Methionine oxidation impairs reverse cholesterol transport by apolipoprotein A-I Export

@article{citeulike:3170283, abstract = {10.1073/pnas.0802025105 HDL protects against vascular disease by accepting free cholesterol from macrophage foam cells in the artery wall. This pathway is critically dependent on lecithin:cholesterol acyltransferase (LCAT), which rapidly converts cholesterol to cholesteryl ester. The physiological activator of LCAT is apolipoprotein A-I (apoA-I), the major HDL protein. However, cholesterol removal is compromised if apoA-I is exposed to reactive intermediates. In humans with established cardiovascular disease, myeloperoxidase (MPO) oxidizes HDL, and oxidation by MPO impairs apoA-I's ability to activate LCAT . Because a single methionine residue in apoA-I, Met-148, resides near the center of the protein's LCAT activation domain, we determined whether its oxidation by MPO could account for the loss of LCAT activity. Mass spectrometric analysis demonstrated that oxidation of Met-148 to methionine sulfoxide associated quantitatively with loss of LCAT activity in both discoidal HDL and HDL, the enzyme's physiological substrates. Reversing oxidation with methionine sulfoxide reductase restored HDL's ability to activate LCAT. Discoidal HDL prepared with apoA-I containing a Met-148→Leu mutation was significantly resistant to inactivation by MPO. Based on structural data in the literature, we propose that oxidation of Met-148 disrupts apoA-I's central loop, which overlaps the LCAT activation domain. These observations implicate oxidation of a single Met in apoA-I in impaired LCAT activation, a critical early step in reverse cholesterol transport.}, author = {Shao, Baohai and Cavigiolio, Giorgio and Brot, Nathan and Oda, Michael N. and Heinecke, Jay W.}, citeulike-article-id = {3170283}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0802025105}, citeulike-linkout-1 = {http://www.pnas.org/content/105/34/12224.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/105/34/12224.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/18719109}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=18719109}, day = {26}, doi = {10.1073/pnas.0802025105}, journal = {Proceedings of the National Academy of Sciences}, keywords = {1, a, apo, cholesterol, hdl, inactivation, lcat, myeloperoxidase, oxidation, potential, reverse, therapeutic, transport}, number = {34}, pages = {12224--12229}, posted-at = {2008-08-28 19:01:32}, priority = {2}, title = {Methionine oxidation impairs reverse cholesterol transport by apolipoprotein A-I}, url = {http://dx.doi.org/10.1073/pnas.0802025105}, volume = {105}, year = {2008} }

TY - JOUR ID - citeulike:3170283 L3 - citeulike-article-id:3170283 N2 - 10.1073/pnas.0802025105 HDL protects against vascular disease by accepting free cholesterol from macrophage foam cells in the artery wall. This pathway is critically dependent on lecithin:cholesterol acyltransferase (LCAT), which rapidly converts cholesterol to cholesteryl ester. The physiological activator of LCAT is apolipoprotein A-I (apoA-I), the major HDL protein. However, cholesterol removal is compromised if apoA-I is exposed to reactive intermediates. In humans with established cardiovascular disease, myeloperoxidase (MPO) oxidizes HDL, and oxidation by MPO impairs apoA-I's ability to activate LCAT . Because a single methionine residue in apoA-I, Met-148, resides near the center of the protein's LCAT activation domain, we determined whether its oxidation by MPO could account for the loss of LCAT activity. Mass spectrometric analysis demonstrated that oxidation of Met-148 to methionine sulfoxide associated quantitatively with loss of LCAT activity in both discoidal HDL and HDL, the enzyme's physiological substrates. Reversing oxidation with methionine sulfoxide reductase restored HDL's ability to activate LCAT. Discoidal HDL prepared with apoA-I containing a Met-148→Leu mutation was significantly resistant to inactivation by MPO. Based on structural data in the literature, we propose that oxidation of Met-148 disrupts apoA-I's central loop, which overlaps the LCAT activation domain. These observations implicate oxidation of a single Met in apoA-I in impaired LCAT activation, a critical early step in reverse cholesterol transport. IS - 34 JF - Proceedings of the National Academy of Sciences EP - 12229 TI - Methionine oxidation impairs reverse cholesterol transport by apolipoprotein A-I VL - 105 SP - 12224 KW - 1 KW - a KW - apo KW - cholesterol KW - hdl KW - inactivation KW - lcat KW - myeloperoxidase KW - oxidation KW - potential KW - reverse KW - therapeutic KW - transport AU - Shao, Baohai AU - Cavigiolio, Giorgio AU - Brot, Nathan AU - Oda, Michael AU - Heinecke, Jay PY - 2008//26/ UR - http://dx.doi.org/10.1073/pnas.0802025105 ER -