Golgi apparatus, secretory protein synthesis

Early work on protein secretion, largely performed by Palade and coworkers in the late 1960s, focused on the organellar route of a secreted protein from its synthesis to its release into the extracellular fluid (Palade, 1975). Their work showed that exported proteins are synthesized on polysomes bound to the membrane of the rough endoplasmic reticulum (RER). These proteins are not found in the cytoplasm, but are immediately sequestered in the lumen of the endoplasmic reticulum (ER) they are subsequently transported to the Golgi apparatus and then to secretory vesicles, from which they are secreted. This export route is called the Palade pathway. 

The mRNA for PTH codes for pre-proPTH, which contains 115 amino acids (M.W. 13,000). The N-terminal presequence of 25 residues is hydrophobic and is similar to leader sequences of other secreted proteins. It is removed within 1 minute ofcompletion of synthesis of pre-proPTH, leaving proPTH. During transport of proPTH to the Golgi apparatus for packaging into secretory vesicles, the N-terminal hexapeptide is cleaved to form PTH. The time elapsed from formation of proPTH to conversion to PTH is about 15-20 minutes. 

The answer is e. (Murray, pp 452-467. Scriver, pp 3-45. Sack, pp 1—40. Wilson, pp 101-120.) Protein synthesis occurs in the cytoplasm, on groups of free ribosomes called polysomes, and on ribosomes associated with membranes, termed the rough endoplasmic reticulum. However, proteins destined for secretion are only synthesized on ribosomes of the endoplasmic reticulum and are synthesized in such a manner that they end up inside the lumen of the endoplasmic reticulum. From there the secretory proteins are packaged in vesicles. The Golgi apparatus is involved in the glycosylation and packaging of macromolecules into membranes for secretion. 

Based on the Amaryllidaceae alkaloid galanthamine, a biomimetic solid-phase synthesis of 2527 compounds was reported by Shair and coworkers (Figure 11.13) The core scaffold, initially prepared in several steps, was diversified by means of four successive reactions Mitsunobu reaction of the phenolic moiety with five primary alcohols, Michael addition of the a, 3-unsatnrated cyclohexenone with thiols, iV-acylation or A -alkylation of the cyclic secondary amine, and treatment of the ketone with hydrazines and hydroxylamines. Further evaluation of library constituents for their ability to block protein trafficking in the secretory pathway of mammalian cells led to the discovery of sercramine as a potent inhibitor of the VSVG-GFP protein movement from the Golgi apparatus to the plasma m brane. 

---