Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.1 (chymotrypsin)
 10,938 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serum alpha1-antichymotrypsin (alpha1-ACT) of the patient with rheumatoid arthritis was studied by means of single radial immunodiffusion method. There was a significant elevation of the alpha1-ACT concentration in the patients with rheumatoid arthritis, and positive relationships were observed between the concentrations of alpha1-ACT and of other glycoproteins such as alpha1-acid glycoprotein and alpha1-antitrypsin in individual patients, and between C-reactive protein (CRP) rates and the (CRP) rates and the alpha1-ACT concentrations in individual specimens. These facts suggest that alpha1-ACT belongs to a group of acute phase proteins like alpha1-antitrypsin or CRP. An inverse proportional correlation was revealed between alpha1-ACT and fibrinolytic activity. No influences were observed on the alpha1-ACT concentration, activity index or articular index by the oral administration of alpha-chymotrypsin in patients with rheumatoid arthritis.
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PMID:Alpha1-antichymotrypsin in rheumatoid arthritis. 108 4

The ability of neutrophils to generate free radicals is a crucial component of host defense (Babior, B. M. (1978) N. Engl. J. Med. 298, 659-668, 721-725. Neutrophil oxidants, however, can cause significant host tissue destruction (Weiss, S. J. (1989) N. Engl. J. Med. 320, 365-376), and the regulation of free radical production is not well understood. We have previously shown that recombinant antichymotrypsin (rACT), a serine protease inhibitor, inhibits superoxide production in intact neutrophils (Kilpatrick, L., Johnson, J. L., Nickbarg, E. B., Wang, Z., Clifford, T. F., Banach, M., Cooperman, B. S., Douglas, S. D., and Rubin, H. (1991) J. Immunol. 146, 2388-2393). Using a cell-free NADPH oxidase preparation, we now demonstrate that rACT alone has no effect on superoxide production and that antichymotrypsin-chymotrypsin (rACT.CT) complexes are required to inhibit superoxide, suggesting that neutrophil chymotrypsin-like proteases produce conformational changes in ACT, allowing it to become active in regulating superoxide production. Additionally, we have identified NADPH oxidase itself as the target for rACT.CT and have demonstrated that rACT.CT interferes specifically with activation of the NADPH oxidase without changing the Km for NADPH or the rate constant describing the rate-limiting step in activation. These observations suggest an important role for antichymotrypsin in the regulation of NADPH-oxidase activation, which is a prerequisite for neutrophil superoxide production, and predict possible therapeutic uses for rACT in conditions where unregulated neutrophil-free radical production has been implicated in the mechanism of tissue destruction.
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PMID:Regulation of neutrophil superoxide by antichymotrypsin-chymotrypsin complexes. 131 83

Cerebrospinal fluid (CSF) from 20 male patients with nonneurologic disease (age 64.5 +/- 2.8 SEM) was analyzed for the presence of the serpin alpha 1-antichymotrypsin (alpha 1-ACT). A chymotrypsin-specific chromogenic substrate (succinyl-Ala-Ala-Pro-Phe-p-nitroanilide) was used to examine the CSF samples. All CSF samples showed inhibitory activity ranging from 45 to 80% inhibition. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of the samples revealed the presence of a 68-kDa protein migrating identical to authentic human plasma alpha 1-ACT. Complex formation was performed with iodinated bovine chymotrypsin for several representative CSF samples having the highest chymotrypsin inhibitory activity. Comparison was made with complex formation performed with commercially available authentic human plasma alpha 1-ACT. These studies showed the formation of complexes at 37 degrees C, regardless of whether the sample was subsequently boiled or not. In the case of CSF, two complex bands, mass smaller than with plasma alpha 1-ACT, were formed at the lower temperature whereas a single higher Mr band was formed when the samples were boiled. To determine whether cleavage of the serpin occurred, these studies were repeated using human neutrophil cathepsin G as target protease. A complex of approximately 90 kDa was formed with human alpha 1-ACT under these same conditions. alpha 1-ACT has been detected in senile amyloid plaques in brains of Alzheimer's disease patients, the only plasma serine protease inhibitor localized to these structures. Another serpin, protease nexin I, is also found in these plaques, but this inhibitor does not circulate in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of the serpin, alpha 1-antichymotrypsin, in normal human cerebrospinal fluid. 172 48

A comparative study of large cell lymphoma (LCL) (ten B and ten T), Hodgkin's disease (15 cases), and true histiocytic lymphoma (two cases) was undertaken, using formalin-fixed paraffin-embedded tissue sections, a panel of eight antibodies, and one lectin to determine if any particular antibody or immunologic profile could reliably distinguish between these entities. The antibodies used were against Leu-M1, alpha-1-anti-chymotrypsin (alpha-ACT), alpha-anti-trypsin (alpha-AT), lysozyme, kappa, lambda, leukocyte common antigen (LCA), and S-100 protein. The lectin used was peanut agglutinin (PNA). Although Leu-M1 staining was positive in 11 of 15 cases (73%) of Hodgkin's disease, it was also positive in 4 of 10 cases (40%) of T-cell lymphoma, 2 of 10 cases (20%) of B-cell lymphoma, and 1 of 2 cases (50%) of true histiocytic lymphoma. Peanut-agglutinin staining results were similar to Leu-M1. The only staining profile that emerged was the presence of Leu-M1, PNA-, alpha-ACT, and alpha-AT staining in Reed-Sternberg (RS) cells in 11 of 15 cases of Hodgkin's disease. Leu-M1 and its staining pattern is characteristic, but not entirely specific for RS cells, and it was not positive in at least 25% of the cases of Hodgkin's disease in formalin-fixed, paraffin-embedded tissues. The limitations of this antibody and others should be recognized.
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PMID:A comparative marker study of large cell lymphoma, Hodgkin's disease, and true histiocytic lymphoma in paraffin-embedded tissue. 294 20

