HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 31, 22254-22266, August 3, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/31/22254    most recent M703169200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wada, M. Articles by Smith, W. L. Search for Related Content PubMed PubMed Citation Articles by Wada, M. Articles by Smith, W. L. Related Collections Papers Of The Week Social Bookmarking                      What's this?

Enzymes and Receptors of Prostaglandin Pathways with Arachidonic Acid-derived Versus Eicosapentaenoic Acid-derived Substrates and Products^*

Masayuki Wada¹, Cynthia J. DeLong¹, 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, De Xin Sui, John W. Regan, and William L. Smith²

From the Department of Biological Chemistry and Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, the ^¶Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, the ^||21st Century Center of Excellence Program, Department of Cellular Physiological Chemistry, Tokyo Medical and Dental University, 1-5-45, Yushima, Tokyo-113-8549, Japan, the ^**Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, the Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48109, and the Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721

Dietary fish oil containing 3 highly unsaturated fatty acids has cardioprotective and anti-inflammatory effects. Prostaglandins (PGs) and thromboxanes are produced in vivo both from the 6 fatty acid arachidonic acid (AA) and the 3 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 TP 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 3 fatty acids such as EPA.

Received for publication, April 16, 2007 , and in revised form, May 11, 2007.

^* This work was supported in part by National Institutes of Health (NIH) Grant GM68848 (to W. L. S.), NIH HL56773 (to R. M. G.), and NIH NSRA HL075993 (to C. J. D.) and by a postdoctoral fellowship from the Heart and Stroke Foundation of Canada (to R. S. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Biological Chemistry, University of Michigan Medical School, 5301 Medical Science Research Bldg. III, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0606. Tel.: 734-647-6180; Fax: 734-764-3509; E-mail: smithww{at}umich.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				G. L. Milne, H. Yin, and J. D. Morrow Human Biochemistry of the Isoprostane Pathway J. Biol. Chem., June 6, 2008; 283(23): 15533 - 15537. [Full Text] [PDF]

				J. D. Brooks, G. L. Milne, H. Yin, S. C. Sanchez, N. A. Porter, and J. D. Morrow Formation of Highly Reactive Cyclopentenone Isoprostane Compounds (A3/J3-Isoprostanes) in Vivo from Eicosapentaenoic Acid J. Biol. Chem., May 2, 2008; 283(18): 12043 - 12055. [Abstract] [Full Text] [PDF]

				U. R. Mbonye, C. Yuan, C. E. Harris, R. S. Sidhu, I. Song, T. Arakawa, and W. L. Smith Two Distinct Pathways for Cyclooxygenase-2 Protein Degradation J. Biol. Chem., March 28, 2008; 283(13): 8611 - 8623. [Abstract] [Full Text] [PDF]

				W.-L. Song, J. A. Lawson, D. Reilly, J. Rokach, C.-T. Chang, B. Giasson, and G. A. FitzGerald Neurofurans, Novel Indices of Oxidant Stress Derived from Docosahexaenoic Acid J. Biol. Chem., January 4, 2008; 283(1): 6 - 16. [Abstract] [Full Text] [PDF]

				H. Yin, J. D. Brooks, L. Gao, N. A. Porter, and J. D. Morrow Identification of Novel Autoxidation Products of the {omega}-3 Fatty Acid Eicosapentaenoic Acid in Vitro and in Vivo J. Biol. Chem., October 12, 2007; 282(41): 29890 - 29901. [Abstract] [Full Text] [PDF]