Convergence of the 5-LOX and COX-2 pathways: heme-catalyzed cleavage of the 5S-HETE-derived di-endoperoxide into aldehyde fragments.
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.
Griesser
Markus
M
Division of Clinical Pharmacology, Department of Pharmacology, Vanderbilt University Medical School, Nashville, TN 37232, USA.
Boeglin
William E
WE
Suzuki
Takashi
T
Schneider
Claus
C
D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism*; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry / Q000378:metabolism*; D055162:Biocatalysis; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism*; D005296:Ferrous Compounds / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D006427:Hemin / Q000378:metabolism; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D008315:Malondialdehyde / Q000737:chemistry / Q000378:metabolism*; D010545:Peroxides / Q000378:metabolism*; D013237:Stereoisomerism
D000447:Aldehydes; D005296:Ferrous Compounds; D006893:Hydroxyeicosatetraenoic Acids; D010545:Peroxides; D006418:Heme; D008315:Malondialdehyde; D006427:Hemin; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; C027576:4-hydroxy-2-nonenal; C029451:ferrous chloride