Abstract
Oxygenation of the 5-lipoxygenase product 5S-hydroxyeicosatetraenoic acid by cyclooxygenase-2 yields a bicyclic di-endoperoxide. The di-endoperoxide contains two peroxides spanning from carbons 9 to 11 and 8 to 12, and two hydroxyls at carbons 5 and 15 of arachidonic acid (Schneider C., et al. 2006. Convergent oxygenation of arachidonic acid by 5-lipoxygenase and cyclooxygenase-2. J. Am. Chem. Soc. 128: 720). Here, we report that treatment of the di-endoperoxide with hematin or ferrous chloride results in cleavage of both peroxide O-O bonds and of the bonds between the carbons that carry the peroxide groups, producing the aldehydes 4-hydroxy-2E-nonenal (4-HNE), 8-oxo-5S-hydroxy-6E-octenoic acid, and malondialdehyde (MDA). The hematin- and ferrous iron-catalyzed transformation of the di-endoperoxide proceeded with a similar yield of products as the cleavage of the prostaglandin endoperoxide PGH(2) to 12S-hydroxy-5Z,8E,10E-heptadecatrienoic acid and MDA. Chiral phase HPLC analysis of the 4-HNE cleavage product showed greater than 98% 4S and thus established the S configuration of the 15-carbon of the di-endoperoxide that had not previously been assigned. This transformation of the 5-lipoxygenase/cyclooxygenase-2 derived di-endoperoxide invokes the possibility of a novel pathway to formation of the classic lipid peroxidation products 4-HNE and MDA.
Highlights
Oxygenation of the 5-lipoxygenase product 5Shydroxyeicosatetraenoic acid by cyclooxygenase-2 yields a bicyclic di-endoperoxide
During the transformation of 5S-HETE, COX-2 consumes 3 mol of oxygen and forms a di-endoperoxide that is structurally reminiscent of the prostaglandin endoperoxide (PGH2) derived from double oxygenation of arachidonic acid by either COX isozyme (Fig. 1)
Heme-catalyzed transformation of the 5-LOX/COX-2 derived di-endoperoxide of arachidonic acid resulted in chain cleavage between the carbons carrying the peroxide groups and between the O-O bonds of both peroxide groups (Fig. 5A)
Summary
Oxygenation of the 5-lipoxygenase product 5Shydroxyeicosatetraenoic acid by cyclooxygenase-2 yields a bicyclic di-endoperoxide. The hematin- and ferrous iron-catalyzed transformation of the di-endoperoxide proceeded with a similar yield of products as the cleavage of the prostaglandin endoperoxide PGH2 to 12S-hydroxy-5Z,8E,10E-heptadecatrienoic acid and MDA. Chiral phase HPLC analysis of the 4-HNE cleavage product showed greater than 98% 4S and established the S configuration of the 15-carbon of the diendoperoxide that had not previously been assigned This transformation of the 5-lipoxygenase/cyclooxygenase-2 derived di-endoperoxide invokes the possibility of a novel pathway to formation of the classic lipid peroxidation products 4-HNE and MDA.—Griesser, M.,W. The 5-lipoxygenase (5-LOX) product 5S-hydroxy-eicosatetra-6E,8Z,11Z,14Z-enoic acid (5S-HETE) is an efficient substrate for oxygenation by the so-called “inducible” form of prostaglandin H synthase, cyclooxygenase-2 (COX-2) [1]. Identification of an unstable peroxide product similar to PGH2, but formed by consecutive action of 5-LOX and COX-2, has invoked the possibility of a cross-over of the leukotriene and prostaglandin biosynthetic pathways.
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