Química Orgánica, Facultad de Química, Pontificia Universidad Católica de Chile, Chile.
authors.forename: Angélica
authors.initials: A
authors.lastname: Fierro
authors.affiliation: Laboratorio de Diseño y Síntesis de Ligandos Cannabinoides, Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Chile.
authors.forename: C David
authors.initials: CD
authors.lastname: Pessoa-Mahana
authors.affiliation: Laboratorio de Farmacología y Toxicología Molecular, Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Chile; Laboratorio de Diseño y Síntesis de Ligandos Cannabinoides, Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Chile.
authors.forename: Javier
authors.initials: J
authors.lastname: Romero-Parra
authors.affiliation: Laboratorio de Biología Celular, Programa de Biología Celular y Molecular, Instituto de Ciencias Biomedicas, Facultad de Medicina, Universidad de Chile, Chile.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Cabrera
authors.affiliation: Laboratorio de Farmacología y Toxicología Molecular, Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Chile. Electronic address: mfaundeza@uc.cl.
authors.forename: Mario
authors.initials: M
authors.lastname: Faúndez
mesh_terms: D003600:Cytosol / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D009504:Neutrophils / Q000166:cytology; D008063:Thioctic Acid / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D008063:Thioctic Acid; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase
keywords: Alpha lipoic acid; Leukotriene A(4); Leukotriene A(4) hydrolase; Leukotrienes synthesis; Proline-glycine-proline