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 microM AA as substrate, the IC(50) value for 7,17(S)-diHDHA was found to be 7 microM, whereas IC(50) for 10,17(S)-DiHDHA was 15 microM. Similar inhibition by the diHDHAs was observed with sLOX, a quintessential 15LOX, although the strongest inhibition was produced by 10,17(S)-diHDHA (IC(50) = 4 microM). Inhibition of sLOX by 7,17(S)-diHDHA was slightly less potent, with an IC(50) value of 9 microM. 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.
Highlights
During aerobic oxidation of docosahexaenoic acid (DHA), soybean lipoxygenase 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 obtained via sLOX-catalyzed oxidation of either 17(S)-hydroperoxydocosahexaenoic acid [17(S)-HPDHA] or 17(S)-hydroxydocosahexaenoic acid [17(S)-HDHA]
It was proposed that protectin D1 (PD1) was produced in vivo from 17(S)-hydroperoxydocosahexaenoic acid [17(S)-HPDHA] by a lipoxygenaselike enzyme via an epoxidation/isomerization pathway (8– 11 and references cited therein)
During our potato tuber lipoxygenase (ptLOX) studies, we noticed that while oxidizing DHA, ptLOX quickly lost its activity, which was indicative of enzyme inhibition and/or inactivation during the reaction [16]. We reported that it required relatively large amounts of sLOX to make 10,17(S)- and 7,17(S)-diH(P)DHA from either DHA or 17(S)-H(P)DHA [18]
Summary
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 obtained via sLOX-catalyzed oxidation of either 17(S)-hydroperoxydocosahexaenoic acid [17(S)-HPDHA] or 17(S)-hydroxydocosahexaenoic acid [17(S)-HDHA]. 10,17(s)dihydroxydocosahexaenoic acid with postulated 4Z, 7Z, 11E, 13E, 15Z, 19Z geometry of the double bonds, which has several names—10,17(S)-docosatriene [10], neuroprotectin D1 [11], and, most recently, protectin D1 (PD1) [9]—was found to have potent anti-inflammatory properties. This compound showed antiapoptotic neuroprotective activity in brain [12], promoted the apoptosis of T-cells [13], and facilitated corneal wound healing by mechanisms that differed from its antiinflammatory activity [14]. The plant enzyme-generated PD1 was used in physiological studies and, apparently, was considered to be identical to the compound formed by mammals [8,9,10,11,12,13,14,15]
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