Peptidases plasma

An efficient biocatalytic method for the production of amides in multigrara scale has been developed for the synthesis of a pyrrole-amide, which is an intermediate for the synthesis of the dipeptidyl peptidase IV that regulates plasma levels of the insulinotropic proglucagon. CALB catalyzes the ammonolysis of the ester with ammonium carbamate as source of ammonia (Scheme 7.8) [22]. The use of ascarite and calcium chloride as adsorbents for carbon dioxide and ethanol by-products. 

Hosono O, HommaT, Kobayashi H et al (1999) Decreased dipeptidyl peptidase IV enzyme activity of plasma soluble CD26 and its inverse correlation with HIV-1 RNA in HIV-1 infected individuals. Qin Immunol 91 283-295... 

Numerous studies have been published on the in vivo metabolism of peptides. However, these studies are concerned mainly with assessment of pharmacokinetic parameters such as half-life and clearance. Only seldom is the in vivo biotransformation of peptides that contain only common amino acids investigated in any detail, due to the difficulty of monitoring products of proteolysis that are identical to endogenous peptides and amino acids. More importantly, such studies fail to yield mechanistic and biochemical insights. For this reason, we begin here with a discussion of the metabolism of just a few peptides in some selected tissues, namely portals of entry (mouth, gastro-intestinal tract, nose, and skin), plasma, organs of elimination (liver, kidney), and pharmacodynamic sites (brain and cerebrospinal fluid). These examples serve as introduction for the presentation in Sect. 6.4.2 of the involvement of individual peptidases in peptide metabolism. 

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. 

The pattern and efficiency of hydrolysis of [Leu5]enkephalin, like that of any peptide, depends to a large extent on its compartmentalization. In other words, the qualitative and quantitative aspects of its degradation vary considerably as a function of species, tissue, and concentration profile. Thus, hydrolysis of [Leu5] enkephalin in rat brain is catalyzed mainly by aminopeptidase, ACE, and neprilysin, in rat lungs by aminopeptidase and ACE, and in rat plasma by aminopeptidase, dipeptidyl peptidase III, and ACE [171][172],... 

Another informative prodrug of TRH is its /V-lauroyl derivative (6.81 R = lauroyl R = R" = H) [200][201], which was absorbed several-fold better by the intestine than TRH, indicating good stability toward intestinal peptidases. It was also far more stable than TRH in plasma. The i.v. administration of this prodrug to rats resulted in bioactivity that was not statistically different than that of TRH, indicating that it is activated in situ to TRH. Thus, lauroyl-TRH appears to be a more promising candidate than the series of carbamates, an outcome that appears impossible to forecast. 

Early endosomes are the main sorting station in the endocytic pathway. In their acidic interior (pH 5.9-6.0), the receptor and its ligand can be released. The receptor may be recycled to the surface by vesicles that fuse with the plasma membrane. Material that cannot escape from the early endosomes is further transported via multivesicular bodies to late endosomes and digesting lysosomes that contain a broad spectrum of peptidases and hydrolases in an acidic surrounding [for reviews on endocytosis see Refs. (10-12), for review on clathrin uptake see Refs. (9,13)]. 

They are quickly hydrolyzed by plasma and tissue peptidases, and exhibit a short biological half-life, although there are exceptions to this. 

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. 

Among these are the well-known E. coli leader peptidase355 356 and other signal peptidases.357 These are integral membrane proteins that cleave N-terminal signal sequences from proteins incorporated into plasma membranes. Another enzyme of this class is the lexA repressor and protease discussed in Chapter 28. 

Atrial Natriuretic Peptide Potentiator Diuretics. Neural endopeptidase inhibitors or atrial peptidase inhibitors are compounds that inhibit the enzyme (hat degrades ANP. resulting in higher plasma concemratioas, and longer duration of action, of ANP. The diuretic effects of this class... 

To improve the absorption of peptides and proteins, the employment of different enzymatic inhibitors has been suggested. For example, some authors have demonstrated the usefulness of inhibitors of both exo- and endopeptidases to promote calcitonin absorption across rat vaginal mucosa [93]. A direct relationship was found between the effect of peptidase inhibitors of in vitro degradation constant of calcitonin in vaginal mucosa homogenates and in vivo promotion of drug absorption, indicated by the decrease in plasma calcium levels after calcitonin administration in rats. The peptidase inhibitors tested were pepstatin, bestatin, and leupeptin. 

RE Dalbey, W Wickner. Leader peptidase catalyzes the release of exported proteins from the outer surface of the Escherichia coli plasma membrane. J Biol Chem 260 15925-15931, 1985. 

Nonhuman plasma is known to have different levels of certain peptidases compared to human serum and may in turn give misleading (too high or too low) stability results (28,29). 

Plasma from patients with pancreatitis or other disease states may change the plasma peptidase activity—for example, certain viral diseases (30). 

Plasma prepared with strong chelators such as ethylene diamine tetraacetic acid (EDTA) may act as peptidase inhibitors for metalloproteases and peptidases using divalent cations as cofactors (28). 

Several 2-ketoazetidines have shown dipeptidyl peptidase IV (DPP IV) inhibition property <2004BML5579>. 2-Thiazole, 2-benzothiazole and 2-pyridyl ketones were optimal ST binding groups for potency against DPP IV. Both 2-(/ )- and 2-(V)-isomers are equipotent. Certain stabilized azetidin-2-ones maintained their in vitro potency and inhibited DPP IV in the plasma for up to 6h. 

To summarize, pre-pro-apoA-I undergoes intracellular cotranslational cleavage to pro-apoA-I (G25). Pro-apoA-I is secreted from the cell and undergoes posttranslational proteolytic cleavage to mature apoA-I in plasma by a pro-apoA-I peptidase (Gl, G25). Pro-apoA-I is isoprotein 2 in plasma and apoA-I is isoprotein 4. Isoprotein 3 seems likely to be a variant of pro-apoA-I, and isoprotein 5 a variant of isoprotein 4. A postulated converting enzyme is responsible for the conversion of pro-apoA-I to mature apoA-I in the plasma compartment. 

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