Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.4 (trypsin)
 42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Eight different di- and tripeptidyl aldehyde derivatives, each having at its C-terminus an aldehyde analog of L-norleucine, L-methionine, or L-phenylalanine with a preceding L-leucine residue, were synthesized and tested for their inhibitory effects on several serine and cysteine endopeptidases. These compounds showed almost no inhibition of trypsin, and only weak inhibition of alpha-chymotrypsin and cathepsin H, while they exhibited marked inhibition of cathepsin B less than calpain II congruent to calpain I less than cathepsin L, being stronger in this order. The mode of inhibition of these cysteine proteinases was competitive for the peptide substrate used and inhibitor constants (Ki) were calculated from the Dixon plot. The best inhibitors found were: 4-phenyl-butyryl-Leu-Met-H for calpain I (Ki, 36 nM) and calpain II (Ki, 50 nM); acetyl-Leu-Leu-nLeu-H for cathepsin L (Ki, 0.5 nM); acetyl-Leu-Leu-Met-H for cathepsin B (Ki, 100 nM).
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PMID:Inhibitory effect of di- and tripeptidyl aldehydes on calpains and cathepsins. 207 36

Many unexpected biological functions as bioreactants of the intracellular proteases and their endogenous inhibitors have been found recently. Chymase and tryptase in histamine granules of mast cells and basophile cells play an important role in the process of IgE-mediated degranulation and in the formation of an allergic inflammation profile. Furthermore, the relationship between membrane proteases and their endogenous inhibitor has been taken up as a key and key-hole relation which plays an important role for special recognition apparatus of biological information like the relation of peptide hormones (growth factors) and their specific receptors. Amino acid sequences of the active site of trypstatin are homologous with the neutralizing epitope beta of gp120 of AIDS virus (HIV-1). The trypstatin and anti-tryptase M antibody inhibited syncytium formation in HIV infected Molt 4, clone 8 cells. Therefore, the relationship between tryptase M with trypstatin and the recognition site of epitope beta of HIV-1 with the receptor of helper T-cells are the common keys. The precursor of Alzheimer's deposition protein contains a Kunitz-type trypsin inhibitor domain. The A4-precursor proteins are located in axons of pyramidal neurons in brain and secretory granules of chromaffin cells in adrenal medulla. Those may be secreted into the extracellular milieu. We propose that the A4 inhibitor inhibits a special type of tryptase in the brain and disturbs the complete degradation of secreted A4-precursor protein causing amyloid deposition in alzheimer disease by abnormal proteolysis. Human c-Ha-ras p21 shows 58% homology with cystatin beta, an endogenous inhibitor of cathepsin. Actually, p21 inhibits cathepsin L specifically, but not cathepsin H, papain and cathepsin B. However, the metabolic significance of this inhibitory activity is still unknown.
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PMID:New biological functions of intracellular proteases and their endogenous inhibitors as bioreactants. 220 23

Hydrolytic activity of cathepsins B, H and trypsin-like proteases was measured in 38 serous middle ear effusion (MEE) samples. The concentrations of (alpha 1-AT) and alpha 2-macroglobulin (alpha 2-M) were also quantitated. The mean value of cathepsin B activity was 25.0 +/- 20.7 RFU and that of cathepsin H was 14.3 +/- 3.0--both significantly higher than those in plasma (1.8 +/- 0.4 RFU, 1.2 +/- 0.3 RFU, p less than 0.005). Very low trypsin-like protease activity could be observed. The mean concentrations of alpha 1-AT and alpha 2-M were 368 +/- 94.8 mg/dl and 57.5 +/- 57.3 mg/dl. The bulk of alpha 1-AT in MEEs was occupied by free alpha 1-AT, which can saturate exogenous trypsin. Due to the very low molar concentration of alpha 2-M in MEEs, thiol proteases (mainly cathepsin B) could be a possible major factor inflicting proteolytic injury on the middle ear mucosa and reflecting the severity of the inflammatory process.
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PMID:Lysosomal thiol proteases (cathepsin B-like proteases) in serous middle ear effusions from adult patients. 242 71

