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 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. © 2018 by the authors.

Authors
Chistyakov D.V.1 , Filimonov I.S.2 , Azbukina N.V.3 , Goriainov S.V. 4 , Chistyakov V.V. 4 , Fomich M.A.5 , Bekish A.V.5 , Shmanai V.V.5 , Sergeeva M.G. 1 , Shchepinov M.S.6
Journal
Publisher
MDPI AG
Number of issue
12
Language
English
Status
Published
Number
3331
Volume
23
Year
2018
Organizations
  • 1 Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, 119992, Russian Federation
  • 2 All-Russian Research Institute for Optophysical Measurements (VNIIOFI), Ozernaya 46, Moscow, 119361, Russian Federation
  • 3 Faculty of Bioengineering and Bioinformatics, Moscow Lomonosov State University, Moscow, 119234, Russian Federation
  • 4 SREC PFUR, Peoples’ Friendship University of Russia (RUDN University), Moscow, 117198, Russian Federation
  • 5 Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, Surganova Str 13, Minsk, 220072, Belarus
  • 6 Retrotope, Incorporated, 4300 El Camino Real, Suite 201, Los Altos, CA 94022, United States
Keywords
Deuterated arachidonic acids; Eicosanoids; Human 15-lipoxygenase-2; Human 5-lipoxygenase; Human cyclooxygenase 2; Isotope effect
Date of creation
04.02.2019
Date of change
04.02.2019
Short link
https://repository.rudn.ru/en/records/article/record/36178/
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