Peptidases circulating

P cells of the pancreatic islets in combination with atoms of zinc, but when required to regulate blood glucose concentration, the prohormone is cleaved and functional insulin is released into the circulation along with the C-peptide. This example of post-translational processing is mediated by peptidases which are contained in the vesicles along with the proinsulin. The fusion of the secretory vesicles with the cell membrane and activation of the peptidase prior to exocytosis of the insulin are prompted by an influx of calcium ions into the P-cell in response to the appropriate stimulus. Similarly, catecholamines are synthesized and held within the cell by attachment to proteins called chromogranins. 

Preliminary information useful in prodrug design has been obtained with amino acids attached to model aromatic amines. Thus, N-(naphthalen-2-yl) amides of amino acids (6.1, R=side chain of amino acid, R =H) proved to be of interest as test compounds to monitor peptidase activity such as ami-nopeptidase M (membrane alanyl aminopeptidase, microsomal aminopepti-dase, EC 3.4.11.2) [16][17], In the presence of purified rabbit kidney aminopeptidase M or human cerebrospinal fluid (CSF) aminopeptidase activity, the rate of hydrolysis decreased in the order Ala-> Leu->Arg->Glu-2-naphthyl-amide. Ala-2-naphthylamide, in particular, proved to be a good test compound, as its rate of hydrolysis was influenced by experimental conditions (preparation, inhibitors, etc.), as was the hydrolysis of a number of low-molecular-weight opioid peptides and circulating vasoactive peptides. 

Peptide and protein drugs must be transported without metabolic degradation to the systemic circulation in order to exhibit or exert their pharmacological action. Although active transport of linear peptides and oligopeptides by intestinal oligopeptide transporters has been reported, overall intestinal absorption of peptides is very poor because of metabolic degradation by peptidases. " ... 

Ahmad, S., Wang, L.H. and Ward, P.E. (1992). Dipep-tidyl(amino)peptidase-IV and aminopeptidase-M metabolize circulating substance-P in vim. ]. Pharmacol. Exp. Ther. 260, 1257-1261. 

TAP are small peptides that are released when trypsinogen is activated to trypsin. Under physiologic conditions, trypsinogen activation occurs in the intestinal lumen and is mediated by enteropeptidase. Within the intestinal brush border membranes, TAP is quickly degraded by peptidases. In AP, trypsinogen is prematurely activated within pancreatic acinar cells, and TAP is released into the peripheral circulation and potentially can be detected in serum and urine (Saez et al., 2005). Significant increases in plasma and/ or urine TAP concentrations have been reported in fehne, canine, and human patients with AP (Johnson et al., 2004). In humans, there is enough data in the hterature to show... 

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