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Selected Publication:
Panzenböck, U; Kritharides, L; Raftery, M; Rye, KA; Stocker, R.
Oxidation of methionine residues to methionine sulfoxides does not decrease potential antiatherogenic properties of apolipoprotein A-I.
J Biol Chem. 2000; 275(26): 19536-19544.
Doi: 10.1074/jbc.M000458200
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- Panzenboeck Ute
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- Abstract:
- The initial stage of oxidation of high density lipoproteins (HDL) is accompanied by the lipid hydroperoxide-dependent, selective oxidation of two of the three Met residues of apolipoprotein A-I (apoA-I) to Met sulfoxides (Met(O)). Formation of such selectively oxidized apoA-I (i.e. apoA-I(+32)) may affect the antiatherogenic properties of HDL, because it has been suggested that Met(86) and Met(112) are important for cholesterol efflux and Met(148) is involved in the activation of lecithin:cholesterol acyl transferase (LCAT). We therefore determined which Met residues were oxidized in apoA-I(+32) and how such oxidation of apoA-I affects its secondary structure, the affinity for lipids, and its ability to remove lipids from human macrophages. We also assessed the capacity of discoidal reconstituted HDL containing apoA-I(+32) to act as substrate for LCAT, and the dissociation of apoA-I and apoA-I(+32) from reconstituted HDL. Met(86) and Met(112) were present as Met(O), as determined by amino acid sequencing and mass spectrometry of isolated peptides derived from apoA-I(+32). Selective oxidation did not alter the alpha-helicity of lipid-free and lipid-associated apoA-I as assessed by circular dichroism, and the affinity for LCAT was comparable for reconstituted HDL containing apoA-I or apoA-I(+32). Cholesteryl ester transfer protein mediated the dissociation of apoA-I more readily from reconstituted HDL containing apoA-I(+32) than unoxidized apoA-I. Also, compared with native apoA-I, apoA-I(+32) had a 2- to 3-fold greater affinity for lipid (as determined by the rate of clearance of multilamellar phospholipid vesicles) and its ability to cause efflux of [(3)H]cholesterol, [(3)H]phospholipid, and [(14)C]alpha-tocopherol from lipid-laden human monocyte-derived macrophages was significantly enhanced. By contrast, no difference was observed for cholesterol and alpha-tocopherol efflux to lipid-associated apolipoproteins. Together, these results suggest that selective oxidation of Met residues enhances rather than diminishes known antiatherogenic activities of apoA-I, consistent with the overall hypothesis that detoxification of lipid hydroperoxides by HDL is potentially antiatherogenic.
- Find related publications in this database (using NLM MeSH Indexing)
- Apolipoprotein A-I - chemistry
- Arteriosclerosis - drug therapy
- Cells, Cultured - drug therapy
- Chromatography, High Pressure Liquid - drug therapy
- Circular Dichroism - drug therapy
- Dose-Response Relationship, Drug - drug therapy
- Enzyme Activation - drug therapy
- Humans - drug therapy
- Kinetics - drug therapy
- Lipoproteins, HDL - metabolism
- Lipoproteins, LDL - metabolism
- Mass Spectrometry - metabolism
- Methionine - analogs and derivatives
- Monocytes - metabolism
- Oxygen - metabolism
- Phosphatidylcholine-Sterol O-Acyltransferase - metabolism
- Time Factors - metabolism