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Deuterated Arachidonic Acids Library for Regulation of Inflammation and Controlled Synthesis of Eicosanoids: An In Vitro Study

1
Belozersky Institute of Physico-Chemical Biology, Moscow State University, 119992 Moscow, Russia
2
All-Russian Research Institute for Optophysical Measurements (VNIIOFI), Ozernaya 46, 119361 Moscow, Russia
3
Faculty of Bioengineering and Bioinformatics, Moscow Lomonosov State University, 119234 Moscow, Russia
4
SREC PFUR, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia
5
Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, Surganova Str 13, 220072 Minsk, Belarus
6
Retrotope, Incorporated, 4300 El Camino Real, Suite 201, Los Altos, CA 94022, USA
*
Authors to whom correspondence should be addressed.
Molecules 2018, 23(12), 3331; https://doi.org/10.3390/molecules23123331
Received: 26 November 2018 / Revised: 10 December 2018 / Accepted: 10 December 2018 / Published: 15 December 2018
(This article belongs to the Section Chemical Biology)
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Abstract

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, Vmax) 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. View Full-Text
Keywords: human 15-lipoxygenase-2; human 5-lipoxygenase; human cyclooxygenase 2; deuterated arachidonic acids; eicosanoids; isotope effect human 15-lipoxygenase-2; human 5-lipoxygenase; human cyclooxygenase 2; deuterated arachidonic acids; eicosanoids; isotope effect
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Chistyakov, D.V.; Filimonov, I.S.; Azbukina, N.V.; Goriainov, S.V.; Chistyakov, V.V.; Fomich, M.A.; Bekish, A.V.; Shmanai, V.V.; Sergeeva, M.G.; Shchepinov, M.S. Deuterated Arachidonic Acids Library for Regulation of Inflammation and Controlled Synthesis of Eicosanoids: An In Vitro Study. Molecules 2018, 23, 3331.

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