Endoplasmic reticulum transport

Formation of PTH begins with the synthesis of several precursor molecules. PreproPTH is the initial peptide that is synthesized within the parathyroid gland, and it serves as a precursor to both proPTH and PTH. PreproPTH is formed within the rough endoplasmic reticulum, transported into the cisternal space, and then cleaved to form proPTH. The proPTH polypeptide is transported into the cisternal space, where another proteolytic cleavage occurs, forming PTH. 

Regulation is also accomplished by compartmentaliza-tion of enzyme systems involved in anabolic and catabolic pathways into different cell organelles. For example, fatty acid synthesis occurs in the soluble fraction of the cytoplasm, whereas fatty acid oxidation takes place in mitochondria. Heme synthesis begins and is completed in mitochondria, but some of the intermediate reactions take place in the cytosol. Heme catabolism is initiated in the smooth endoplasmic reticulum. Transport of key metabolites across an organelle membrane system is also a form of regulation. 

Collagen chains are synthesized as longer precursors, called procollagens, with globular extensions—propeptides of about 200 residues—at both ends. These procollagen polypeptide chains are transported into the lumen of the rough endoplasmic reticulum where they undergo hydroxylation and other chemical modifications before they are assembled into triple chain molecules. The terminal propeptides are essential for proper formation of triple... 

Brefeldin A, an antiviral agent which impedes protein transport from the endoplasmic reticulum to the Golgi complex, was synthesized as the racemate using a number of interesting diastereoselective reactions. 

FIGURE 23.8 Glu cose-6-phosphatase is localized in the endoplasmic reticulum membrane. Conversion of glucose-6-phosphate to glucose occurs during transport into the ER. 

HDL and VLDL are assembled primarily in the endoplasmic reticulum of the liver (with smaller amounts produced in the intestine), whereas chylomicrons form in the intestine. LDL is not synthesized directly, but is made from VLDL. LDL appears to be the major circulatory complex for cholesterol and cholesterol esters. The primary task of chylomicrons is to transport triacylglycerols. Despite all this, it is extremely important to note that each of these lipoprotein classes contains some of each type of lipid. The relative amounts of HDL and LDL are important in the disposition of cholesterol in the body and in the development of arterial plaques (Figure 25.36). The structures of the various... 

The Ca2+-AIPase transports Ca2+ ions into endoplasmic reticulum or out of the cell from the cytoplasm, using the energy of ATP hydrolysis. 

Zimmermann R, Muller L, Wullich B (2006) Protein transport into the endoplasmic reticulum mechanism and pathologies. Trends Mol Med 12 567-573... 

COPII vesicles are transport intermediates from the endoplasmic reticulum. The process is driven by recruitment of the soluble proteins that form the coat structure called COPII from the cytoplasm to the membrane. 

The membrane tubules and lamellae of the endoplasmic reticulum (ER) are extended in the cell with the use of MTs and actin filaments. Kinesin motors are required for stretching out the ER, whereas depolymerization of microtubules causes the retraction of the ER to the cell centre in an actin-dependent manner. Newly synthesized proteins in the ER are moved by dynein motors along MTs to the Golgi complex (GC), where they are modified and packaged. The resulting vesicles move along the MTs to the cell periphery transported by kinesin motors. MTs determine the shape and the position also of the GC. Their depolymerization causes the fragmentation and dispersal of the GC. Dynein motors are required to rebuild the GC. 

Transport of proteins and lipids occurs between the organelles of the secretory pathway, i.e. endoplasmic reticulum (ER), Golgi, endosomes, lysosomes and the plasma membrane. 

In contrast to the small transmitter molecules, the neuropeptides are synthesized in the rough endoplasmic reticulum of the neuronal perikarya. They are enclosed in vesicles in the Golgi apparatus. The vesicles travel down to the terminals by axonal transport. 

Chrispeels, M.J. Greenwood, J.S. (1987). Heat stress enhances phytohemagglutinin synthesis but inhibits its transport out of the endoplasmic reticulum. Plant Physiology, 83, 778-84. 

Many of the phase 1 enzymes are located in hydrophobic membrane environments. In vertebrates, they are particularly associated with the endoplasmic reticulum of the liver, in keeping with their role in detoxication. Lipophilic xenobiotics are moved to the liver after absorption from the gut, notably in the hepatic portal system of mammals. Once absorbed into hepatocytes, they will diffuse, or be transported, to the hydrophobic endoplasmic reticulum. Within the endoplasmic reticulum, enzymes convert them to more polar metabolites, which tend to diffuse out of the membrane and into the cytosol. Either in the membrane, or more extensively in the cytosol, conjugases convert them into water-soluble conjugates that are ready for excretion. Phase 1 enzymes are located mainly in the endoplasmic reticulum, and phase 2 enzymes mainly in the cytosol. 

