Apoprotein, modification

Zgoda VG, Karuzina II, Archakov AI (1999) Heme and apoprotein modification of cytochrome P450 2B4 during its oxidative inactivation in monooxigenase reconstituted system. Free Radic Biol Med 26 620-632... 

As summarized in the previous paragraph, LDL cholesterol is oxidized to various oxysterols due with high cytotoxicity and promoting vascular injury [63]. Oleuropein and a mixture of phenols extracted firom virgin oil inhibited dose-dependently the formation of oxysterols and prevented apoprotein modification in UV irradiated LDL. IC50 are shown in table 4 ... 

LOX-catalyzed oxidation of LDL has been studied in subsequent studies [26,27]. Belkner et al. [27] showed that LOX-catalyzed LDL oxidation was not restricted to the oxidation of lipids but also resulted in the cooxidative modification of apoproteins. It is known that LOX-catalyzed LDL oxidation is regio- and enantio-specific as opposed to free radical-mediated lipid peroxidation. In accord with this proposal Yamashita et al. [28] showed that LDL oxidation by 15-LOX from rabbit reticulocytes formed hydroperoxides of phosphatidylcholine and cholesteryl esters regio-, stereo-, and enantio-specifically. Sigari et al. [29] demonstrated that fibroblasts with overexpressed 15-LOX produced bioactive minimally modified LDL, which is probably responsible for LDL atherogenic effect in vivo. Ezaki et al. [30] found that the incubation of LDL with 15-LOX-overexpressed fibroblasts resulted in a sharp increase in the cholesteryl ester hydroperoxide level and a lesser increase in free fatty acid hydroperoxides. 

Postulated scheme for the synthesis, assembly, and secretion of VLDL by a hepatocyte (liver cell). (1) Synthesis The apoproteins, phospholipid, triacylglycerol, cholesterol, and cholesteryl esters are synthesized in the endoplasmic reticulum. (2) Assembly These components are assembled into a prelipoprotein particle in the lumen of the endoplasmic reticulum. (3) Processing The particle moves to the Golgi apparatus, where modification of the apoproteins occurs. 

F20. Franceschini, G., Sirtori, C. R., Capurso, A., Weisgraber, K. H., and Mahley, R. W., A-I Milano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family. J. Clin. Invest. 66, 892-900 (1980). 

M14. Mahley, R. W., Innerarity, T. L., Pitas, R. E., Weisgraber, K. H., Brown, J. H., and Gross, E., Inhibition of lipoprotein binding to cell surface receptors of fibroblasts following selective modification of arginyl residues in arginine-rich and B apoproteins. J. Biol. Chem. 252, 7279-7287 (1977). 

B. Identity of a Distal Ligand Selective Modifications of THE Apoprotein... 

Some proteins tightly bind their cognate metal ion only after the nascent apoprotein (L) undergoes a covalent modification reaction (prodncing L ), as shown in equations (3) and (4). 

There is substantial evidence that indicates that dietary fat can influence significantly not only serum levels of cholesterol and triacylglycerols but also the lipid composition and content of Apoproteins (156-159). Much attention has been placed on the effects of diet on LDL levels, and saturated fatty acid and cholesterol itself have been identified as the major nutritional factors that can raise serum LDL-cholesterol levels. However, LDL cholesterol is only one of the many risk factors for atherosclerosis, and it is not known if oxidative modification of LDL is an equally or more important factor in the pathogenesis of atherosclerosis than total LDL cholesterol per se. More longitudinal studies are needed to answer these questions. If lipid peroxidation is a major risk factor for atherosclerosis, then excess consumption of highly unsaturated fats may not be advisable. 

Most prokaryotes employ dedicated PPTs active toward specific apoprotein substrates. Fungi also utilize separate PPTs for modification of the ACPs associated with the cytosolic and mitochondrial FAS systems, as well as the a-aminoadipate reductase involved in lysine biosynthesis [8]. The former is unusual in that it is a constituent domain of the multifunctional a-subunit (Fig. 4). Surprisingly, animals appear to employ a single PPT for servicing three different apoproteins the ACP domain of the cytosolic FAS, the ACP component of the mitochondrial FAS, and the a-aminoadipate semialdehyde dehydrogenase involved in lysine catabolism. The human PPT has recently been identified and characterized (S. Smith, 2003) and its crystal structure determined in complex with Mg, CoA, and the ACP domain of the cytosolic FAS (Structural Genomics Consortium). The ACP domain is comprised of a four-helix bundle, as are the ACPs associated with type II systems. The conserved serine residue that is the site of posttranslational modification lies at the N-terminal end of helix-2 (Fig. 6B), closely juxtaposed with the pyrophosphate of CoA that is cleaved during the phosphopantetheine transfer. Helix-2 makes multiple... 

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