Pancreatic proteases

Food vitamin B 2 appears to bind to a saUvary transport protein referred to as the R-protein, R-binder, or haptocorrin. In the stomach, R-protein and the intrinsic factor competitively bind the vitamin. Release from the R-protein occurs in the small intestine by the action of pancreatic proteases, leading to specific binding to the intrinsic factor. The resultant complex is transported to the ileum where it is bound to a cell surface receptor and enters the intestinal cell. The vitamin is then freed from the intrinsic factor and bound to transcobalamin II in the enterocyte. The resulting complex enters the portal circulation. 

Cured hides must be properly soaked to obtain satisfactory rehydration and removal of unwanted material. InterfibnUar proteins should be degraded in order to increase water uptake. Bacterial proteases and pancreatic proteases are normally preferred, and are compatible with most tannery chemicals used in soaking, ie, most surfactants and preservatives containing sodium chlorite. 

Promotes self-cleavage of pancreatic proteases from their inactive zymogen forms to active enzymes. 

Pathogenesis of systemic abnormalities during pancreatitis is associated with a high concentration of pancreatic proteases in the blood, which reduce activation of the blood proteolytic systems. Alteration of the balance between proteases and their natural inhibitors is a trigger of endogenous intoxication syndrome, which controls disease severity and the clinical outcome. Therefore, drugs which act as inhibitors of proteases are an important component of a complex treatment of acute pancreatitis. 

On entering the small intestine, large polypeptides produced in Ihe stomach by the action of pepsin are further cleaved to oligopeptides and amino acids by a group of pancreatic proteases. 

Cleavage of dietary protein by proteases from the pancreas. The peptide bonds susceptible to hydrolysis are shown for each of the five major pancreatic proteases. [Note Enteropeptidase is synthesized in the intestine.]... 

Lopinavir/Ritonavir (Kaletra) [Anrirelroviral/Protease Inhibitor] Uses HIV Infxn Action Protease inhibitor Dose Adults. Tx naive 2 tab PO daily or 1 tab PO bid Tx experiencedpt 1 tab PO bid (T dose if w/ amprenavir, efavirenz, fosamprenavir, nelfinavir, nevirapine) Peds. 7-15 kg 12/3 mg/kg PO bid 15-40 kg 10/2.5 mg/kg PO bid >40 kg Adult dose w/ food Caution [C, /-] Numerous interactions Contra w/drugs dependent on CYP3A/CYP2D6 (Table VI-8) Disp Tab, soln SE Avoid disulfiram (soln has EtOH), metronidazole GI upset, asthenia, T cholesterol/triglycerides, pancreatitis protease metabolic synd Interactions T Effects Wl clarithromycin, erythromycin T effects OF amiodarone, amprenavir, azole andfungals, bepridil, cisapride, cyclosporine, CCBs, ergot alkaloids, flecainide, flurazepam, HMG-CoA reductase inhibitors, indinavir, lidocaine, meperidine, midazolam, pimozide, propafenone, propoxyphene, quinidine, rifabutin, saquinavir, sildenafil, tacrolimus, terfenadine, triazolam, zolpidem 1 effects Wl barbiturates, carbamazepine, dexamethasone, didanosine, efavirenz, nevirapine, phenytoin, rifabutin, rifampin, St. John s wort 1 effects OF OCPs, warfarin EMS Use andarrhythmics and benzodiazepines... 

Figure 12-8 Cascade of reactions that activate pancreatic proteases. Enteropeptidase, or trypsin, cleaves the proenzyme (zymogen) at specific sites.

New information is also available (35) on stabilization of the DNase I molecule. The presence of 5 mM Ca2+ fully stabilizes the molecule against proteolytic digestion. For many years it has been known that pancreatic proteases, trypsin and both chymotrypsins, are protected from autolysis by 10 mil/ Ca2+. The protection of DNase I is achieved by a lower Ca2+ concentration. 

Pancreatic fluid, secreted in the duodenum is composed of digestive enzymes and bicarbonate. The two major pancreatic proteases are the serine proteases trypsin and chymotrypsin. 

The potentiality of a protein to cause an allergic reaction is related to the size of the protein, its primary, secondary and tertiary structures. Antigenicity of casein hydrolysate prepared by using pancreatic proteases was studied by Mahmoud et al. (1992). 

The GI tract of humans contain a number of enzymes involved in the hydrolysis of proteins and peptides and they are located in a number of sites. It is important to recognize that peptidase enzymes never occur alone. Throughout the GI tract, there is always a mixture of peptidases working synergistic. The main event in the intraluminal digestion of proteins consists of cleavage of polypeptides by pancreatic proteases, such as trypsin,... 

