title: Lipoxygenase interactions with natural flavonoid, quercetin, reveal a complex with protocatechuic acid in its X-ray structure at 2.1 A resolution.
abstract: PUFA metabolites have a profound effect on inflammatory diseases and cancer progression. Blocking their production by inhibiting PUFA metabolizing enzymes (dioxygenases: cyclooxygenases and LOXs) might be a successful way to control and relieve such problems, if we learn to better understand their actions at a molecular level. Compounds with strong antioxidative and free radical scavenging properties, such as polyphenols, could be effective in blocking PUFA activities, and natural flavonoids possess such qualities. Quercetin belongs to the group of natural catecholic compounds and is known as a potent, competitive inhibitor of LOX. Structural analysis reveals that quercetin entrapped within LOX undergoes degradation, and the resulting compound has been identified by X-ray analysis as protocatechuic acid (3,4-dihydroxybenzoic acid) positioned near the iron site. Its C3-OH group points toward His523, C4-OH forms a hydrogen bond with O=C from the enzyme's C-terminus, and the carboxylic group is incorporated into the hydrogen bonding network of the active-site neighborhood via Gln514. This unexpected result, together with our previous observations concerning other polyphenols, yields new evidence about the metabolism of natural flavonoids. These compounds might be vulnerable to the co-oxidase activity of LOX, leading to enzyme-stimulated oxidative degradation, which results in an inhibitor of a lower molecular weight.
authors.affiliation: Medical College of Ohio, Urology Research Center, Department of Urology, Toledo, Ohio 43614, USA.
authors.forename: Oleg Y
authors.initials: OY
authors.lastname: Borbulevych
authors.forename: Jerzy
authors.initials: J
authors.lastname: Jankun
authors.forename: Steven H
authors.initials: SH
authors.lastname: Selman
authors.forename: Ewa
authors.initials: E
authors.lastname: Skrzypczak-Jankun
mesh_terms: D018360:Crystallography, X-Ray; D062385:Hydroxybenzoates / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008084:Lipoxygenase / Q000737:chemistry* / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D046911:Macromolecular Substances; D008958:Models, Molecular; D011794:Quercetin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D062385:Hydroxybenzoates; D016859:Lipoxygenase Inhibitors; D046911:Macromolecular Substances; C009091:protocatechuic acid; D011794:Quercetin; C095864:lipoxygenase 3; D008084:Lipoxygenase