An Insight into the Regiospecificity of Linoleic AcidPeroxidation Catalyzed by Mammalian 15-Lipoxygenases.

15-Lipoxygenases(15-LOs) catalyze the peroxidation reaction oflinoleic acid (LA) in mammals producing almost exclusively 13-(S)-hydroperoxyoctadecadienoic acid (13-(S)-HPODE). Although several hypotheses have been formulated, the molecularbasis of such enzymatic regiospecificity is unclear. We have herecombined quantum mechanics/molecular mechanics (QM/MM) calculationswith molecular dynamics simulations to analyze the peroxidation mechanismusing a complete rabbit 15-LO-1/LA solvated model. C9andC13being equivalent for planarity and spin density, theQM/MM potential energy profiles of the O2addition to thosetwo atoms were calculated. The difference in the potential energybarrier heights is clear enough to justify that O2selectivelyattacks C13giving 13-(S)-HPODE. Oxygenationat C9is hindered by two steric-shielding residues (Leu597and Gln548). The calculated free energy profile at 300 K for the O2addition to C13confirms that the peroxidationon C13is a reversible viable process in agreement withexperiments. Thus, the subsequent reduction of the peroxyl radicalto give the final hydroperoxidated product is expected to give theirreversibility character to the overall process. [ABSTRACT FROM AUTHOR]