Endoplasmic reticulum mammalian

GPI anchoring is a posttranslational modification occurring in the endoplasmic reticulum where preassembled GPI anchor precursors are transferred to proteins bearing a C-terminal GPI signal sequence. The GPI anchor precursors are synthesized in the endoplasmic reticulum by sequential addition of sugar and other components to phosphatidylinositol. Protein GPI anchors are ubiquitous in eukaryotic cells. In mammalian cells, GPI anchored proteins are often found in lipid rafts which are subdomains of the plasma membrane, containing various signaling components. 

Biosynthesis of Unsaturated Fatty Acids. In the mammalian tissues, the forma-tion of monoene fatty acids is only possible. Oleic acid is derived from stearic acid, and palmitooleic acid, from palmitic acid. This synthesis is carried out in the endoplasmic reticulum of the liver cells via the monooxigenase oxidation chain. Any other unsaturated fatty acids are not produced in the human organism and must be supplied in vegetable food (plants are capable of generating polyene fatty acids). Polyene fatty acids are essential food factors for mammals. 

Cinti, D. L., Cook, L., Nagi, M. N. and Suneja, K. J. The fatty acid chain elongation system of mammalian endoplasmic reticulum. Prog. Lipid Res. 31 1-51,1992. 

Much work has demonstrated the presence of complex multienzyme monooxygenase systems within the endoplasmic reticulum of several mammalian species (for Reviews 1, 2, 3). These monooxygenase systems are responsible for the oxidative metabolism of many exogenous and endogenous substances, and the unusual non-specificity of these monooxygenase enzymes allows the metabolism of compounds with diverse chemical structures. Early work demonstrated that the terminal microsomal oxidase involved in xenobio-tic biotransformation was a hemoprotein, which has been subsequently named cytochrome P-450. 

Weissman, A. M., and Wojcikiewicz, R. j. H. Inositol 1,4,5-trisphosphate receptor ubiquitmation is mediated by mammalian Ubc7, a component of the endoplasmic reticulum-assodated degradation pathway, and is inhibited by chelation of intracellular Zn +. ]. Biol. Chem. 2003, 278, 38238-46. 

Figure 2. General topological feature of PS translocation and decarboxylation in mammalian cells. PS is synthesized by PSS I and II in endoplasmic reticulum (ER) or mitochondria-associated membrane (MAM). The nascent PS is transported other membranes such as plasma membrane, nucleus, and mitochondria. The PS transported to the mitochondrial outer membrane is then translocated to the inner membrane, in which PS is converted to PE by PS decarboxylase (PSD). The PE formed in mitochondria is dynamic and can be exported to other organelles for membrane biogenesis.

The majority of PC is synthesized in mammalian cells by the CDP-choline or Kennedy pathway in the endoplasmic reticulum (Eigiue 1). In this pathway, choline taken up from the external medium or released in the cytosol by breakdown of choline containing compoimds, is first converted to phosphocholine by the enzyme choline kinase (CK) (Ishidate, 1997). There are two isoforms of CK cloned which both can convert also ethanolamine to phosphoethanolamine, albeit with a lesser affinity (Aoyama et al 2000). Alternatively phosphocholine can be generated by enzymes that preferentially phosphorylate ethanolamine and are therefore designated ethanolamine kinases (EK). As yet also two different EKs are known (EKI 1 and 2 Lykidis etal., 2001). 

Both catalyze chain cleavage and transfer reactions (Eqs. 17-14 and 17-15) that involve the same group of substrates. These enzymes use the two basic types of C-C bond cleavage, adjacent to a carbonyl group (a) and one carbon removed from a carbonyl group ((3). Both types are needed in the pentose phosphate pathways just as they are in the citric acid cycle. The enzymes of the pentose phosphate pathway are found in the cytoplasm of both animal and plant cells.n7c Mammalian cells appear to have an additional set that is active in the endoplasmic reticulum and plants have another set in the chloroplasts.117c... 

Figure 32-4 Sketch illustrating only a few of the many aspects of apoptosis in a mammalian cell. Emphasis here is on the death receptor pathways and cytochrome c-activated apoptosis. A third pathway is initiated by stress in endoplasmic reticulum membranes. In addition, attack by cytolytic T cells sometimes causes apoptosis by action of a granzyme on protein Bid or via a death receptor. Objects in scheme are not drawn to a single scale.

Enzyme complexes occur in the endoplasmic reticulum of animal cells that desaturate at A5 if there is a double bond at the A8 position, or at A6 if there is a double bond at the A9 position. These enzymes are different from each other and from the A9-desaturase discussed in the previous section, but the A5 and A6 desaturases do appear to utilize the same cytochrome b5 reductase and cytochrome b5 mentioned previously. Also present in the endoplasmic reticulum are enzymes that elongate saturated and unsaturated fatty acids by two carbons. As in the biosynthesis of palmitic acid, the fatty acid elongation system uses malonyl-CoA as a donor of the two-carbon unit. A combination of the desaturation and elongation enzymes allows for the biosynthesis of arachidonic acid and docosahexaenoic acid in the mammalian liver. As an example, the pathway by which linoleic acid is converted to arachidonic acid is shown in figure 18.17. Interestingly, cats are unable to synthesize arachidonic acid from linoleic acid. This may be why cats are carnivores and depend on other animals to make arachidonic acid for them. Also note that the elongation system in the endoplasmic reticulum is important for the conversion of palmitoyl-CoA to stearoyl-CoA. 

Synthesis in mammalian tissues of arachidonic acid from linoleic acid. The A5 and A6 desaturases are separate enzymes and are also different from the A9 desaturase (fig. 18.16). The mechanisms, however, seem to be the same, involving cytochrome b5 and cytochrome reductase. The enzymes for elongation of unsaturated fatty acid such as 18 3 to 20 3 occur on the endoplasmic reticulum. 

Immunization with the monoclonal AB reactive against the 18 kDa major surface protein in the oncosphere of T. saginata, HP6, confers protection in cattle (Harrison and Rarkhouse, 1986). The HP6-encoding gene of T. saginata has been cloned and transfected into normal rat kidney cells. Localization studies revealed HP6 in the endoplasmic reticulum, the Golgi apparatus and at the cell surface (Bonay et al., 2002). The deduced amino acid sequence of HP6 was similar to the mammalian extracellular matrix protein,... 

Distribution of CYPs within the cell has been studied primarily in the mammalian liver, where it is present in greatest quantity in the smooth endoplasmic reticulum and in smaller but appreciable amounts in the rough endoplasmic reticulum. The nuclear membrane has also been reported to contain CYP and to have detectable aryl hydrocarbon hydroxylase activity, an observation that may be of considerable importance in studies of the metabolic activation of carcinogens. 

Sulfoxide Reduction. The reduction of sulfoxides has been reported to occur in mammalian tissues. Soluble thioredoxin-dependent enzymes in the liver are responsible in some cases. It has been suggested that oxidation in the endoplasmic reticulum followed by reduction in the cytoplasm may be a form of recycling that could extend the in vivo half-life of certain toxicants. 

Gonzalez, D. S., Karaveg, K., Vandersall-Naim, A S., Lai., A., and Moremen. K. W. (1999). Identification, expressetion, and characterization of a cDNA encoding human endoplasmic reticulum mannosidase I, the enzyme that catalyzes the first mannose trimming step in mammalian Asn-linked oligosaccharide biosynthesis../. Biol. Chem., 274, 21375-21386. 

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