Conjugation of the linoleic acid oxidation product, 13-oxooctadeca-9,11-dienoic acid,a bioactive endogenous substrate for mammalian glutathione transferase |
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| Institution: | 1. Department of Chemistry, Oakland University, Rochester, MI 48309-4477, USA;2. Department of Science and Math, Kettering University, Flint, MI 48504, USA;3. Department of Biochemistry, Uppsala University, SE-751 23 Uppsala, Sweden;1. Key Laboratory of Nonferrous Metals Chemistry and Resources Utilization of Gansu Province and State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, PR China;2. College of Bioresources Chemistry and Materials Engineering, Shaanxi University of Science and Technology, Xi''an 710021, PR China;3. State Key Laboratory of Pulp and Paper Engineering, South China University of Technology, Guangzhou 510640, China;1. Synthace Limited, London Bioscience Innovation Centre, 2 Royal College St, London NW1 0NH, UK;1. Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima-city, Kagoshima 890-8580, Japan;2. Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama 642-0017, Japan;3. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan;1. International Joint Research Center for Photoresponsive Molecules and Materials, School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, China;2. Public Health Research Center at Jiangnan University, Wuxi 214122, China |
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| Abstract: | The oxidation of linoleic acid leads to the generation of several products with biological activity, including 13-oxooctadeca-9,11-dienoic acid (13-OXO), a bioactive 2,4-dienone that has been linked to cell differentiation. In the current work, the conjugation of 13-OXO by human glutathione transferases (GSTs) of the alpha (A1–1, A4–4), mu (M1–1, M2–2) and pi (the allelic variants P1–1/ile, and P1–1/val) classes, and a rat theta (rT2–2) class enzyme has been evaluated. The kinetics and stereoselectivity of the production of the 13-OXO-glutathione conjugate (13-OXO-SG) have been examined. In contrast to many xenobiotic substrates, the endogenous substrate 13-OXO does not exhibit an appreciable non-enzymatic rate of conjugation under physiological conditions. Therefore, the GST-catalyzed conjugation takes on greater significance as it provides the only realistic means for formation of 13-OXO-SG in most biological systems. Alpha class enzymes are most efficient at catalyzing the formation of 13-OXO-SG with kcat/Km values of 8.9 mM−1 s−1 for GST A1–1 and 2.14 mM−1 s−1 for GST A4–4. In comparison, enzymes from the mu and pi classes exhibit specificity constants from 0.4 to 0.8 mM−1 s−1. Conjugation of 13-OXO with glutathione at C-9 of the substrate can yield a pair of diastereomers that can be resolved by chiral HPLC. GSTs from the mu and pi classes are the most stereoselective enzymes and there is no apparent relationship between catalytic efficiency and stereoselectivity. The role of GST in the metabolic disposition of the bioactive oxidation products of linoleic acid has implications for the regulation of normal cellular functions by these versatile enzymes. |
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