After mRNA splicing, the tropoelastin mRNA is translated at the surface of the rough endoplasmic reticulum (RER) in a variety of cells smooth muscle cells, endothelial and microvascular cells, chondrocytes and fibroblasts. The approximately 70 kDa precursor protein (depending on isoform) is synthesized with an N-terminal 26-amino-acid signal peptide. This nascent polypeptide chain is transported into the lumen of the RER, where the signal peptide is removed cotranslationally [9]. 

Bilirubin formed in peripheral tissues is transported to the hver by plasma albumin. The further metabolism of bihtubin occuts primarily in the hver. It can be divided into thtee processes (1) uptake of bilirubin by hver parenchymal cells, (2) conjugation of bilirubin with glucuronate in the endoplasmic reticulum, and (3) secretion of conjugated bilirubin into the bile. Each of these processes will be considered separately. 

Figure 46-6. Flow of membrane proteins from the endoplasmic reticulum (ER) to the cell surface. Horizontal arrows denote steps that have been proposed to be signal independent and thus represent bulkflow. The open vertical arrows in the boxes denote retention of proteins that are resident in the membranes of the organelle indicated. The open vertical arrows outside the boxes indicate signal-mediated transport to lysosomes and secretory storage granules. (Reproduced, with permission, from Pfeffer SR, Rothman JE Biosynthetic protein transport and sorting by the endoplasmic reticulum and Golgi. Annu Rev Biochem 1987 56 829.)...

Membrane proteins inside transport vesicles bud off the endoplasmic reticulum on their way to the Golgi final sorting of many membrane proteins occurs in the trans-Golgi network. 

Like other cells, a neuron has a nucleus with genetic DNA, although nerve cells cannot divide (replicate) after maturity, and a prominent nucleolus for ribosome synthesis. There are also mitochondria for energy supply as well as a smooth and a rough endoplasmic reticulum for lipid and protein synthesis, and a Golgi apparatus. These are all in a fluid cytosol (cytoplasm), containing enzymes for cell metabolism and NT synthesis and which is surrounded by a phospholipid plasma membrane, impermeable to ions and water-soluble substances. In order to cross the membrane, substances either have to be very lipid soluble or transported by special carrier proteins. It is also the site for NT receptors and the various ion channels important in the control of neuronal excitability. 

The reaction of choline with mitochondrial bound acetylcoenzyme A is catalysed by the cytoplasmic enzyme choline acetyltransferase (ChAT) (see Fig. 6.1). ChAT itelf is synthesised in the rough endoplasmic reticulum of the cell body and transported to the axon terminal. Although the precise location of the synthesis of ACh is uncertain most of that formed is stored in vesicles. It appears that while ChAT is not saturated with either acetyl-CoA or choline its synthesising activity is limited by the actual availability of choline, i.e. its uptake into the nerve terminal. No inhibitors of ChAT itself have been developed but the rate of synthesis of ACh can, however, be inhibited by drugs like hemicholinium or triethylcholine, which compete for choline uptake into the nerve. 

In the family of cation pumps, only the Na,K-ATPase and H,K-ATPase possess a p subunit glycoprotein (Table II), while the Ca-ATPase and H-ATPase only consist of an a subunit with close to 1 000 amino acid residues. It is tempting to propose that the p subunit should be involved in binding and transport of potassium, but the functional domains related to catalysis in Na,K-ATPase seem to be contributed exclusively by the a subunit. The functional role of the P subunit is related to biosynthesis, intracellular transport and cell-cell contacts. The P subunit is required for assembly of the aj8 unit in the endoplasmic reticulum [20]. Association with a j8 subunit is required for maturation of the a subunit and for intracellular transport of the xP unit to the plasma membrane. In the jSl-subunit isoform, three disulphide... 

Our discussion here will concentrate on the various forms of the Ca " transport ATPases that occur in the sarcoplasmic reticulum of muscle cells of diverse fiber types and in the endoplasmic reticulum of nonmuscle cells (SERCA). The structure of these enzymes will be compared with the Ca transport ATPases of surface membranes (PMCA) [3,29-32,34] and with other ATP-dependent ion pumps that transport Na, K, andH [46,50-52]. 

The coupling of solute transport in the GI lumen with solute lumenal metabolism (homogeneous reaction) and membrane metabolism (heterogeneous reaction) has been discussed by Sinko et al. [54] and is more generally treated in Cussler s text [55], At the cellular level, solute metabolism can occur at the mucosal membrane, in the enterocyte cytosol, and in the endoplasmic reticulum (or microsomal compartment). For peptide drugs, the extent of hydrolysis by lumenal and membrane-bound peptidases reduces drug availability for intestinal absorption [56], Preferential hydrolysis (metabolic specificity) has been targeted for reconversion... 

---