Dihydroxydocosahexaenoic acids of the neuroprotectin D family: synthesis, structure, and inhibition of human 5-lipoxygenase
Dihydroxydocosahexaenoic acids of the neuroprotectin D family: synthesis, structure, and inhibition of human 5-lipoxygenase
复制标题
DOI：
10.1194/jlr.m600280-jlr200
复制
发表时间：
2006-11-01
影响因子：
6.5
通讯作者：
Bachmann, Carl
中科院分区：
文献类型：
--
作者：
Butovich, Igor A.;Lukyanova, Svetlana M.;Bachmann, Carl
在二十二碳六烯酸（DHA）的有氧氧化过程中，大豆脂氧合酶（sLOX）已显示形成7，17（S）-二氢（佩罗）氧基二十二碳六烯酸[7，17（S）diH（P）DHA]及其先前描述的位置异构体10，17（S）-二氢（佩罗）氧基二十二碳六烯酸-4 Z，7 Z，11 E，13 Z，15 E，19 Z-烯酸。7，17（S）-diH（P）DHA也通过17（S）-氢过氧二十二碳六烯酸[17（S）-HPDHA]或17（S）-羟基二十二碳六烯酸[17（S）-HDHA]的sLOX催化氧化获得。通过正相、反相和手性HPLC分析以及紫外、NMR和串联质谱和GC-MS来阐明产物的结构。显示7，17（S）-diH（P）DHA具有4Z、8E、10Z、13Z、15E、19Z的双键几何构型。此外，在17（S）-HPDHA或17（S）-HDHA的氧化反应中，通过另一种酶马铃薯块茎LOX产生了与sLOX衍生的7，17（S）-diH（P）DHA明显相同的化合物。所有的二羟基-二十二碳六烯酸（diHDHA）形成的酶都清楚地通过双脂氧合相应的基板。7，17（S）-diHDHA在花生四烯酸（AA）氧化反应中抑制人重组5-脂氧合酶。在以100 μ M AA为底物的标准条件下，发现7，17（S）-diHDHA的IC 50值为7 mM，而10，17（S）-DiHDHA的IC 50为15 mM。用典型的15 LOX sLOX观察到diHDHA的类似抑制作用，尽管最强的抑制作用是由10，17（S）-diHDHA产生的（IC 50 = 4 μ M）。7，17（S）-diHDHA对sLOX的抑制作用略弱，IC 50值为9 mM。这些发现表明，7，17（S）-diHDHA沿着其10，17（S）对应物可能具有抗炎和抗癌活性，其至少部分可通过直接抑制15 LOX和15 LOX来发挥。
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)-hydroperoxydoco-sahexaenoic 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 dihydroxy-docosahexaenoic 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 mu M AA as substrate, the IC50 value for 7,17(S)-diHDHA was found to be 7 mM, whereas IC50 for 10,17(S)-DiHDHA was 15 mM. 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 mu M). Inhibition of sLOX by 7,17(S)-diHDHA was slightly less potent, with an IC50 value of 9 mM. 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 15LOX and 15LOX.