Peptidases blood

A proteolytic cascade occurs when one peptidase activates the next in a proteolytic pathway, and this in turn activates the next and so on. This is a mechanism to amplify the initial signal, because one peptidase molecule can activate many zymogen molecules. Examples of proteolytic cascades include blood coagulation, activation of digestive peptidases in the intestine, and apoptosis. 

Alternate ways to interfere with the orexin system may be via inhibition of dipeptidyl peptidases or proteolysis-resistant peptide analogs as shown for other peptides. This could prolong and boost orexinergic signaling. OX-A but not OX-B can enters the brain by simple diffusion via the blood-brain barrier. Abundance of orexins and their receptors in the olfactory bulb and throughout all parts of the central olfactory system may offer transnasal routes for drug application. 

Christopherson KW 2nd, Hangoc G, Broxmeyer HE. Cell surface peptidase CD26/ dipeptidylpeptidase IV regulates CXCL12/stromal cell-derived factor-1 alpha-mediated chemotaxis of human cord blood CD34+ progenitor cells. J Immunol 2002 169(12) 7000-7008. 

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. 

Extracellular peptidases are relatively easy to isolate and are, therefore, well-studied. In higher organisms, they perform a variety of different functions such as food digestion, control of blood pressure and blood clotting, and complement activation, among others. A few examples are compiled in Table 2.2. 

After intravenous administration to rabbits, the t-amino acid derivatives of dapsone were rapidly (f1/2<2 min) and quantitatively converted to dapsone. The corresponding D-amino acid derivatives were also quantitatively converted to dapsone, but the f1/2 values ranged from 30 to 60 min. In human blood, the f1/2 values for hydrolysis of the L-amino acid prodrugs ranged from 1.7 to 20 min (Leuleucine peptidase, with decreasing specificity constants (kcat/Km) Leu=Ala>Phe>Lys=Gly. Interestingly, only L-Lys-dapsone was a substrate of trypsin, whereas only L-Phe-dapsone was a substrate of chymotrypsin. 

A number of observations converge to indicate that much of plasma peptidase activity is due to aminopeptidases, with A-protection markedly increasing peptide stability in blood. Dipeptidyl-peptidase is another noteworthy peptidase in blood. In human plasma, some of the peptides showed very small tm values of only a few minutes, but a majority of f1/2 values were on the order of 10-30 min. 

ACE is a rather nonspecific peptidase that can cleave C-terminal dipeptides from various peptides (dipeptidyl carboxypeptidase). As kininase 11, it contributes to the inactivation of kinins, such as bradykinin. ACE is also present in blood plasma however, enzyme localized in the luminal side of vascular endothelium is primarily responsible for the formation of angiotensin 11. The lung is rich in ACE, but kidneys, heart, and other organs also contain the enzyme. 

This enzyme [EC 3.4.17.3] (also referred to as lysine carboxypeptidase, arginine carboxypeptidase, kininase I, or anaphylatoxin inactivator) is a zinc-dependent member of peptidase family M14. The enzyme hydrolyzes the peptide bond at the C-terminus provided that the C-terminal amino acid is either arginine or lysine. The enzyme inactivates bradykinin and anaphylatoxins in blood plasma. 

The hormone-hke peptide incretin stimulates the release of insuhn by a feedback process that involves cleaving the molecule to an inactive form. The protease enzyme dipeptidal peptidase (DPP) in turn cleaves incretin, in effect inactivating this enzyme. Inhibition of DPP consequently extends the action of incretin. This inhibition thus prevents the increased levels of blood glucose that mark diabetes. The protease inhibitor vidagliptin, which is modeled in part on the terminal sequence in DPP, has been found to sustain levels of insulin in Type II diabetics. The inhibition is apparently reversible in spite of the presence in the structure of the relatively reactive a-aminonitrile function. Construction of one intermediate in the convergent synthesis comprises the reaction of amino adamantamine (21-1) with a mixture of nitric and... 

Asn-Pro, Asp-Met, Asp-Leu, Ala-Val, and Gly-Val were isolated from fermented sardine sauce further, the ACE-inhibitory peptides Ala-Pro, Arg-Pro, Gly-Pro, and Ala-Gly-Pro were isolated from fermented bonito sauce. Val-Pro was also identified in salted and fermented anchovy by Lee (1996). Among the peptides identified by Ichimura et al. (2003), Ala-Pro, Lys-Pro, and Arg-Pro showed strong and similar inhibitory activity. Ichimura et al. (2003) also isolated nine types of peptides containing Pro residues in their carboxy terminals. Due to the unique structure of Pro as an imino acid, peptide bonds containing Pro residues are often resistant to hydrolysis by common peptidases. This may be the reason why these Pro-containing dipeptides survived after long-term fermentation. Among these peptides, Lys-Pro was further evaluated in vivo in male SHRs (Charles River Japan, Yokohama) by oral administration. As shown in Fig. 5.3, orally administered Lys-Pro shows a tendency to lower the blood pressure of SHRs. 

Lukacs Z, Santavuori P, Keil A, Steinfeld R, Kohlschiitter A (2003) Rapid and simple assay for the determination of tripeptidyl peptidase and palmitoyl protein thioesterase activities in dried blood spots. Clin Chem 49 509-511... 

As some of the newer drugs such as hormones, growth factors, and cytokines now being produced are peptides and certain toxins are also peptides or proteins, the role of peptidases may be important. Peptidases are especially active in the lumen of the gut, and consequently many such drugs are administered intravenously. Also some natural protein toxins may bypass the gut by via bites or stings into tissue. However, peptidase activity is also found in blood and other tissues. Peptidases are also important in the further metabolism of glutathione conjugates (see below). 

Peptidases Involved in the Digestion of Blood and Tissue Proteins.353... 

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