Biosynthetic Crossover of 5-Lipoxygenase and Cyclooxygenase-2 Yields 5-Hydroxy-PGE 2 and 5-Hydroxy-PGD 2
Year: 2021
Type: article
Abstract: 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-PGH2 that spontaneously rearranges to 5-OH-PGE2 and 5-OH-PGD2, the 5-hydroxy analogs of arachidonic acid derived PGE2 and PGD2. The endoperoxide was identified via its predicted degradation product, 5,12-dihydroxy-heptadecatri-6E,8E,10E-enoic acid, and by SnCl2-mediated reduction to 5-OH-PGF2a. Both 5-OH-PGE2 and 5-OH-PGD2 were unstable and degraded rapidly upon treatment with weak base. The instability hampered detection in biologic samples which was overcome by in situ reduction using NaBH4 to yield the corresponding stable 5-OH-PGF2 diastereomers and enabled detection of 5-OH-PGF2a in activated primary human leukocytes. 5-OH-PGE2 and 5-OH-PGD2 were unable to activate EP and DP prostanoid receptors suggesting their bioactivity is distinct from PGE2 and PGD2.
Source: JACS Au
Institutions: Vanderbilt University, Juntendo University
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,000
Funders: American Heart Association, Vanderbilt University, Georgia Clinical and Translational Science Alliance, Ministry of Education, Culture, Sports, Science and Technology, National Institutes of Health, Japan Society for the Promotion of Science, National Institute of General Medical Sciences, National Center for Research Resources
Awards: G1531600799, Identification and characterization of the target proteins of anti-inflammatory lipid mediator, G185044200, 5-hydroxy-prostaglandins as novel modulators of prostaglandin receptor signaling, G2043477120, The in vivo roles of polyunsaturated fatty acid species, G4878912258, G4910700291, G560889077, G563474107, G5705944061, The Vanderbilt Institute for Clinical and Translational Research (VICTR) UL1, G7004084984, The in vivo roles of biosynthetic enzyme and receptors for leukotriene B4, Development of BLT2 agonist based on the structure of BLT2, G9000043901, G9000057858, G9000142379, G9000300101, G949362299
OpenAlex ID: W3156458317