Advertisement

Pgg211r-Hpete and 15r/S-Hpete are Formed From Different Conformers of Arachidonic Acid in the Prostaglandin Endoperoxide H Synthase-1 Cyclooxygenase Site

  • Elizabeth D. Thuresson
  • Karen M. Lakkides
  • William L. Smith
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 507)

Abstract

Prostaglandin endoperoxide H synthases-1 and -2 (PGHS-1 and -2) catalyze the committed step in the formation of prostanoids (prostaglandins, thromboxane A2 (l-6). PGHSs catalyze two separate reactions: a cyclooxygenase reaction in which arachidonate is converted to prostaglandin G2 (PGG2) and a peroxidase reaction in which PGG2undergoes a two-electron reduction to PGH2. The cyclooxygenase reaction begins with a rate-limiting abstraction of the 13-proS hydrogen from arachidonate to yield an arachidonyl radical (7,8). This is followed by sequential oxygen additions at C-11 and C-15 to yield the prostaglandin endoperoxide PGG2. PGHSs exhibit some lipoxygenase activity producing small amounts of 11-hydroperoxy-5Z,8Z,12E,14Z-eicosatetraenoic acid (11-HPETE) and 15-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (15-HPETE) from arachidonic acid (9, 10). Aspirin-acetylated PGHS-2, which has no cyclooxygenase activity, synthesizes 15R-HPETE (10,11). Studies comparing native and aspirinacetylated PGHS-2 have raised the possibility that arachidonate can bind in distinct orientations in the PGHS-2 active site to produce either PGG2, 1 l R-HPETE or 15RHPETE (10). Here we develop the concept that arachidonate can be bound in the cyclooxygenase active site of ovine (o)PGHS-1 in at least three different, catalytically competent arrangements that lead to PGG2, 11R-HPETE, and 15R/S-HPETE, respectively, and that these three arrangements of arachidonate occur subsequent to its entry into the cyclooxygenase active site.

Keywords

Arachidonic Acid Lipoxygenase Activity Cyclooxygenase Activity Prostaglandin Endoperoxide Eicosatetraenoic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Smith, W. L., Marnett, L. J., and DeWitt, D. L. (1991) Pharmacol. Ther.49 153–179PubMedCrossRefGoogle Scholar
  2. 2.
    Smith, W. L., and DeWitt, D. L. (1996) in Advances in Immunology, Vol. 62 (Dixon, F. J., ed), pp. 167–215, Academic Press, San Diego, CAGoogle Scholar
  3. 3.
    Smith, W. L., Garavito, R. M., and DeWitt, D. L. (1996)J. Biol. Chem.271 33157–33160PubMedCrossRefGoogle Scholar
  4. 4.
    Marnett, L. J., Rowlinson, S. W., Goodwin, D. C., Kalgutkar, A. S., and Lanzo, C. A. (1999) J. Biol. Chem.274 22903–22906PubMedCrossRefGoogle Scholar
  5. 5.
    DeWitt, D. L. (1999)Mol. Pharmacol.55 625–631PubMedGoogle Scholar
  6. 6.
    Smith, W. L., Garavito, R. M., and DeWitt, D. L. (2000) Ann. Rev. Biochem.in press.Google Scholar
  7. 7.
    Hamberg, M., and Samuelsson, B. (1967)J. Biol. Chem. 242 5336–5343PubMedGoogle Scholar
  8. 8.
    Tsai, A., Kulmacz, R. J., and Palmer, G. (1995)J. Biol. Chem.270 10503–10508PubMedCrossRefGoogle Scholar
  9. 9.
    Hecker, M., Ullrich, V., Fischer, C., and Meese, C.O. (1987)Eur. J. Biochem.169 113–123PubMedCrossRefGoogle Scholar
  10. 10.
    Xiao, G., Tsai, A. L., Palmer, G., Boyar, W. C., Marshall, P. J., and Kulmacz, R. J. (1997) Biochemistry 36 1836–1845PubMedCrossRefGoogle Scholar
  11. 11.
    Lecomte, M., Laneuville, O., Ji, C., DeWitt, D. L., and Smith, W. L. (1994)J. Biol. Chem.269 13207–13215PubMedGoogle Scholar
  12. 12.
    Gierse, J. K., Hauser, S. D., Creely, D. P., Koboldt, C., Rangwala, S. H., Isakson, P. C., and Seibert, K. (1995) Biochem. J.305 479–484PubMedCentralPubMedGoogle Scholar
  13. 13.
    Barnett, J., Chow, J., Ives, D., Chiou, M., Mackenzie, R., Osen, E., Nguyen, B., Tsing, S., Bach, C., Freire, J., et al. (1994)Biochim. Biophys. Acta 1209, 130–139PubMedCrossRefGoogle Scholar
  14. 14.
    Meade, E. A., Smith, W. L., and DeWitt, D. L. (1993) J. Biol. Chem.268 6610–6614PubMedGoogle Scholar
  15. 15.
    Laneuville, O. I., Breuer, D. K., Xu, N., Huang, Z. H., Gage, D. A., Watson, J. T., Lagarde, M., DeWitt, D. L., and Smith, W. L. (1995) J. Biol. Chem. 270 19330–19336PubMedCrossRefGoogle Scholar
  16. 16.
    Shimokawa, T., and Smith, W. L. (1992)J. Biol.Chem. 267 12387–12392PubMedGoogle Scholar
  17. 17.
    Laneuville, O., Breuer, D. K., Dewitt, D. L., Hla, T., Funk, C. D., and Smith, W. L. (1994) J. Pharmacol. Exp. Ther. 271 927–934PubMedGoogle Scholar
  18. 18.
    Oliw, E. H., Hornsten, L., Sprecher, H., and Hamberg, M. (1993)Arch. Biochem. Biophys.305288–297PubMedCrossRefGoogle Scholar
  19. 19.
    Schneider, C., and Brash, A.R. (1999) J. Biol. Chem. 275 4743–4746CrossRefGoogle Scholar
  20. 20.
    Porter, N.A., Wolf, R.A., Pagels, W.R., and Marnett, L.J. (1980) Biochem. Biophys. Res. Commun. 92 349–355PubMedCrossRefGoogle Scholar
  21. 21.
    Hamberg, M., Su, C., and Oliw, E. (1998) J. Biol. Chem. 273 13080–13088PubMedCrossRefGoogle Scholar
  22. 22.
    Picot, D., Loll, P.J., and Garavito, M. (1994)Nature 367 243–249PubMedCrossRefGoogle Scholar
  23. 23.
    DeWitt, D. L., El-Harith, E. A., Kraemer, S. A., Andrews, M. J., Yao, E. F., Armstrong, R.L. and Smith, W. L. (1990) J. Biol. Chem. 265 5192–5198PubMedGoogle Scholar
  24. 24.
    Loll, P. J., Picot, D., and Garavito, R. M. (1995) Nature Str. Biol. 2 637–643.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Elizabeth D. Thuresson
    • 1
  • Karen M. Lakkides
    • 1
  • William L. Smith
    • 1
  1. 1.Department of BiochemistryMichigan State University

Personalised recommendations