title: Robust inhibitory effects of conjugated linolenic acids on a cyclooxygenase-related linoleate 10S-dioxygenase: Comparison with COX-1 and COX-2.
abstract: There are many reports of the anti-inflammatory, anti-cancer, and anti-atherosclerotic activities of conjugated linolenic acids (cLNA). They constitute a small percentage of fatty acids in the typical human diet, although up to 80% of the fatty acids in certain fruits such as pomegranate. In the course of studying a bacterial fatty acid dioxygenase (Nostoc linoleate 10S-DOX, an ancient relative of mammalian cyclooxygenases), we detected strong inhibitory activity in a commercial sample of linoleic acid. We identified two cLNA isomers, β-eleostearic (9E,11E,13E-18:3) and β-calendic acid (8E,10E,12E-18:3), as responsible for that striking inhibition with a Ki of ~49nM and ~125nM, respectively, the most potent among eight cLNA tested. We also examined the effects of all eight cLNA on the activity of COX-1 and COX-2. Jacaric acid (8Z,10E,12Z-18:3) and its 12E isomer, 8Z,10E,12E-18:3, strongly inhibit the activity of COX-1 with a Ki of ~1.7 and ~1.1μM, respectively. By contrast, COX-2 was ≤30% inhibited at 10μM concentrations of the cLNA. Identifying the activities of the naturally occurring fatty acids is of interest in terms of understanding their interaction with the enzymes, and for explaining the mechanistic basis of their biological effects. The study also highlights the potential presence of inhibitory fatty acids in commercial lipids prepared from natural sources. Analysis of seven commercial samples of linoleic acid by HPLC and UV spectroscopy is illustrated as supplementary data.
authors.affiliation: Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Mashhadi
authors.affiliation: Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Boeglin
authors.affiliation: Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: alan.brash@vanderbilt.edu.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Brash
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry*; D051545:Cyclooxygenase 1 / Q000737:chemistry*; D051546:Cyclooxygenase 2 / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D008042:Linolenic Acids / Q000737:chemistry*; D046937:Nostoc / Q000201:enzymology*; D013237:Stereoisomerism
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D008042:Linolenic Acids; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human
keywords: 10S-DOX; Conjugated fatty acid; Cyclooxygenase; Fatty acid dioxygenase; Linoleic acid; Nostoc punctiforme