Endoplasmic-reticulum-specific pathway

The last enzyme in the pathway, g/ucose 6-phosphatase, occurs in the liver, but not in muscle. It is located in the interior of the smooth endoplasmic reticulum. Specific transporters allow glucose 6-phosphate to enter the ER and allow the glucose formed there to return to the cytoplasm. From there, it is ultimately released into the blood. 

The biosynthetic, secretory pathway is responsible for protein sorting and delivery and allows, among other functions, for cell-cell communication through secreted products. This delivery process starts at the endoplasmic reticulum (ER), to finish in the cell plasma membrane or, in some cases, in specific intracellular organelles. To accomplish this, specific proteins must be properly directed to the correct destination, while other proteins are retained as residents within specific organelles along the way. 

As noted above, synaptic vesicles are not typically generated at the level of the TGN. Instead, they are assembled from endocytosed material retrieved from the synaptic plasma membrane. Synaptic vesicle and plasma membrane lipids and proteins are synthesized in the endoplasmic reticulum and modified in the Golgi apparatus, where they are then packaged in secretory vesicles. These synaptic precursors are delivered to the plasma membrane from the cell body by the constitutive secretory pathway. Synaptic vesicle proteins must be retrieved by clathrin-mediated synaptic vesicle endocytosis, a variant of RME with some neuron-specific components. Once the vesicle sheds its clathrin coat, the uncoated vesicle fuses with a... 

Substrate availability to the cell is affected by the supply of raw materials from the environment. The plasma membranes of cells incorporate special and often specific transport proteins (translocases) or pores that permit the entry of substrates into the cell interior. Furthermore pathways in eukaryotic cells are often compartmentalized within cytoplasmic organelles by intracellular membranes. Thus we find particular pathways associated with the mitochondria, the lysosomes, the peroxisomes, the endoplasmic reticulum for example. Substrate utilization is limited therefore by its localization at the site of need within the cell and a particular substrate will be effectively concentrated within a particular organelle. The existence of membrane transport mechanisms is crucial in substrate delivery to, and availability at, the site of use. 

Figure 1 The mode of action for bacterial AB-type exotoxins. AB-toxins are enzymes that modify specific substrate molecules in the cytosol of eukaryotic cells. Besides the enzyme domain (A-domain), AB-toxins have a binding/translocation domain (B-domain) that specifically interacts with a cell-surface receptor and facilitates internalization of the toxin into cellular transport vesicles, such as endosomes. In many cases, the B-domain mediates translocation of the A-domain into the cytosol by pore formation in cellular membranes. By following receptor-mediated endocytosis, AB-type toxins exploit normal vesicle traffic pathways into cells. One type of toxin escapes from early acidified endosomes (EE) into the cytosol, thus they are referred to as short-trip-toxins . In contrast, the long-trip-toxins take a retrograde route from early endosomes (EE) through late endosomes (LE), trans-Golgi network (TGN), and Golgi apparatus into the endoplasmic reticulum (ER) from where the A-domains translocate into the cytosol to modify specific substrates.

Jakob CA, Burda P, Roth J, Aebi M (1998) Degradation of misfolded endoplasmic reticulum glycoproteins in Saccharomyces cerevisiae is determined by a specific oligosaccharide structure. J Cell Biol 142 1223-1233 Janson LW, Ragsdale K, Luby-Phelps K (1996) Mechanism and size cutoff for steric exclusion from actin-rich cytoplasmic domains. Biophys ) 71 1228-1234 Jeffers M, Taylor GA, Weidner KM, Omura S, Vande Woude GF (1997) Degradation of the Met tyrosine kinase receptor by the ubiquitin-proteasome pathway. Mol Cell Biol 17 799-808... 

The biosynthesis in yeast of two enzymes that are D-mannoproteins has been studied. A membrane-associated isozyme of invertase (EC 3.2.1.26) has been shown to be a precursor of the external invertase.190 Its molecular weight, as determined by SDS-poly(acrylamide) gel electrophoresis, is 50,000, that is, smaller than that of the external invertase, and it correlates well with the presence of only the inner-core sugars of the final form. It is strictly bound to membranes, possibly those of the endoplasmic reticulum, and it can be completely split191 by endo-/3-N-acetylglucosaminidase H (EC 3.2.1.30). The addition of tunicamycin, which specifically inhibits formation of d-GIcNAc-PP-DoI, inhibits synthesis of external invertase, as well as further formation of the membrane-associated form, which completely disappears after addition of the antibiotic.190 In these aspects, the synthesis of this extracellular enzyme follows the pathway for secreted glycoproteins in animal systems. 

Endoplasmic A highly specific pathway for the degradation of misfolded proteins in the Reticulum- endoplasmic reticulum, which serves as a control mechanism for protein... 

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