alpha 1-Antichymotrypsin (alpha 1-ACT) is an early-stage acute-phase plasma protein and a serpin that preferentially inactivates chymotrypsin, cathepsin G, and chymase. Using immunofluorescence with four rabbit polyclonal and two monoclonal specific antibodies against human alpha 1-ACT, we have localized alpha 1-ACT at human and rat neuromuscular junctions (NMJs). Strong alpha 1-ACT immunoreactivity (IR) was present at all NMJs identified by bound alpha-bungarotoxin (alpha-BT). alpha 1-ACT immunoreactivity typically extended slightly deeper into the muscle fiber than alpha-BT, and it closely co-localized with immunoreactivities of post-synaptic desmin, beta-amyloid precursor protein, and dystrophin at the same double- or triple-labeled NMJs. Topography of alpha 1-ACT-IR was the same at human and rat NMJs. The muscle non-junctional sarcolemma was either not immunoreactive or was only very slightly so. When the primary antibody was omitted, absorbed, or replaced by a non-immune serum, there was no immunostaining. Thus, alpha 1-ACT is a novel component of the NMJ. Although its role in the postsynaptic domain of the NMJ is unknown, it might be involved in the interaction between the presynaptic and postsynaptic components and/or inhibit excessive or unwanted serine proteases that may exist in the region of the NMJ.
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PMID:Alpha 1-antichymotrypsin is strongly immunolocalized at normal human and rat neuromuscular junctions. 805 38

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

Monoclonal antibodies were raised against prostate-specific antigen (PSA) by immunization with purified free PSA, i.e. not in complex with any protease inhibitor (F-PSA) and PSA in complex with alpha1-anti-chymotrypsin (PSA-ACT). Epitope mapping of PSA using the established monoclonal antibody revealed a complex pattern of independent and partly overlapping antigenic domains in the PSA molecule. Four independent antigenic domains and at least three partly overlapping domains were exposed both in F-PSA and in the PSA-ACT complex, while one antigenic domain was specific for F-PSA. The different domains contained both continuous and discontinuous epitopes. The combination of antibodies recognizing antigenic domains exposed both in F-PSA and PSA-ACT made it possible to develop several highly sensitive sandwich immunoassays for determination of total PSA, i.e. F-PSA + PSA-ACT, with the same molar response for F-PSA and PSA-ACT. Assays specific for F-PSA (cross-reactivity between F-PSA and PSA-ACT < 1%) were developed by the combination of antibodies recognizing epitopes exposed only in F-PSA and antibodies recognizing epitopes exposed both in F-PSA and PSA-ACT.
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PMID:Antigenic determinants of prostate-specific antigen (PSA) and development of assays specific for different forms of PSA. 906 97

Serpins, serine proteinase inhibitors, form enzymatically inactive, 1:1 complexes (denoted E*I*) with their target proteinases, that only slowly release I*, in which the P1-P1' linkage is cleaved. Recently we presented evidence that the serpin antichymotrypsin (ACT, I) reacts with the serine proteinase chymotrypsin (Chtr, E) to form an E*I* complex via a three-step mechanism, E + I <==> E .I <==> EI' <==> E*I* in which EI', which retains the P1-P1' linkage, is formed in a partly or largely rate-determining step, depending on temperature (O'Malley, K. H, Nair, S. A., Rubin, H., and Cooperman, B. S. (1997) J. Biol. Chem. 272, 5354-5359). Here we extend these studies through the introduction of a new assay for the formation of the postcomplex fragment, corresponding to ACT residues 359 (the P1' residue) to 398 (the C terminus), coupled with rapid quench flow kinetic analysis. We show that the E.I encounter complex of wild type-rACT and Chtr forms both E*I* and postcomplex fragment with the same rate constant, so that both species arise from EI' conversion to E*I*. These results support our earlier conclusion that the P1-P1' linkage is preserved in EI' and imply that E*I* corresponds to a covalent adduct of E and I, either acyl enzyme or the tetrahedral intermediate formed by water attack on acyl enzyme. Furthermore, we show that the A347R (P12) variant of rACT, which is a substrate rather than an inhibitor of Chtr, has a rate constant for postcomplex fragment formation from the E.I complex very similar to that observed for WT-rACT, implying that EI' is the common intermediate from which partitioning to inhibitor and substrate pathways occurs. These results are used to elaborate a proposed scheme for ACT interaction with Chtr that is considered in the light of relevant results from studies of other serpin-serine proteinase pairs.
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PMID:Antichymotrypsin interaction with chymotrypsin. Reactions following encounter complex formation. 965 34