The detailed mechanism of the enzymic transformation of proinsulin has not yet been elucidated, but it appears to be a complex process requiring the participation of several proteolytic activities. A useful model system is described in which ordinary pancreatic trypsin arid carboxypeptidase B are shown to rapidly and quantitatively convert proinsulin to insulin. This reaction is accompanied by the liberation of the C-peptide and four basic amino acids. Studies on the biosynthesis and conversion of proinsulin in isolated islets of Langerhans suggest that the conversion to insulin begins in the Golgi apparatus and continues within newly formed secretory granules. Evidence bearing on this conclusion is summarized, and experiments are described that demonstrate conversion of proinsulin to insulin in a crude secretory granule fraction prepared from islets of Langerhans. Lysates of this subcellular fraction have been shown to contain low levels of trypsin-like activity. With lightly trypsin-treated proinsulin labeled with [3H]-arginine in the regions of specific cleavage as a substrate, a carboxypeptidase B-like activity has also been detected. Further studies will be required to elucidate the nature of these enzymes and their possible relationship to the pancreatic acinar trypsins and carboxypeptidases. Structural studies on C-peptides from several mammalian species are briefly discussed. Comparisons of these amino acid sequences indicate that considerably greater interspecies variation occurs in this region of the molecule. Extension of these comparative studies of C-peptide structure should shed light on the role of this region in facilitating the correct folding of the proinsulin polypeptide chain, and these also may disclose new aspects of insulin evolution.
On the Biosynthesis, Intracellular Transport and Mechanism of Conversion of Proinsulin to Insulin and C-Peptide
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Wolfgang Kemmler, James D Peterson, Arthur H Rubenstein, Donald F Steiner; On the Biosynthesis, Intracellular Transport and Mechanism of Conversion of Proinsulin to Insulin and C-Peptide. Diabetes 1 June 1972; 21 (Supplement_2): 572–581. https://doi.org/10.2337/diab.21.2.S572
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