Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.1 (chymotrypsin)
10,938 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three related alpha-protease inhibitors, PI2 I, PI3 C and PI4 C2, of blood serum of the pig (Sus scrofa) were isolated. PI2 I inhibited both trypsin and chymotrypsin; PI3 C and PI4 C2 strongly inhibited chymotrypsin, but did not significantly inhibit trypsin. By using SDS-PAGE, the three proteins were found to be composed of single polypeptide chains, and molecular weights were 63,000 for PI2 I, 58,000 for PI3 C and 64,000 for PI4 C2. All three proteins were shown to be glycoproteins. In PI3 C, eight sialic acid residues were found, and in PI4 C2 (similarly as in PI2 F) 10-11 residues were found. Amino acid composition as well as N-terminal sequences of the three proteins were very similar, indicating close homology. Comparison of these partial amino acid sequences with the cDNA-deduced amino acid sequence of pig alpha-antichymotrypsin (AACT; Buchman, 1989, GenBank, Accession No. M29508) revealed great similarities, the sequence of PI2 I being virtually identical with the pig AACT. On the basis of all available results, PI2 is proposed to be pig AACT, an orthologue of human AACT.
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PMID:Pig plasma alpha-protease inhibitors PI2, PI3 and PI4 are members of the antichymotrypsin family. 774 36

The inhibition of alpha-chymotrypsin induced by cerebrospinal fluid from patients with senile dementia of Alzheimer's type, vascular dementia, and nondemented controls was investigated. We optimized the sensitivity of the assay so that the inhibition of alpha-chymotrypsin could be measured in all samples. The competitive inhibition was proportional to the amount of cerebrospinal fluid (CSF) added to the reaction mixture. After correction for protein concentration, the inhibition was higher with CSF from patients with senile dementia of Alzheimer's type than with those from patients with vascular dementia or controls. Inhibitory activity appeared to be specific for alpha-chymotrypsin because no inhibition for papain was found. Moreover, the depletion of alpha 1-antichymotrypsin from CSF by immunoadsorption revealed that this serpin was responsible for the disappearance of the inhibitory activity. Our findings suggested that the increased alpha-chymotrypsin inhibitory activity might represent an in vivo functional index of an abnormal protease metabolism in patients with Alzheimer's disease.
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PMID:Cerebrospinal fluid of patients with senile dementia of Alzheimer's type shows an increased inhibition of alpha-chymotrypsin. 788 54

A cDNA clone, pCP9, has been isolated from a common carp liver cDNA library by immunoscreening with polyclonal antiserum raised against purified bighead carp alpha 1-antitrypsin. This clone is 1,396 bp in length and has an open reading frame encoding a protein of 410 amino acid residues. The deduced amino acid sequence shows moderate homology to human alpha 1-antitrypsin (38%), guinea pig contrapsin (35%), human alpha 1-antichymotrypsin (34%), and human proteinase C inhibitor (31%), all members of the serine protease inhibitor (serpin) family. To confirm further that the cDNA clone was derived from the authentic carp alpha 1-antitrypsin gene, the presumptive mature protein of pCP9 was expressed in Escherichia coli. The molecular mass of the recombinant protein matched that predicted from the nucleotide sequence. This recombinant protein, which was recognized by antiserum against native alpha 1-antitrypsin, was capable of formation of serpin-enzyme complexes with trypsin, chymotrypsin, and elastase. Therefore, we conclude that the protein encoded by the pCP9 clone is indeed carp alpha 1-antitrypsin. Expression of alpha 1-antitrypsin in brain was confirmed by reverse transcription and polymerase chain reaction performed on mRNA derived from both common carp and bighead carp brain.
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PMID:A protease inhibitor of the serpin family is a major protein in carp perimeningeal fluid: II. cDNA cloning, sequence analysis, and Escherichia coli expression. 789 Nov

