Oxygenation of Arachidonic Acid by Cyclooxygenases Generates Reactive Intermediates That Form Adducts with Proteins

  • Olivier Boutaud
  • Junyu Li
  • Pierre Chaurand
  • Cynthia J. Brame
  • Lawrence J. Marnett
  • L. Jackson Roberts
  • John A. Oates
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 500)

Abstract

Cyclooxygenase-2 (COX-2) catalyzes the oxygenation of arachidonic acid into the prostaglandin endoperoxide, PGH2. PGH2 is then processed by different isomerases into prostaglandins and thromboxane A2. PGH2 also undergoes rearrangement in aqueous solution into PGE2, PGD2 and into the levuglandins (LG) E2 and D2 1. LG’s are highly reactive γ-ketoaldehydes that have been shown to form adducts and cross-links with proteins 2, 3, primarily through their reaction with the ε-amine of lysine. The potential that these levuglandin adducts of proteins could be biologically important may be inferred from the knowledge that lipid-modification of proteins is known to influence their function and cellular localization 4–7.

Keywords

Aldehyde Electrophoresis Adduct Lysine Prostaglandin 

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References

  1. 1.
    R.G. Salomon, D.B. Miller, M.G. Zagorski and D.J. Coughlin, Solvent-induced fragmentation of prostaglandin endoperoxides. New aldehyde products from PGH2 and a novelintramolecular 1,2-hydride shift during endoperoxide fragmentation in aqueous solution, Journal of the American Chemical Society 106:6049 (1984).CrossRefGoogle Scholar
  2. 2.
    R.S. Iyer, S. Ghosh and R.G. Salomon, Levuglandin E2 crosslinks proteins, Prostaglandins 37:471 (1989).PubMedCrossRefGoogle Scholar
  3. 3.
    K.K. Murthi, L.R. Friedman, N.L. Oleinick and R.G. Salomon, Formation of DNA-protein cross-links in mammalian cells by levuglandin E2, Biochemistry 32:4090 (1993).PubMedCrossRefGoogle Scholar
  4. 4.
    E.M. Van Cott, L. Muszbek and M. Laposata, Fatty acid acylation of platelet proteins, Prostaglandins, Leukotrienes and Essential Fatty Acids 57:33 (1997).CrossRefGoogle Scholar
  5. 5.
    C.T. Sigal, W. Zhou, C.A. Buser, S. McLaughlin and M.D. Resh, Amino-terminal basic residues of Src mediate membrane binding through electrostatic interaction with acidic phospholipids, Proceedings of the National Academy of Sciences of the United States of America 91:12253 (1994).PubMedCrossRefGoogle Scholar
  6. 6.
    J.T. Dunphy and M.E. Linder, Signalling functions of protein palmitoylation., Biochimica et Biophysica Acta 1436:245 (1998).PubMedCrossRefGoogle Scholar
  7. 7.
    C.A. Buser, C.T. Sigal, M.D. Resh and S. McLaughlin, Membrane binding of myristylated peptides corresponding to the NH2 terminus of Src, Biochemistry 33:13093 (1994).PubMedCrossRefGoogle Scholar
  8. 8.
    O. Boutaud, C.J. Brame, R.G. Salomon, L.J. Roberts, 2nd and J.A. Oates, Characterization of the lysyl adducts formed from prostaglandin H2 via the levuglandin pathway, Biochemistry 38:9389 (1999).PubMedCrossRefGoogle Scholar
  9. 9.
    C.J. Brame, R.G. Salomon, J.D. Morrow and L.J. Roberts, 2nd, Identification of extremely reactive gamma-ketoaldehydes (isolevuglandins) as products of the isoprostane pathway and characterization of their lysyl protein adducts, Journal of Biological Chemistry 274:13139 (1999).PubMedCrossRefGoogle Scholar
  10. 10.
    L.J. Marnett, DNA adducts of alpha,beta-unsaturated aldehydes and dicarbonyl compounds, IARC Scientific Publications (Lyon) 151 (1994).Google Scholar
  11. 11.
    S.W. Rowlinson, B.C. Crews, C.A. Lanzo and L.J. Marnett, The binding of arachidonic acid in the cyclooxygenase active site of mouse prostaglandin endoperoxide synthase-2 (COX2). A putative L-shaped binding conformation utilizing the top channel region, Journal of Biological Chemistry 274:23305 (1999).PubMedCrossRefGoogle Scholar
  12. 12.
    T.A. Worrall, R.J. Cotter and A.S. Woods, Purification of contaminated peptides and proteins on synthetic membrane surfaces for matrix-assisted laser desorption/ionization mass spectrometry, Analytical Chemistry 70:750 (1998).PubMedCrossRefGoogle Scholar
  13. 13.
    R.R. Ogorzalek Loo, C. Mitchell, T.I. Stevenson, J.A. Loo and P.C. Andrews, Diffusive transfer to membranes as an effective interface between gel electrophoresis and mass spectrometry, International Journal of Mass Spectrometry and Ion Processes 169/170:273 (1997).Google Scholar
  14. 14.
    R.J. Kulmacz, Attachment of substrate metabolite to prostaglandin H synthase upon reaction with arachidonic acid, Biochemical & Biophysical Research Communications 148:539 (1987).CrossRefGoogle Scholar
  15. 15.
    M. Lecomte, R. Lecocq, J.E. Dumont and J.M. Boeynaems, Covalent binding of arachidonic acid metabolites to human platelet proteins. Identification of prostaglandin H synthase as one of the modified substrates, Journal of Biological Chemistry 265:5178 (1990).PubMedGoogle Scholar
  16. 16.
    A.G. Wilson, H.C. Kung, M.W. Anderson and T.E. Eling, Covalent binding of intermediates formed during the metabolism of arachidonic acid by human platelet subcellular fractions, Prostaglandins 18:409 (1979).PubMedCrossRefGoogle Scholar
  17. 17.
    A. Tsai, C. Wei, H.K. Baek, R.J. Kulmacz and H.E. Van Wart, Comparison of peroxidase reaction mechanisms of prostaglandin H synthase-1 containing heme and mangano protoporphyrin IX, Journal of Biological Chemistry 272:8885 (1997).PubMedCrossRefGoogle Scholar
  18. 18.
    G. Wu, C. Wei, R.J. Kulmacz, Y. Osawa and A.L. Tsai, A mechanistic study of self-inactivation of the peroxidase activity in prostaglandin H synthase-1, Journal of Biological Chemistry 274:9231 (1999).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Olivier Boutaud
    • 1
  • Junyu Li
    • 1
  • Pierre Chaurand
    • 2
  • Cynthia J. Brame
    • 1
  • Lawrence J. Marnett
    • 2
  • L. Jackson Roberts
    • 1
  • John A. Oates
    • 1
  1. 1.Departments of Medicine and PharmacologyVanderbilt University, School of MedicineNashvilleUSA
  2. 2.Department of BiochemistryVanderbilt University, School of MedicineNashvilleUSA

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