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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.JB

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.

Authors+Show Affiliations

Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts.Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts.Department of Chemistry, Loker Hydrocarbon Institute, University of Southern California, Los Angeles, California 90089.Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts.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.Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts.Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts.Department of Chemistry, Loker Hydrocarbon Institute, University of Southern California, Los Angeles, California 90089.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: cnserhan@zeus.bwh.harvard.edu.

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17244615

Citation

Sun, Yee-Ping, et al. "Resolvin D1 and Its Aspirin-triggered 17R Epimer. Stereochemical Assignments, Anti-inflammatory Properties, and Enzymatic Inactivation." The Journal of Biological Chemistry, vol. 282, no. 13, 2007, pp. 9323-9334.
Sun YP, Oh SF, Uddin J, et al. Resolvin D1 and its aspirin-triggered 17R epimer. Stereochemical assignments, anti-inflammatory properties, and enzymatic inactivation. J Biol Chem. 2007;282(13):9323-9334.
Sun, Y. P., Oh, S. F., Uddin, J., Yang, R., Gotlinger, K., Campbell, E., Colgan, S. P., Petasis, N. A., & Serhan, C. N. (2007). Resolvin D1 and its aspirin-triggered 17R epimer. Stereochemical assignments, anti-inflammatory properties, and enzymatic inactivation. The Journal of Biological Chemistry, 282(13), 9323-9334. https://doi.org/10.1074/jbc.M609212200
Sun YP, et al. 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. PubMed PMID: 17244615.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Resolvin D1 and its aspirin-triggered 17R epimer. Stereochemical assignments, anti-inflammatory properties, and enzymatic inactivation. AU - Sun,Yee-Ping, AU - Oh,Sungwhan F, AU - Uddin,Jasim, AU - Yang,Rong, AU - Gotlinger,Katherine, AU - Campbell,Eric, AU - Colgan,Sean P, AU - Petasis,Nicos A, AU - Serhan,Charles N, Y1 - 2007/01/23/ PY - 2007/1/25/pubmed PY - 2007/5/11/medline PY - 2007/1/25/entrez SP - 9323 EP - 9334 JF - The Journal of biological chemistry JO - J Biol Chem VL - 282 IS - 13 N2 - 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. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/17244615/Resolvin_D1_and_its_aspirin_triggered_17R_epimer__Stereochemical_assignments_anti_inflammatory_properties_and_enzymatic_inactivation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(19)33585-9 DB - PRIME DP - Unbound Medicine ER -