2. Academic Validation
  3. Double dioxygenation by mouse 8S-lipoxygenase: specific formation of a potent peroxisome proliferator-activated receptor alpha agonist

Double dioxygenation by mouse 8S-lipoxygenase: specific formation of a potent peroxisome proliferator-activated receptor alpha agonist

  • Biochem Biophys Res Commun. 2005 Dec 9;338(1):136-43. doi: 10.1016/j.bbrc.2005.08.029.
Mitsuo Jisaka 1,  Chitose Iwanaga,  Nobuyuki Takahashi,  Tsuyoshi Goto,  Teruo Kawada,  Tatsuyuki Yamamoto,  Izumi Ikeda,  Kohji Nishimura,  Tsutomu Nagaya,  Tohru Fushiki,  Kazushige Yokota
Affiliations

Affiliation

  • 1 Department of Life Science and Biotechnology, Shimane University, Matsue, Shimane 690-8504, Japan. jisaka@life.shimane-u.ac.jp
PMID: 16112079 DOI: 10.1016/j.bbrc.2005.08.029
Abstract

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 alpha (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 kcat/Km values for 8S-HPETE and AA were 3.3x10(3) and 2.7x10(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.

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