Deuterated Arachidonic Acids Library for Regulation of Inflammation and Controlled Synthesis of Eicosanoids: An In Vitro Study
The synthesis of signal lipids, including eicosanoids, is not fully understood, although it is key to the modulation of various inflammatory states. Recently, isotopologues of essential polyunsaturated fatty acids (PUFAs) deuterated at bis-allylic positions (D-PUFAs) have been proposed as inhibitors...
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MDPI AG
2018-12-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/23/12/3331 |
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| author | Dmitry V. Chistyakov Ivan S. Filimonov Nadezhda V. Azbukina Sergei V. Goriainov Viktor V. Chistyakov Maksim A. Fomich Andrei V. Bekish Vadim V. Shmanai Marina G. Sergeeva Mikhail S. Shchepinov |
| author_facet | Dmitry V. Chistyakov Ivan S. Filimonov Nadezhda V. Azbukina Sergei V. Goriainov Viktor V. Chistyakov Maksim A. Fomich Andrei V. Bekish Vadim V. Shmanai Marina G. Sergeeva Mikhail S. Shchepinov |
| author_sort | Dmitry V. Chistyakov |
| collection | DOAJ |
| description | The synthesis of signal lipids, including eicosanoids, is not fully understood, although it is key to the modulation of various inflammatory states. Recently, isotopologues of essential polyunsaturated fatty acids (PUFAs) deuterated at bis-allylic positions (D-PUFAs) have been proposed as inhibitors of non-enzymatic lipid peroxidation (LPO) in various disease models. Arachidonic acid (AA, 20:4 n-6) is the main precursor to several classes of eicosanoids, which are produced by cyclooxygenases (COX) and lipoxygenases (LOX). In this study we analyzed the relative activity of human recombinant enzymes COX-2, 5-LOX, and 15-LOX-2 using a library of arachidonic acids variably deuterated at the bis-allylic (C7, C10, and C13) positions. Kinetic parameters (KM, V<sub>max</sub>) and isotope effects calculated from kH/kD for seven deuterated arachidonic acid derivatives were obtained. Spectroscopic methods have shown that deuteration at the 13th position dramatically affects the kinetic parameters of COX-2 and 15-LOX-2. The activity of 5-LOX was evaluated by measuring hydroxyeicosatetraenoic acids (8-HETE and 5-HETE) using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Deuteration at the seventh and 10th positions affects the performance of the 5-LOX enzyme. A flowchart is proposed suggesting how to modulate the synthesis of selected eicosanoids using the library of deuterated isotopologues to potentially fine-tune various inflammation stages. |
| first_indexed | 2024-12-20T04:29:40Z |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-20T04:29:40Z |
| publishDate | 2018-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-f097df83ed3044ddbb6e571b636abba52022-12-21T19:53:26ZengMDPI AGMolecules1420-30492018-12-012312333110.3390/molecules23123331molecules23123331Deuterated Arachidonic Acids Library for Regulation of Inflammation and Controlled Synthesis of Eicosanoids: An In Vitro StudyDmitry V. Chistyakov0Ivan S. Filimonov1Nadezhda V. Azbukina2Sergei V. Goriainov3Viktor V. Chistyakov4Maksim A. Fomich5Andrei V. Bekish6Vadim V. Shmanai7Marina G. Sergeeva8Mikhail S. Shchepinov9Belozersky Institute of Physico-Chemical Biology, Moscow State University, 119992 Moscow, RussiaAll-Russian Research Institute for Optophysical Measurements (VNIIOFI), Ozernaya 46, 119361 Moscow, RussiaFaculty of Bioengineering and Bioinformatics, Moscow Lomonosov State University, 119234 Moscow, RussiaSREC PFUR, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, RussiaSREC PFUR, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, RussiaInstitute of Physical Organic Chemistry, National Academy of Sciences of Belarus, Surganova Str 13, 220072 Minsk, BelarusInstitute of Physical Organic Chemistry, National Academy of Sciences of Belarus, Surganova Str 13, 220072 Minsk, BelarusInstitute of Physical Organic Chemistry, National Academy of Sciences of Belarus, Surganova Str 13, 220072 Minsk, BelarusBelozersky Institute of Physico-Chemical Biology, Moscow State University, 119992 Moscow, RussiaRetrotope, Incorporated, 4300 El Camino Real, Suite 201, Los Altos, CA 94022, USAThe synthesis of signal lipids, including eicosanoids, is not fully understood, although it is key to the modulation of various inflammatory states. Recently, isotopologues of essential polyunsaturated fatty acids (PUFAs) deuterated at bis-allylic positions (D-PUFAs) have been proposed as inhibitors of non-enzymatic lipid peroxidation (LPO) in various disease models. Arachidonic acid (AA, 20:4 n-6) is the main precursor to several classes of eicosanoids, which are produced by cyclooxygenases (COX) and lipoxygenases (LOX). In this study we analyzed the relative activity of human recombinant enzymes COX-2, 5-LOX, and 15-LOX-2 using a library of arachidonic acids variably deuterated at the bis-allylic (C7, C10, and C13) positions. Kinetic parameters (KM, V<sub>max</sub>) and isotope effects calculated from kH/kD for seven deuterated arachidonic acid derivatives were obtained. Spectroscopic methods have shown that deuteration at the 13th position dramatically affects the kinetic parameters of COX-2 and 15-LOX-2. The activity of 5-LOX was evaluated by measuring hydroxyeicosatetraenoic acids (8-HETE and 5-HETE) using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Deuteration at the seventh and 10th positions affects the performance of the 5-LOX enzyme. A flowchart is proposed suggesting how to modulate the synthesis of selected eicosanoids using the library of deuterated isotopologues to potentially fine-tune various inflammation stages.https://www.mdpi.com/1420-3049/23/12/3331human 15-lipoxygenase-2human 5-lipoxygenasehuman cyclooxygenase 2deuterated arachidonic acidseicosanoidsisotope effect |
| spellingShingle | Dmitry V. Chistyakov Ivan S. Filimonov Nadezhda V. Azbukina Sergei V. Goriainov Viktor V. Chistyakov Maksim A. Fomich Andrei V. Bekish Vadim V. Shmanai Marina G. Sergeeva Mikhail S. Shchepinov Deuterated Arachidonic Acids Library for Regulation of Inflammation and Controlled Synthesis of Eicosanoids: An In Vitro Study Molecules human 15-lipoxygenase-2 human 5-lipoxygenase human cyclooxygenase 2 deuterated arachidonic acids eicosanoids isotope effect |
| title | Deuterated Arachidonic Acids Library for Regulation of Inflammation and Controlled Synthesis of Eicosanoids: An In Vitro Study |
| title_full | Deuterated Arachidonic Acids Library for Regulation of Inflammation and Controlled Synthesis of Eicosanoids: An In Vitro Study |
| title_fullStr | Deuterated Arachidonic Acids Library for Regulation of Inflammation and Controlled Synthesis of Eicosanoids: An In Vitro Study |
| title_full_unstemmed | Deuterated Arachidonic Acids Library for Regulation of Inflammation and Controlled Synthesis of Eicosanoids: An In Vitro Study |
| title_short | Deuterated Arachidonic Acids Library for Regulation of Inflammation and Controlled Synthesis of Eicosanoids: An In Vitro Study |
| title_sort | deuterated arachidonic acids library for regulation of inflammation and controlled synthesis of eicosanoids an in vitro study |
| topic | human 15-lipoxygenase-2 human 5-lipoxygenase human cyclooxygenase 2 deuterated arachidonic acids eicosanoids isotope effect |
| url | https://www.mdpi.com/1420-3049/23/12/3331 |
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