Double dioxygenation by mouse 8S-lipoxygenase:: Specific formation of a potent peroxisome proliferator-activated receptor α agonist
Double dioxygenation by mouse 8S-lipoxygenase:: Specific formation of a potent peroxisome proliferator-activated receptor α agonist
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DOI：
10.1016/j.bbrc.2005.08.029
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发表时间：
2005-12-09
影响因子：
3.1
通讯作者：
Yokota, K
中科院分区：
文献类型：
--
作者：
Jisaka, M;Iwanaga, C;Yokota, K
小鼠8 S-脂氧合酶（8-LOX）特异性地将花生四烯酸（AA）代谢为8 S-氢过氧二十碳四烯酸（8 S-HPETE），其在生理环境下将容易地还原为8 S-羟基二十碳四烯酸（8 S-HETE），8 S-HETE是过氧化物酶体增殖物激活受体α（PPAR α）的天然激动剂。在这里，我们研究了8-LOX是否可以进一步激活AA以及产物是否可以激活PPARs。纯化的重组8-LOX将AA仅转化为8 S-HPETE，然后转化为（8 S，15 S）-二氢过氧-5Z，9 E，11 Z，13 E-二十碳四烯酸（8 S，15 S-diHPETE）。8 S-HPETE和AA的k（cat）/K-m值分别为3.3 x 10（3）和2.7 x 10（4）M-1 s（-1）。8-LOX还将8 S-HETE和15 S-H（P）埃特特异性地双氧化成相应的8 S，15 S-二取代衍生物。相比之下，15-LOX-2（8-LOX的人类同源物）从8 S-H（P）埃特产生8 S，15 S-diH（P）埃特，但不从AA或15 S-H（P）埃特产生。8 S，15 S-diHETE比8 S-HETE更强地激活PPAR α。本研究结果表明，8 S，15 S-diH（P）埃特和8 S-H（P）埃特可能参与8-LOX的生理功能，8-LOX可能作为潜在的15-LOX发挥作用。(c)2005年爱思唯尔公司All rights reserved.
Mouse 8S-lipoxygenase (8-LOX) metabolizes arachidonic acid (AA) specifically to 8S-hydroperoxyeicosatetraenoic acid (8S-HPETE), which will be readily reduced under physiological circumstances to 8S-hydroxyeicosatetraenoic acid (8S-HETE), a natural agonist of peroxisome proliferator-activated receptor a (PPAR alpha). Here, we investigated whether 8-LOX could further oxygenate AA and whether the products could activate PPARs. The purified recombinant 8-LOX converted AA exclusively to 8S-HPETE and then to (8S,15S)-dihydroperoxy-5Z,9E,11Z,13E-eicosatetraenoic acid (8S,15S-diHPETE). The k(cat)/K-m values for 8S-HPETE and AA were 3.3 x 10(3) and 2.7 x 10(4) M-1 s(-1), respectively. 8-LOX also dioxygenated 8S-HETE and 15S-H(P)ETE specifically to the corresponding 8S,15S-disubstituted derivatives. By contrast, 15-LOX-2, a human homologue of 8-LOX, produced 8S,15S-diH(P)ETE from 8S-H(P)ETE but not from AA nor 15S-H(P)ETE. 8S,15S-diHETE activated PPAR alpha more strongly than 8S-HETE did. The present results suggest that 8S,15S-diH(P)ETE as well as 8S-H(P)ETE would contribute to the physiological function of 8-LOX and also that 8-LOX can function as a potential 15-LOX. (c) 2005 Elsevier Inc. All rights reserved.