Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, PO Box 5003, 1432 Ås, Norway.
Lipid Mediator Unit, Center for Biochemical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
Bioorg Chem. 2020 Mar;96:103653. doi: 10.1016/j.bioorg.2020.103653. Epub 2020 Feb 8.
Cyclooxygenase-2 and several lipoxygenases convert polyunsaturated fatty acids into a large variety of products. During inflammatory processes, these enzymes form several distinct families of specialized pro-resolving lipid mediators possessing potent anti-inflammatory and pro-resolving effects. These mediators have attracted a great interest as leads in drug discovery and have recently been the subject of biosynthetic pathway studies using docosahexaenoic and n-3 docosapentaenoic acid as substrates. Herein we present enzymatic studies with cyclooxygenase-2 and 5-, 12- and 15-lipoxygenase enzymes using 3-oxa n-3 DPA as a synthetic mimic of n-3 docosapentaenoic acid. Structural elucidation based on data from RP-HPLC UV and LC/MS-MS experiments enabled the identification of novel enzymatically formed products. These findings constitute the basis for further biosynthetic studies towards understanding the mechanisms regulating substrate utilization in the biosynthesis of specialized pro-resolving lipid mediators.
环氧化酶-2 和几种脂氧合酶将多不饱和脂肪酸转化为多种产物。在炎症过程中，这些酶形成几种不同的专门促解决脂质介质家族，具有强大的抗炎和促解决作用。这些介质作为药物发现的先导化合物引起了极大的兴趣，并最近成为使用二十二碳六烯酸和 n-3 二十二碳五烯酸作为底物的生物合成途径研究的主题。在此，我们介绍了使用 3-氧代 n-3 DPA 作为 n-3 二十二碳五烯酸的合成模拟物，通过环氧化酶-2 和 5-、12-和 15-脂氧合酶酶进行的酶学研究。基于从反相高效液相色谱 UV 和 LC/MS-MS 实验获得的数据进行的结构阐明，使能够鉴定出新的酶促形成产物。这些发现为进一步的生物合成研究奠定了基础，旨在了解调节专门促解决脂质介质生物合成中底物利用的机制。
