The role of secretory granules in peptide biosynthesis

There are many events in the posttranslational processing of bioactive peptides that occur in secretory granules and not to any great extent in other cellular organelles and that do not appear as modifications of the structure of many conventional neurotransmitters. In addition, at least two very important steps are unique to peptide-containing granules: (1) the peptides must begin their trek to the secretory granule in the RER as a larger precursor, rather than being taken up as a finished or nearly finished product into a mature granule; (2) there is at least one crucial sorting step on the way from the RER to the secretory granule that must occur faithfully before the peptide correctly appears in the granule. As for small molecules such as the catecholamines, the posttranslational processing enzymes and any required cofactors must also be put into the granules if the final events of processing are to occur with fidelity. Many of the posttranslational processing enzymes are only beginning to be identified. It is clear from these studies on purified PAM and peptide alpha-amidation as it occurs in cells that correlating test tube studies with the functioning of secretory granules is a worthwhile, if difficult, pursuit. The unique milieu inside the granule is difficult to mimic in a test tube. Transfection of peptide-producing cells with cDNAs encoding precursors with specific alterations in processing sites offers perhaps the best way to interface the studies of secretory granules and the posttranslational processing enzymes that mediate those functions.