title: Introducing mutations to modify the C13/C9 ratio in linoleic acid oxygenations catalyzed by rabbit 15-lipoxygenase: a QM/MM and MD study.
abstract: Lipoxygenases (LOs) are a family of nonheme iron-containing enzymes that catalyze the hydroperoxidation of several polyunsaturated fatty acids with a huge regio- and stereospecificity. Mammalian 15-LO-1 yields almost exclusively oxygenation at the C13 position of the linoleic acid (LA), its preferred substrate. This is very important because metabolites derived from oxidation in distinct positions produce opposite physiological effects. We have combined here quantum mechanics/molecular mechanics calculations with molecular dynamics simulations to show how a suitable mutation of the rabbit 15-LO-1 enzyme can produce a significant amount of products derived from oxygenation at the C9 position of LA. In effect, the Leu597Val or Leu597Ala mutants are predicted to lead to a diminution of the oxygenation C13/C9 ratio in LA as huge as five orders of magnitude. This shows that the conserved residue Leu597 actually drives the regiospecific hydroperoxidation of LA catalyzed by 15-LO-1 enzyme.
authors.affiliation: Departament de Química, Universitat Autònoma de Barcelona, Bellaterra 08193, Barcelona (Spain); Institut de Biotecnologia i de Biomedicina (IBB), Universitat Autònoma de Barcelona, Bellaterra 08193, Barcelona (Spain).
authors.forename: Reynier
authors.initials: R
authors.lastname: Suardíaz
authors.forename: Laura
authors.initials: L
authors.lastname: Masgrau
authors.forename: José M
authors.initials: JM
authors.lastname: Lluch
authors.forename: Àngels
authors.initials: À
authors.lastname: González-Lafont
mesh_terms: D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D019787:Linoleic Acid / Q000737:chemistry / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D010084:Oxidation-Reduction; D017354:Point Mutation; D011817:Rabbits; D013379:Substrate Specificity
chemical_list: D019787:Linoleic Acid; D001093:Arachidonate 15-Lipoxygenase
keywords: 15-lipoxygenases; QM/MM calculations; computational chemistry; linoleic acid; mutants