Here we demonstrate significant similarities between the amino acid sequences of trypsin (a serine protease) and the N-terminal piece of a specific fragment of the poliovirus polyprotein encompassing the sequence of the viral proteinase 3C, and also between cathepsin H (a cysteine protease) and the C-terminal piece of the same fragment. A coherent alignment of the sequences of the 3 proteases was obtained, in which the principal catalytically active residues occupy identical positions. A hypothesis is proposed that the viral enzyme may provide an evolutionary link between serine and cysteine protease families.
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PMID:Poliovirus-encoded proteinase 3C: a possible evolutionary link between cellular serine and cysteine proteinase families. 300 Aug 29

It has been found that two active in neutral medium thiol proteinases from bovine spleen, cathepsin L and cathepsin H, bring about rapid and irreversible inactivation of alpha 1-proteinase inhibitor (alpha 1PI)--one of the major plasma inhibitors of serine proteinases. The activity of the enzymes studied did not change upon the interaction with alpha 1PI. With stoichiometric proteinase/inhibitor ratio, the inactivation of alpha 1PI under the effect of cathepsin L was instantaneous, while under the effect of cathepsin H it occurred within 30-60 min. The products of alpha 1PI inactivation had an inhibitory effect on the rate of its reaction with cathepsin L. alpha 1PI inactivation under the action of cathepsin L and cathepsin H was accompanied by the decrease in the molecular mass of the inhibitor from 54 kDA to 46 kDa. This was, probably, caused by the hydrolysis of the peptide bond formed by NH2 group of threonine. The 46 kDa fragment did not undergo further degradation. It did not bind to immobilized trypsin but retained antigenic properties. The results obtained show that the limited proteolysis is a mechanism of the inhibitor inactivation. It is suggested that under some conditions thiol proteinases, upon their release from the cell, participate in the control of effective alpha 1PI concentration.
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PMID:[Inactivation of blood plasma alpha 1-proteinase inhibitor as affected by 2 splenic thiol proteinases active in a neutral medium]. 329 92

The effect of vitamin E deficiency on levels of proteinase inhibitors in sex glands of male rats was studied. Inhibitor levels against cysteine proteinases, such as ficin and cathepsin H, and against serine proteinase such as trypsin were examined. Vitamin E deficiency for 4 mo after weaning induced a fivefold increase in cysteine proteinase inhibitor level in testis, a two- to fourfold increase in prostate and epididymis and no change in seminal vesicle. No appreciable change was observed in trypsin inhibitor level in testis, epididymis or seminal vesicle. Therefore, vitamin E deficiency was reflected most sensitively by the cysteine proteinase inhibitor level in testis. These observations agree with our previous findings that alpha-cysteine proteinase inhibitors in serum increased greatly whereas trypsin inhibitor in serum did not change in vitamin E-deficient rats. Major histological changes were observed in the testes of rats fed a vitamin E-deficient diet for 4 mo, although testis weight was not significantly affected by vitamin E deficiency.
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PMID:Enhancement of testicular cysteine proteinase inhibitor level in vitamin E-deficient rats. 349 20