Cathepsin G, a cationic serine proteinase present in neutrophils and monocytes, is able to cleave biologically important proteins and may thus participate in tissue destruction during inflammation. Its activity is physiologically controlled by the fast-acting serpins, alpha 1-anti-chymotrypsin (ka = 5 x 10(7) M-1 S-1) and alpha 1-proteinase inhibitor (ka = 2.7 x 10(5) M-1 S-1). We have shown that cathepsin G forms a tightly bound 1:1 complex with a 5-kDa heparin fragment (Kd = 1.9 x 10-8 M). The partial enzymatic activity retained by this complex is inhibited extremely slowly by the above 68- and 53-kDa serpins. The activity of the complex is also virtually resistant to inhibition by eglin c, and 8-kDa non-serpin inhibitor. A detailed kinetic investigation showed that the inhibition of heparin-bound cathepsin G by the three proteins proceeded via a two-step mechanism. [formula: see text] The three inhibitors have widely different Ki* values (0.18-13 microM) (Ki* = k-1/k1). Their isomerization constants k2 are, however, all in the same range and their extremely low values (0.7-3 ms-1) account for the very low rate of cathepsin G inhibition. The second-order inhibition rate constants k2/Ki* were 4300, 700, and 52 M-1 S-1 for alpha 1-antichymotrypsin, alpha 1-antitrypsin, and eglin c, respectively, indicating that, if heparin is present in vivo, the two former physiological inhibitors will be unable to prevent cathepsin G-mediated proteolysis. Neutrophil elastase binds the 5-kDa heparin fragment with an affinity identical to that of cathepsin G. alpha 1-Proteinase inhibitor reacts, however, much faster with heparin-elastase (ka = 1.8 x 10(6) M-1 S-1) than with heparin-cathepsin G (k2/Ki* = 700 M-1 S-1).
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PMID:Heparin protects cathepsin G against inhibition by protein proteinase inhibitors. 796 33

The protease inhibitor alpha 1-antichymotrypsin and the lipid transport protein apolipoprotein E (apoE) are intimately associated with the 42-amino-acid beta-peptide (A beta) in the filamentous amyloid deposits of Alzheimer's disease. We report here that these two amyloid-associated proteins serve a strong stimulatory role in the polymerization of A beta into amyloid filaments. Addition of either alpha 1-anti-chymotrypsin or apoE to the A beta peptide promoted a 10- to 20-fold increase in filament formation, with apoE-4, the isoform recently linked to the development of late-onset Alzheimer's disease, showing the highest catalytic activity. These and other experiments suggest that Alzheimer amyloid deposits arise when A beta is induced to form filaments by amyloid-promoting factors (pathological chaperones) expressed in certain brain regions.
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PMID:Amyloid-associated proteins alpha 1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments. 796 18

An inhibitor of pancreatic elastase (EI), which can also inhibit chymotrypsin, and an inhibitor of trypsin (TI), which can also inhibit plasmin, have been isolated from bovine plasma. EI and TI belong to the serpin family of inhibitors. The size of both inhibitors is approx. 60 kDa and they are able to form SDS-stable complexes with proteinases. Curiously, TI dimerizes in the presence of SDS, a feature which has been observed previously only in non-denaturing gels of human alpha 1-antitrypsin (alpha 1PI). EI and TI are glycosylated [16% and 19% (w/w) respectively] and their amino acid compositions are similar to those of other plasma serpins. Neither EI nor TI is the equivalent of bovine alpha 1PI, as revealed by partial sequence analysis of their N-termini and reactive sites. Rather, both inhibitors appear to be related to human alpha 1-antichymotrypsin. Inhibition of pancreatic elastase and chymotrypsin by EI occurs with a kass. approximately 10(5) M-1.s-1. TI inhibits trypsin with a kass. approximately 10(5) M-1.s-1. Plasmin is inhibited by TI with a kass. approximately 10(3) M-1.s-1. The values of the kinetic constants are similar to those determined for the well-studied human serpins. Antibodies to EI and TI reveal a set of four antigenically related proteins of similar size in plasma. In addition, they detect the same set of proteins in milk. The inhibitors isolated from milk are identical to EI and TI from plasma. EI could control the activity of chymotrypsin-like proteinases in milk. In contrast, no target proteinases of TI in milk can be suggested.
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PMID:Characterization of two serpins from bovine plasma and milk. 798 Mar 96

