Modulation of Protein Function by Isoketals and Levuglandins
Oxidative stress, defined as an increase in reactive oxygen species, leads to peroxidation of polyunsaturated fatty acids and generates a vast number of biologically active molecules, many of which might contribute in some way to health and disease. This chapter will focus on one specific class of peroxidation products, the levuglandins and isoketals (also called isolevuglandins). These γ-ketoaldehydes are some of the most reactive products derived from the peroxidation of lipids and exert their biological effects by rapidly adducting to primary amines such as the lysyl residues of proteins. The mechanism of their formation and remarkable reactivity will be described, along with evidence for their increased formation in disease conditions linked with oxidative stress and inflammation. Finally, the currently known effects of these γ-ketoaldehydes on cellular function will then be discussed and when appropriate compared to the effects of α,β-unsaturated fatty aldehydes, in order to illustrate the significant differences between these two classes of peroxidation products that modify proteins.
KeywordsAldehydes Isoketals Levuglandins Lipid Peroxidation Protein Modification
Unable to display preview. Download preview PDF.
- Boutaud, O., Brame, C.J., Chaurand, P., Li, J., Rowlinson, S.W., Crews, B.C., Ji, C., Marnett, L.J., Caprioli, R.M., Roberts, L.J., 2nd, and Oates, J.A. Characterization of the lysyl adducts of prostaglandin H-synthases that are derived from oxygenation of arachidonic acid. Biochemistry 40 (2001) 6948–6955.PubMedCrossRefGoogle Scholar
- Davies, S.S., Amarnath, V., Brame, C.J., Boutaud, O., and Roberts, L.J. Measurement of chronic oxidative and inflammatory stress by quantification of isoketal/levuglandin gamma-ketoaldehyde protein adducts using liquid chromatography tandem mass spectrometry. Nat Protoc 2 (2007) 2079–2091.PubMedCrossRefGoogle Scholar
- Davies, S.S., Amarnath, V., Montine, K.S., Bernoud-Hubac, N., Boutaud, O., Montine, T.J., and Roberts, L.J., Effects of reactive gamma-ketoaldehydes formed by the isoprostane pathway (isoketals) and cyclooxygenase pathway (levuglandins) on proteasome function. Faseb J 16 (2002) 715–717.PubMedGoogle Scholar
- Davies, S.S., Brantley, E.J., Voziyan, P.A., Amarnath, V., Zagol-Ikapitte, I., Boutaud, O., Hudson, B.G., Oates, J.A., and Ii, L.J. Pyridoxamine Analogues Scavenge Lipid-Derived gamma-Ketoaldehydes and Protect against H(2)O(2)-Mediated Cytotoxicity. Biochemistry 45 (2006) 15756–15767.PubMedCrossRefGoogle Scholar
- Fukuda, K., Davies, S.S., Nakajima, T., Ong, B.H., Kupershmidt, S., Fessel, J., Amarnath, V., Anderson, M.E., Boyden, P.A., Viswanathan, P.C., Roberts, L.J., 2nd, and Balser, J.R. Oxidative mediated lipid peroxidation recapitulates proarrhythmic effects on cardiac sodium channels. Circ Res 97 (2005) 1262–1269.PubMedCrossRefGoogle Scholar
- Govindarajan, B., Laird, J., Salomon, R.G., and Bhattacharya, S.K. 2008. Isolevuglandin-Modified Proteins, Including Elevated Levels of Inactive Calpain-1, Accumulate in Glaucomatous Trabecular Meshwork. Biochemistry in press.Google Scholar
- Metz, T.O., Alderson, N.L., Chachich, M.E., Thorpe, S.R., and Baynes, J.W. Pyridoxamine traps intermediates in lipid peroxidation reactions in vivo: evidence on the role of lipids in chemical modification of protein and development of diabetic complications. J Biol Chem 278 (2003) 42012–42019.PubMedCrossRefGoogle Scholar
- Poliakov, E., Brennan, M.L., Macpherson, J., Zhang, R., Sha, W., Narine, L., Salomon, R.G., and Hazen, S.L. Isolevuglandins, a novel class of isoprostenoid derivatives, function as integrated sensors of oxidant stress and are generated by myeloperoxidase in vivo. Faseb J 17 (2003) 2209–2220.PubMedCrossRefGoogle Scholar
- Salomon, R.G., Miller, D.B., Zagorski, M.G., and Coughlin, D.J. Solvent Induced Fragmentation of Prostaglandin Endoperoxides. New Aldehyde Products from PGH2 and Novel Intramolecular 1,2-Hydride Shift During Endoperoxide Fragmentation in Aqueous Solution. J Am Chem Soc 106 (1984) 6049–6060.CrossRefGoogle Scholar
- Salomon, R.G., Batyreva, E., Kaur, K., Sprecher, D.L., Schreiber, M.J., Crabb, J.W., Penn, M.S., DiCorletoe, A.M., Hazen, S.L., and Podrez, E.A. Isolevuglandin-protein adducts in humans: products of free radical-induced lipid oxidation through the isoprostane pathway. Biochim Biophys Acta 1485 (2000) 225–235.PubMedGoogle Scholar