期刊
JACS AU
卷 1, 期 9, 页码 1380-1388出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacsau.1c00177
关键词
arachidonic acid; prostaglandin; eicosanoid; bioactive lipid; catalysis; endoperoxide; leukocyte
资金
- National Institute of General Medical Sciences [R01GM076592]
- Vanderbilt CTSA (NCRR/NIH) [UL1 RR024975]
- MEXT/JSPS KAKENHI [19K07357, 18H02627, 19KK0199]
- American Heart Association [16POST30690001]
- Grants-in-Aid for Scientific Research [19KK0199, 19K07357] Funding Source: KAKEN
The collaboration between COX-2 and 5-LOX can convert arachidonic acid into unique prostaglandins. The unstable 5-OH-PGE(2) and 5-OH-PGD(2) can be detected in activated leukocytes after reduction to stable products.
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-6E,8E,10E-enoic acid, and by SnCl2-mediated reduction to 5-OH-PGF(2 alpha). 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 NaBH4 to yield the corresponding stable 5-OH-PGF(2) diastereomers and enabled detection of 5-OH-PGF(2), 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).
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