Resolvin D1 and its aspirin-triggered 17R epimer. Stereochemical assignments, anti-inflammatory properties, and enzymatic inactivation

  • J Biol Chem. 2007 Mar 30;282(13):9323-9334. doi: 10.1074/jbc.M609212200.
Yee-Ping Sun  1 ,  Sungwhan F Oh  1 ,  Jasim Uddin  2 ,  Rong Yang  1 ,  Katherine Gotlinger  3 ,  Eric Campbell  1 ,  Sean P Colgan  1 ,  Nicos A Petasis  2 ,  Charles N Serhan  4
Affiliations
  • 1. Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
  • 2. Department of Chemistry, Loker Hydrocarbon Institute, University of Southern California, Los Angeles, California 90089.
  • 3. Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine and Harvard Medical School, Boston, Massachusetts 02115.
  • 4. Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine and Harvard Medical School, Boston, Massachusetts 02115. Electronic address: [email protected].
PMID: 17244615 DOI: 10.1074/jbc.M609212200
Abstract

We recently uncovered two new families of potent docosahexaenoic acid-derived mediators, termed D series resolvins (Rv; resolution phase interaction products) and protectins. Here, we assign the stereochemistry of the conjugated double bonds and chirality of alcohols present in resolvin D1 (RvD1) and its aspirin-triggered 17R epimer (AT-RvD1) with compounds prepared by total organic synthesis. In addition, docosahexaenoic acid was converted by a single Lipoxygenase in a "one-pot" reaction to RvD1 in vitro. The synthetic compounds matched the physical and biological properties of those enzymatically generated. RvD1 proved to be 7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid, AT-RvD1 matched 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid, and they both stopped transendothelial migration of human neutrophils (EC(50) approximately 30 nM). In murine peritonitis in vivo, RvD1 and AT-RvD1 proved equipotent (at nanogram dosages), limiting polymorphonuclear leukocyte infiltration in a dose-dependent fashion. RvD1 was converted by eicosanoid oxidoreductase to novel 8-oxo- and 17-oxo-RvD1 that gave dramatically reduced bioactivity, whereas enzymatic conversion of AT-RvD1 was sharply reduced. These results establish the complete stereochemistry and actions of RvD1 and AT-RvD1 as well as demonstrate the stereoselective basis for their enzymatic inactivation. RvD1 regulates human polymorphonuclear leukocyte transendothelial migration and is anti-inflammatory. When its carbon 17S alcohol is enzymatically converted to 17-oxo-RvD1, it is essentially inactive, whereas the 17R alcohol configuration in its aspirin-triggered form (AT-RvD1) resists rapid inactivation. These results may contribute to the beneficial actions of aspirin and omega-3 fish oils in humans.

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