Trypsin proinsulin cleavage

Figure 42-12. Structure of human proinsulin. Insulin and C-peptide molecules are connected at two sites by dipeptide links. An initial cleavage by a trypsin-like enzyme (open arrows) followed by several cleavages by a car-boxypeptidase-like enzyme (solid arrows) results in the production of the heterodimeric (AB) insulin molecule (light blue) and the C-peptide.

Various trypsin-like serine proteases such as kallikreins [37] and plasmin or plasminogen activator [38] have been suggested to be involved in the cleavage of hormone precursors. However, it is not clearly known whether any of these proteases can correctly process proinsulin to generate both native insulin and C-peptide. Cleavage of proinsulin by plasmin is shown to result in equal amounts of insulin and a form of insulin with a residual Arg residue before the Gly at the N-terminus of the A-chain [39]. There may possibly be a novel amino peptidase for removing this... 

Arg residue, but none, as yet, has been demonstrated. Trypsin cleavage of proinsulin generates small amounts (< 5%) of Arg-(A)-insulin, the form which is present in native insulin at very low levels (< 0.5%). In the absence of carboxypeptid-ase-B, both plasmin and trypsin tend to cleave Lys-Ala or Lys-Thr bonds in proinsulin, resulting in a partially degraded form of insulin that does not occur naturally [40], These serine proteases therefore seem to carry out the rare cleavage at single basic residue sites. 

Conversion of proinsulin to insulin and C-peptide in secretory granules involves site-specific cleavages at the Arg-Arg and Lys-Arg sequences (Figure 22-6) these serve as signals for proteolytic processing of many other proteins. Cleavage occurs at the C-terminal end of each pair by trypsin-like enzymes and is followed by... 

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