jp312747q_si_001.pdf (112.79 kB)
An Insight into the Regiospecificity of Linoleic Acid Peroxidation Catalyzed by Mammalian 15-Lipoxygenases
journal contribution
posted on 2013-04-11, 00:00 authored by Reynier Suardíaz, Laura Masgrau, José
M. Lluch, Àngels González-Lafont15-Lipoxygenases
(15-LOs) catalyze the peroxidation reaction of
linoleic acid (LA) in mammals producing almost exclusively 13-(S)-hydroperoxyoctadecadienoic acid (13-(S)-HPODE). Although several hypotheses have been formulated, the molecular
basis of such enzymatic regiospecificity is unclear. We have here
combined quantum mechanics/molecular mechanics (QM/MM) calculations
with molecular dynamics simulations to analyze the peroxidation mechanism
using a complete rabbit 15-LO-1/LA solvated model. C9 and
C13 being equivalent for planarity and spin density, the
QM/MM potential energy profiles of the O2 addition to those
two atoms were calculated. The difference in the potential energy
barrier heights is clear enough to justify that O2 selectively
attacks C13 giving 13-(S)-HPODE. Oxygenation
at C9 is hindered by two steric-shielding residues (Leu597
and Gln548). The calculated free energy profile at 300 K for the O2 addition to C13 confirms that the peroxidation
on C13 is a reversible viable process in agreement with
experiments. Thus, the subsequent reduction of the peroxyl radical
to give the final hydroperoxidated product is expected to give the
irreversibility character to the overall process.