Pancreatic serine protease

The stratum corneum is likely to contain a number of inhibitors of the various proteases present. CS may be of special interest. Accumulation of CS in the stratum corneum in RXI may be causative of this disease, in which there is evidence of a delayed degradation of desmosomes.28 CS has been shown to inhibit pancreatic serine proteases in vitro, and application of CS on mouse skin in vivo causes a scaling condition.34 In addition to direct effects on enzymes, CS could cause delayed desquamation by acting as a substrate modifier or by changing the physical-chemical conditions in the stratum corneum extracellular space. 

M. S. Kang, D.B. Ha, C.H. Chung, The P-1 Reactive Site Methionine Residue of Ecotin Is Not Cmcial for Its Specificity on Target Proteases - a Potent Inhibitor of Pancreatic Serine Proteases from Escherichia Coli. J. Biol. Chem. 1994,... 

The pancreatic serine proteases trypsin, ch)unotrypsin, and elastase all hydrolyze peptide bonds. These enz)mies are the result of divergent evolution in which a single ancestral gene first duplicated and then each copy evolved individually. They have similar primary structures, sirtrilar tertiary structures (Figure 20.13), and virtually identical mechanisms of action. However, as a result of evolution, these enzymes all have different specificities ... 

Proteolytic enzymes (proteases) catalyze the hydrolysis of peptide bonds. The pancreatic serine proteases chymotrypsin, trypsin, and elastase have similar structures and mechanisms of action, but different substrate specificities. It is thought that they evolved from a common ancestral protease. 

Compare the cleavage specificity of thrombin with those of the pancreatic serine proteases. 

The primary and tertiary structures of E. are very similar to those of the other pancreas proteinases. Of the 240 amino acids in E. (Af, 25,700), 52 % are identical to those in trypsin and chymotrypsin A and B. These include the catalytically important residues HiS57, Aspio2 and Seri, , the ion pair Vali Aspj, which is important for the conformation, and the 4 disulfide bridges. As might be expected, the 3-dimensional structure of E. is very similar to that of the other pancreatic serine proteases (see Chymotrypsin, Trypsin). 

A number of teams have continued their work on the structures of the proteins involved in the complex processes of blood clotting. The elucidation of the sequences of the y and -chains of human fibrin has been completed. Homologies between the , /S, and y chains have been discussed. Wiman has reported the complete primary structure of the B-chain of plasmin in this work an ambiguity was resolved because of the pronounced homologies between this protein, the B-chains of thrombin and factor XA and the pancreatic serine proteases. 

Many secreted proteins, as well as smaller peptide hormones, are acted upon in the endoplasmic reticulum by tryptases and other serine proteases. They often cut between pairs of basic residues such as KK, KR, or RR.214-216 A substilisin-like protease cleaves adjacent to methionine.217 Other classes of proteases (e.g., zinc-dependent carboxypeptidases) also participate in this processing. Serine carboxypeptidases are involved in processing human prohormones.218 Among the serine carboxypeptidases of known structure is one from wheat219 and carboxypeptidase Y, a vacuolar enzyme from yeast.220 Like the pancreatic metallocarboxypeptidases discussed in Section 4, these enzymes remove one amino acid at a time, a property that has made carboxypeptidases valuable reagents for determination of amino acid sequences. Carboxypeptidases may also be used for modification of proteins by removal of one or a few amino acids from the ends. 

About 20 families of protein inhibitors of proteases have been described.488 The egg white ovomucoids comprise one family. Turkey ovomucoid is a three-domain protein whose 56-residue third domain is a potent inhibitor of most serine proteases.455 489 The 58-residue pancreatic trypsin inhibitor490 is a member of another family of small proteins. A 36-residue insect (locust) protease inhibitor is even smaller.491... 

The mammalian serine proteases have a common tertiary structure as well as a common function. The enzymes are so called because they have a uniquely reactive serine residue that reacts irreversibly with organophosphates such as diisopropyl fluorophosphate. The major pancreatic enzymes—trypsin, chymotrypsin, and elastase—are kinetically very similar, catalyzing the hydrolysis of peptides... 

The mammalian serine proteases appear to represent a classic case of divergent evolution. All were presumably derived from a common ancestral serine protease.23 Proteins derived from a common ancestor are said to be homologous. Some nonmammalian serine proteases are 20 to 50% identical in sequence with their mammalian counterparts. The crystal structure of the elastase-like protease from Streptomyces griseus has two-thirds of the residues in a conformation similar to those in the mammalian enzymes, despite having only 186 amino acids in its sequence, compared with 245 in a-chymotrypsin. The bacterial enzymes and the pancreatic ones have probably evolved from a common precursor. 

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. 

Diazetidin-2,4-dione has been found to be a chymase inhibitor (IC50 4.0nM). It has been found that 1,3-diazetidin-2,4-dione derivatives possess high activities against bovine pancreatic cr-chrymotrypsin, human cathepsin G, and human neutrophil elastase. Some of the derivatives of l,3-diazetidin-2,4-diones have been shown to be effective as a scaffold for serine protease inhibitors <2001BML1691>. Further, 1,3-diazetidinone containing scaffolds have been found to possess potential antibacterial properties (Section 2.13.7.3). 

Recently the effects of alcalase (another protease from subtilisin family), bovine pancreatic chymotrypsin, and papain (from papaya) have been evaluated on the desquamatory process.45 Alcalase (or Optimase) is an alkaline serine proteases derived from Bacillus licheniformis with... 

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