Dihydroxydocosahexaenoic acids of the neuroprotectin D family: Synthesis, structure, and inhibition of human 5-lipoxygenase

Igor A. Butovich, Svetlana M. Lukyanova, Carl Bachmann

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

During aerobic oxidation of docosahexaenoic acid (DHA), soybean lipoxygenase (sLOX) has been shown to form 7,17(S)-dihydro(pero) xydocosahexaenoic acid [7,17(S)-diH(P)DHA] along with its previously described positional isomer, 10,17(S)-dihydro(pero)xydocosahexa-4Z,7Z,11E,13Z, 15E,19Z-enoic acid. 7,17(S)-diH(P)DHA was also obtained via sLOX-catalyzed oxidation of either 17(S)-hydroperoxydocosahexaenoic acid [17(S)-HPDHA] or 17(S)-hydroxydocosahexaenoic acid [17(S)-HDHA]. The structures of the products were elucidated by normal-phase, reverse-phase, and chiral-phase HPLC analyses and by ultraviolet, NMR, and tandem mass spectroscopy and GC-MS. 7,17(S)-diH(P)DHA was shown to have 4Z,8E,10Z,13Z,15E,19Z geometry of the double bonds. In addition, a compound apparently identical to the sLOX-derived 7,17(S)-diH(P)DHA was produced by another enzyme, potato tuber LOX, in the reactions of oxygenation of either 17(S)-HPDHA or 17(S)-HDHA. All of the dihydroxydocosahexaenoic acids (diHDHAs) formed by either of the enzymes were clearly produced through double lipoxygenation of the corresponding substrate. 7,17(S)-diHDHA inhibited human recombinant 5-lipoxygenase in the reaction of arachidonic acid (AA) oxidation. In standard conditions with 100 μM AA as substrate, the IC50 value for 7,17(S)-diHDHA was found to be 7 μM, whereas IC50 for 10,17(S)-DiHDHA was 15 μM. Similar inhibition by the diHDHAs was observed with sLOX, a quintessential 15LOX, although the strongest inhibition was produced by 10,17(S)-diHDHA (IC50 = 4 μM). Inhibition of sLOX by 7,17(S)-diHDHA was slightly less potent, with an IC50 value of 9 μM. These findings suggest that 7,17(S)-diHDHA along with its 10,17(S) counterpart might have anti-inflammatory and anticancer activities, which could be exerted, at least in part, through direct inhibition of 5LOX and 15LOX.

Original languageEnglish (US)
Pages (from-to)2462-2474
Number of pages13
JournalJournal of lipid research
Volume47
Issue number11
DOIs
StatePublished - Nov 1 2006

Keywords

  • 10,17-dihydroxydocosahexaenoic acid
  • 7,17-dihydroxydocosahexaenoic acid
  • Docosahexaenoic acid
  • Double lipoxygenation
  • Neuroprotectins D1 and D5
  • Protectins D1 and D5

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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