Despite the homology with alpha 1-protease inhibitor (alpha 1PI), wild-type antichymotrypsin (ACT) is a substrate for HNE rather than an inhibitor of the enzyme. In order to investigate the nature of the specificity between serpins and serine proteases, the reactions of human neutrophil elastase (HNE) with wild-type recombinant ACT and recombinant variants of ACT were studied. ACT variants were generated where (1) the primary interaction site, the P1 position, was replaced with the P1 residue of alpha 1PI, (2) the residues corresponding to P3-P3' were replaced with those of alpha 1PI, and (3) the residues corresponding to the canonical recognition sequence as well as flanking residues encompassing the exposed reactive loop of the inhibitor were replaced with the corresponding residues of alpha 1PI. Each variant was analyzed to determine the effect of the replacements on reactions with human neutrophil elastase and chymotrypsin with regard to (1) the second-order rate constant for enzyme-serpin complex formation, (2) the number of moles of serpin required to completely inhibit 1 mol of enzyme (the stoichiometry of inhibition, SI), and (3) the stability of the enzyme-serpin complex. Replacing Leu with Met in the P1 position (rACT-L358M) was sufficient to convert rACT into an inhibitor of HNE with an apparent second-order rate constant (k'/[I]) of 4 x 10(4) M-1 s-1 and an SI of 5. The high SI was due to a concurrent hydrolytic reaction at sites in the reactive loop.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Conversion of alpha 1-antichymotrypsin into a human neutrophil elastase inhibitor: demonstration of variants with different association rate constants, stoichiometries of inhibition, and complex stabilities. 801 28

Two protease inhibitors (Inh2 and Inh3) from bovine plasma have been isolated and characterized. The apparent molecular weights of the two proteins are 56 and 58 kDa, respectively. Although Inh2 and Inh3 both inhibit trypsin and human neutrophil elastase, only Inh3 is a good inhibitor of chymotrypsin and cathepsin G. Inh3 is much more sensitive to oxidation than Inh2. One murine monoclonal antibody recognizes Inh3 but not Inh2. Inh3 resembles human alpha 1-antitrypsin both structurally and functionally. Inh2, on the other hand, has some structural homology to human alpha 1-antichymotrypsin, but its specificity does not correspond to that of either human alpha 1-antitrypsin or human alpha 1-antichymotrypsin.
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PMID:Isolation and characterization of two protease inhibitors from bovine plasma. 805 47

This paper reviews recent studies done in the author's laboratory on molecular mechanisms of nickel genotoxicity, using as an experimental model the teratogenic effects of bivalent nickel ions (Ni2+) in South Africa frogs (Xenopus laevis). A Ni(2+)-binding protein, pNiXa, was identified in Xenopus oocytes and embryos (molecular weight 45 kDa, isoelectric point approximately 8.5) with a strong homology to human alpha 1-antitrypsin, alpha 1-antichymotrypsin, and other serine proteinase inhibitors. CNBr peptides of pNiXa showed sequence identity to Ep45. Nondenatured pNiXa, purified by nickel affinity chromatography, inhibits bovine alpha 1-chymotrypsin. The possibility that pNiXa plays a key role in Ni2+ teratogenesis is indicated by (i) the avidity of pNiXa for Ni2+, (ii) the presence of pNiXa when the embryos are susceptible to Ni2+ teragenesis, and (iii) the potential of the (HX)n-motif to form Ni2+ complexes that could catalyze the formation of oxygen free radicals and thereby damage deoxyribonucleic acid (DNA) and chromosomes.
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PMID:Search for molecular mechanisms in the genotoxicity of nickel. 815 80

Alpha 1-antichymotrypsin (alpha 1-ACT) is a serine proteinase inhibitor (serpin) with cathepsin G, mast cell chymase and chymotrypsin as target enzymes. We present the case of a middle-aged man with low plasma levels of alpha 1-ACT, asthma with progression to emphysema, and chronic HCV positive liver disease with selective accumulation of alpha 1-ACT in hepatocytes. This secretory defect is analogous to that seen in Pi Z alpha 1-antitrypsin deficiency. The molecular basis of alpha 1-ACT deficiency in this patient has been characterized by direct sequencing of the alpha 1-ACT genes from the patient and his father. A C-->G transversion in exon III causing a 229Pro-->Ala substitution is proposed to cause a conformational change resulting in abnormal transport through the RER. This mutation was found in one of 20 additional tested patients with chronic obstructive lung disease, but in no control. Two additional polymorphisms of the gene have been identified in unrelated healthy individuals with normal plasma alpha 1-ACT levels. The alpha 1-ACT deficiency state may predispose to obstructive lung disease and influence the course of liver disease. Identification of a specific mutation allows identification of heterozygotes for this deficiency allowing future evaluation of its clinical significance.
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PMID:The molecular basis of alpha 1-antichymotrypsin deficiency in a heterozygote with liver and lung disease. 822 25


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