2026-04-14T05:17:25Zhttps://recercat.cat/oai/request

oai:recercat.cat:2072/4408232026-03-13T06:53:40Zcom_2072_98col_2072_378192

00925njm 22002777a 4500 dc Saura Martínez, Patricia author Maréchal, Jean-Didier author Masgrau, Laura author Lluch López, Josep Maria author González Lafont, Àngels author 2016 In the present work we have combined homology modeling, protein-ligand dockings, quantum mechanics/molecular mechanics calculations and molecular dynamics simulations to generate human 5-lipoxygenase (5-LOX):arachidonic acid (AA) complexes consistent with the 5-lipoxygenating activity (which implies hydrogen abstraction at the C position). Our results suggest that both the holo and the apo forms of human Stable 5-LOX could accommodate AA in a productive form for 5-lipoxygenation. The former, in a tail-first orientation, with the AA carboxylate end interacting with Lys409, gives the desired structures with C close to the Fe-OH cofactor and suitable barrier heights for H abstraction. Only when using the apo form structure, a head-first orientation with the AA carboxylate close to His600 (a residue recently proposed as essential for AA positioning) is obtained in the docking calculations. However, the calculated barrier heights for this head-first orientation are in principle consistent with 5-LOX specificity, but also with 12/8 regioselectivity. Finally, long MD simulations give support to the recent hypothesis that the Phe177 + Tyr181 pair needs to close the active site access during the chemical reaction, and suggest that in the case of a head-first orientation Phe177 may be the residue interacting with the AA carboxylate. Arachidonate 5-lipoxygenase Arachidonic acid Binding sites Catalysis Humans Hydrogen Molecular dynamics simulation Computational insight into the catalytic implication of head/tail-first orientation of arachidonic acid in human 5-lipoxygenase : consequences for the positional specificity of oxygenation