Submitted on January 31, 2007
Revised on March 2, 2007
Accepted on March 2, 2007
Feedback activation of ferrous 5-lipoxygenase during leukotriene synthesis by coexisting linoleic acid
Tokuko Takajo, Kazunori Tsuchida, Koichi Ueno, and Ichiro Koshiishi
Faculty of Pharmaceutical Sciences, Nihon Pharmaceutical University, Saitama 362-0806
Corresponding Author: ikoshi{at}nichiyaku.ac.jp
Ferrous lipoxygenases seem to be activated through a feedback control mechanism via fatty acid hydroperoxides generated from polyunsaturated fatty acids (PUFAs) by partially existing ferric lipoxygenases. However, during leukotriene synthesis, feedback activation of ferrous 5-lipoxygenase in the presence of arachidonic acid (AA) was not observed. In the present study, we examined the feedback activation of ferrous 5-lipoxygenase in the 5-lipoxygenase/AA system in the presence of linoleic aicd (LA), which is a predominant component of membrane phospholipids. When potato 5-lipoxygenase was incubated with arachidonic acid and linoleic acid in the presence of nitroxyl radical, 3-carbamoyl-2,2,5,5-tetramethyl-3-pyrroline-N-oxyl (Cm
P), one-electron redox cycle reaction between ferric 5-lipoxygenase and ferrous one was detected. For each revolution of the cycle, one molecule of PUFA and one molecule of its hydroperoxide were converted into PUFA-allyl radical-CmP adduct ([PUFA-H]-CmP) and PUFA-epoxyallyl radical-CmP adduct ([PUFA-H+O]-CmP), respectively. The ratios, [AA-H]-CmP/[LA-H]-CmP and [AA-H+O]-CmP/[LA-H+O]-CmP, were estimated to be 1.7 and 0.13, respectively. These facts indicate that ferrous 5-lipoxygenase is activated through feedback control in the presence of linoleic acid, and that resulting ferric 5-lipoxygenase catalyzes the stoichiometric synthesis of leukotrienes from arachidonic acid. In conclusion, the biosynthesis of leukotrienes is remarkably efficient.
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