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Journal of Lipid Research, Vol. 47, 2462-2474, November 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

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

Igor A. Butovich^1,*, Svetlana M. Lukyanova^* and Carl Bachmann

^* Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9057
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9057

Published, JLR Papers in Press, August 9, 2006.

¹ To whom correspondence should be addressed. e-mail: igor.butovich{at}utsouthwestern.edu

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.

Supplementary key words 10,17-dihydroxydocosahexaenoic acid • 7,17-dihydroxydocosahexaenoic acid • docosahexaenoic acid • double lipoxygenation • neuroprotectins D1 and D5 • protectins D1 and D5

Abbreviations: AA, arachidonic acid; BSTFA, bis(trimethylsilyl)trifluoroacetamide; DHA, docosahexaenoic acid; diHDA, dihydroxydocosanoic acid; diHDHA, dihydroxydocosahexaenoic acid; hr5LOX, human recombinant 5-lipoxygenase; NP, normal-phase; PD1, protectin D1; ptLOX, potato tuber lipoxygenase; RP, reverse-phase; RT, retention time; sLOX, soybean lipoxygenase; 10,17(S)-diH(P)DHA, 10,17(S)-dihydro(pero)xydocosahexa-4Z,7Z,11E,13Z,15E,19Z-enoic acid; 7,17(S)-diH(P)DHA, 7,17(S)-dihydro(pero)xydocosahexaenoic acid; 17(S)-H(P)DHA, 17(S)-hydro(pero)xydocosahexa-4Z,7Z,11Z,13Z,15E,19Z-enoic acid; 5(S)-HPETE, 5(S)-hydroperoxyeicosatetraenoic acid; 13(S)-HPODE, 13(S)-hydroperoxyoctadecadi-9Z,11E-enoic acid; UV, ultraviolet

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