A number of protease inhibitors are being used currently for treating disease. Trasylol [Bayer s trademark for pancreatic trypsin inhibitor (Kunitz)] is being used currently in Europe for treating pancreatitis. This disease, which is often fatal in young alcoholic men and older women, results in the leakage of pancreatic proteases into the plasma. 

Hydrolysis of peptides and proteins in the GI tract can occur luminally, at the brash border and intracellularly. Luminal activity from the pancreatic proteases trypsin, chymotrypsin, elastase and carboxypeptidase A is mainly directed against large dietary proteins. The main enzymatic activity against small bioactive peptides is derived from the bmsh border of the enterocyte. Brash border proteases, such as aminopeptidase A and N, diaminopeptidease IV and Zn-stable Asp-Lys peptidase, preferentially cleave oligopeptides of up to 10 ammo acid residues and are particularly effective in the cleavage of tri- and tetra-peptides. 

Figure 26-2. The pancreatic enzyme cascade. Pancreatic proteases enter the intestinal lumen as inactive zymogens. Within the duodenum, a specific enzyme of the duodenal mucosa, enterokinase, activates trypsinogen by releasing the trypsinogen activation peptide (TAP). Subsequently, active trypsin activates the other zymogens and acts autocat-alytically.

Ghosh and Kim recently disclosed a new chiral auxiliary (47) that exhibits an enhanced diastereoselectivity over the previously utilized auxiliary (44) in the anti -aldol reaction196 (Scheme 2.2s). Based on this anti -aldol strategy, Ghosh and Fidanze achieved an asymmetric synthesis of (-)-tetrahydrolipstatin (50), which was isolated from Streptomyces toxytricini20 (Scheme 2.2t). (-)-Tetrahydrolipstatin is a potent inhibitor of pancreatic protease and has been... 

Question Are there any similarities in the mechanisms of catalysis of the pancreatic proteases ... 

Three of the four pancreatic proteases (trypsin, chymotrypsin, and elastase) are called serine proteases because they are all dependent for activity on the side chain of a serine residue in the active site. This serine residue attacks the carbonyl group of the peptide bond to cleave the peptide, giving an acyl-enzyme intermediate (Chap. 8). This ester bond is then hydrolyzed in a second step ... 

Pepsin and the pancreatic proteases catalyze the conversion of dietary protein to peptides and amino acids. The aminopeptidases and the dipeptidases in the intestinal mucosa almost complete the hydrolysis of the peptides to amino acids, but some peptides, especially those containing glutamate, pass into the gut mucosal cells with the free amino acids. The aminopeptidases remove amino acids from the N-terminus of a peptide. 

Enterokinase, a brush-border enzyme, activates trypsinogen into trypsin, which in tnm converts a number of precursor pancreatic proteases into their active forms. 

A. L. Goldberg, Purification from Escherichia coli of a periplasmic protein that is 10 a potent inhibitor of pancreatic proteases. 

Ehetary proteins may escape digestion in the mildly acidic stomach of the human newborn. After feeding, the pH of the infant s stomach may remain near neutral or drop to only pH 4.0, in contrast with the pH of 2.0 reached in children and adults after eating. The output of pepsin, the protease of the stomach, also may remain low for the first several months of life. Consequently, proteins may escape acid denaturation and proteolysis in the shtmach of the newborn. Therefore, proteolysis by pancreatic proteases assumes increased importance. 

Because dietary vitamin B12 is protein bound, the first step in absorption is its release in the stomach. Release is enhanced by gastric pH and pancreatic proteases. The freed vitamin is bound immediately to a glycoprotein, the intrinsic factor, secreted by parietal cells of the gastric mucosa. The vitamin Bi -intrinsic factor complex is carried to the intestines, where it binds with receptors in the ileum. Absorption is mainly by an active proccs.s, which can be saturated by 1.3 to 3 /eg of vitamin B, Excess amounts may be absorbed passively. 

Fricker and Drewe describe the luminal enzymes of the upper small intestine as the second barrier.3 Trypsin, chymotrypsin, elastase, and carboxypeptidase A and B are positioned in the lumen of the duodenum. Their highest activity occurs at pH 8. These enzymes degrade 30-40% of large proteins within the duodenum to small peptides within 10 minutes.3 Small peptides have been shown to be stable against these pancreatic proteases. 

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