Enzymes and receptors of prostaglandin pathways with arachidonic acid-derived versus eicosapentaenoic acid-derived substrates and products

Masayuki Wada, Cynthia J. DeLong, Yu H. Hong, Caroline J. Rieke, Inseok Song, Ranjinder S. Sidhu, Chong Yuan, Mark Warnock, Alvin H. Schmaier, Chieko Yokoyama, Emer M. Smyth, Stephen J. Wilson, Garret A. FitzGerald, R. Michael Garavito, Xin Sui De, John W Regan, William L. Smith

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269 Scopus citations

Abstract

Dietary fish oil containing ω3 highly unsaturated fatty acids has cardioprotective and anti-inflammatory effects. Prostaglandins (PGs) and thromboxanes are produced in vivo both from the ω6 fatty acid arachidonic acid (AA) and the ω3 fatty acid eicosapentaenoic acid (EPA). Certain beneficial effects of fish oil may result from altered PG metabolism resulting from increases in the EPA/AA ratios of precursor phospholipids. Here we report in vitro specificities of prostanoid enzymes and receptors toward EPA-derived, 3-series versus AA-derived, 2-series prostanoid substrates and products. The largest difference was seen with PG endoperoxide H synthase (PGHS)-1. Under optimal conditions purified PGHS-1 oxygenates EPA with only 10% of the efficiency of AA, and EPA significantly inhibits AA oxygenation by PGHS-1. Two- to 3-fold higher activities or potencies with 2-series versus 3-series compounds were observed with PGHS-2, PGD synthases, microsomal PGE synthase-1 and EP1, EP2, EP3, and FP receptors. Our most surprising observation was that AA oxygenation by PGHS-2 is only modestly inhibited by EPA (i.e. PGHS-2 exhibits a marked preference for AA when EPA and AA are tested together). Also unexpectedly, TxA3 is about equipotent to TxA2 at the TPα receptor. Our biochemical data predict that increasing phospholipid EPA/AA ratios in cells would dampen prostanoid signaling with the largest effects being on PGHS-1 pathways involving PGD, PGE, and PGF. Production of 2-series prostanoids from AA by PGHS-2 would be expected to decrease in proportion to the compensatory decrease in the AA content of phospholipids that would result from increased incorporation of α3 fatty acids such as EPA.

Original languageEnglish (US)
Pages (from-to)22254-22266
Number of pages13
JournalJournal of Biological Chemistry
Volume282
Issue number31
DOIs
Publication statusPublished - Aug 3 2007

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ASJC Scopus subject areas

  • Biochemistry

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