Biosynthetic Crossover of 5-Lipoxygenase and Cyclooxygenase-2 Yields 5-Hydroxy-PGE₂ and 5-Hydroxy-PGD₂

Abstract

The biosynthetic crossover of 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) enzymatic activities is a productive pathway to convert arachidonic acid into unique eicosanoids. Here, we show that COX-2 catalysis with 5-LOX derived 5-hydroxy-eicosatetraenoic acid yields the endoperoxide 5-hydroxy-PGH 2 that spontaneously rearranges to 5-OH-PGE 2 and 5-OH-PGD 2 , the 5-hydroxy analogs of arachidonic acid derived PGE 2 and PGD 2 . The endoperoxide was identified via its predicted degradation product, 5,12-dihydroxy-heptadecatri-6 E ,8 E ,10 E -enoic acid, and by SnCl 2 -mediated reduction to 5-OH-PGF 2α . Both 5-OH-PGE 2 and 5-OH-PGD 2 were unstable and degraded rapidly upon treatment with weak base. This instability hampered detection in biologic samples which was overcome by in situ reduction using NaBH 4 to yield the corresponding stable 5-OH-PGF 2 diastereomers and enabled detection of 5-OH-PGF 2α in activated primary human leukocytes. 5-OH-PGE 2 and 5-OH-PGD 2 were unable to activate EP and DP prostanoid receptors, suggesting their bioactivity is distinct from PGE 2 and PGD 2 .

The Link between Prostanoids and Cardiovascular Diseases

“…In addition to hemiketals, the diendoperoxide produced by the crossover between 5-LOX and COX-2, is even converted into hydroxy-prostaglandin D2 (5-OH-PGD2) and hydroxy-prostaglandin E2 (5-OH-PGE2) in human activated leukocytes. As in HKD2 synthesis, H-PGDS uses the diendoperoxide to produce 5-OH-PGD2 [ 312 ]. However, neither 5-OH-PGD2 nor 5-OH-PGE2 interact with PGD2 and PGE2 receptors, likely indicating a different role that has not yet been uncovered [ 312 ].…”

“…As in HKD2 synthesis, H-PGDS uses the diendoperoxide to produce 5-OH-PGD2 [ 312 ]. However, neither 5-OH-PGD2 nor 5-OH-PGE2 interact with PGD2 and PGE2 receptors, likely indicating a different role that has not yet been uncovered [ 312 ].…”

Modifiable Innate Biology within the Gut–Brain Axis for Alzheimer’s Disease

“…Overall, the modulation of 5-LOX could affect different innate immune myeloid cell developmental processes, including, among others, macrophage metabolism and specialized proresolving mediators, as well as gene transcription and protein expression in human neutrophils. In addition, 5-LOX and COX-2 are involved in the biosynthesis of 5-hydroxy-prostaglandins (5-OH-PGE2 and 5-OH-PGD2) [ 89 ] and hemiketal eicosanoids (HKE2 and HKD2) [ 90 ], which are the result of crossover between the 5-LOX and COX-2 pathways [ 91 , 92 ]. These metabolites are truly novel molecules and information on their biological activities is limited.…”

“…These metabolites are truly novel molecules and information on their biological activities is limited. 5-OH-PGs failed to activate EP and DP receptors [ 89 ], suggesting a different biological activity of PGE2 and PGD2. HKE2 and HKD2 promote inhibition of platelet aggregation [ 93 ] as well as tubulogenic promotion and migration in endothelial cells [ 90 ], which are processes related to chronic inflammatory diseases such as cardiovascular diseases and atherosclerosis.…”

The 5-LOX/COX-2 cross-over metabolite, hemiketal E2, enhances VEGFR2 activation and promotes angiogenesis

“…Following the initial oxidation of arachidonic acid by 5-lipoxygenase (5-LOX) or cyclooxygenase-2 (COX-2), respectively, the biosynthetic reactions proceed along separate pathways (1-3). Arachidonic acid can also undergo consecutive oxygenation by 5-LOX and COX-2 to yield two hemiketal (HK) eicosanoids, HKE 2 and HKD 2 (4) as well as the 5-hydroxyprostaglandins, 5-OH-PGE 2 and 5-OH-PGD 2 (5). The cross-over biosynthetic pathway entails initial oxygenation of arachidonic acid by 5-LOX to form 5 S -HETE that subsequently undergoes oxygenation by COX-2.…”