The papain inhibitor from human spleen was purified by extraction in isotonic sucrose, acetone fractionation, papain-Sepharose affinity chromatography and gel filtration on Sephadex G-50. The purified inhibitor was fractionated by electrofocusing into four major isoelectric variants with pI values of 4.7, 5.0, 6.0 and 6.5. These variants can be classified into two groups: the acidic type, comprising the variants with pI 4.7 and 5.0, and the neutral type, comprising the variants with pI 6.0 and 6.5. The following properties distinguish the two types: 1. Immunological properties: antibodies raised against either of the neutral variants precipitated both of these, but not the acidic variants. The antiserum against the human epidermal cysteineproteinase inhibitor precipitated the acidic variants, but not the neutral variants. 2. Molecular size: two-dimensional electrophoresis of the purified inhibitor gave molecular weights of 11400 for the acidic variants and 12000 for the neutral variants. The pI 6.0 variant contained two compounds with molecular weights of 12000 and 12800. 3. Enzyme spectrum: human cathepsin B was inhibited by the acidic type, while the neutral type was a poor inhibitor. Both types inhibited cathepsin H, papain, ficin and bromelain, although the inhibition of bromelain did not exceed 70%. Human cathepsin D, bovine trypsin and chymotrypsin and porcine elastase were not inhibited by either type.
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PMID:Human spleen cysteineproteinase inhibitor. Purification, fractionation into isoelectric variants and some properties of the variants. 618 75

A new papain inhibitor was purified from psoriatic epidermal scales using gel chromatography and anion exchange chromatography. The purified protein inhibited papain and ficin but not cathepsin B, cathepsin H, trypsin, or chymotrypsin. Isoelectric focusing revealed 3 major inhibitor variants with pI's of 7.3, 6.9, and 6.5. A Mr of 38,000 was obtained by a gel chromatographic method for the crude inhibitor. After sodium dodecyl sulfate-polyacrylamide gel electrophoresis the Mr values of the isoelectric variants were: 43,000 for the variant pI 7.3, 43,000 and 35,000 for the variant pI 6.9, and 34,000-35,000 for the variant pI 6.5. An antiserum of the inhibitor was used to locate the inhibitor in the psoriatic and normal epidermis. In psoriatic epidermis, the inhibitor was found in the peripheral cytoplasm of spinous cells and in the scale. In normal epidermis, the staining was seen only in orifices of hair follicles. An inhibitor with similar size and antigenic properties to that isolated from the psoriatic scales was demonstrated in extracts made from the whole-thickness epidermis but not in extracts from the healthy epidermal scales, the dermis, the liver, the spleen, or the blood serum.
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PMID:Partial purification and some properties of a new papain inhibitor from psoriatic scales. 639 31

Thiol protease inhibitors were found in the cytosol fractions of various rat tissues. An inhibitor, named cytosol thiol protease inhibitor, was purified from rat liver cytosol by acid treatment and column chromatographies on Sephadex G-50, DEAE-Sephadex and Sephadex G-75. The purified inhibitor gave a single protein band on sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis. The molecular weight of the inhibitor was found to be 12 400 by gel filtration on Sephadex G-75 and SDS-polyacrylamide gel electrophoresis, and its isoelectric point was found to be 5.04. This inhibitor inhibited rat liver lysosomal cathepsin B, B2, C, H and L and papain, but not cathepsin A or D, trypsin or chymotrypsin. The inhibitor caused noncompetitive inhibition of the hydrolytic activity of cathepsin H on alpha-N-benzoyl-DL-arginine 2-naphthylamide and its Ki value was 4.08 . 10(-8) M. Heat treatment at 80 degrees C for 10 min reduced the activity 40%.
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PMID:Purification and properties of thiol protease inhibitor from rat liver cytosol. 702 26

A series of N-peptidyl-O-acyl hydroxamates with a lysine in P1 was synthesized and tested as inactivators of lysosomal cysteine proteinases (cathepsins S, L, B and H) and trypsin-like serine proteinases (trypsin, thrombin, plasmin, t-PA). N-peptidyl-O-acyl hydroxamates were shown to be selective inhibitors of cysteine proteinases. With the exception of cathepsin H, the lysosomal cysteine proteinases were inactivated 2-5 orders of magnitude more rapidly than serine proteinases with a comparable primary substrate specificity. The highest second-order rate constants of inactivation for the cysteine proteinases are in the range of 10(5)-10(6) M-1 s-1. The order of inhibitor specificity for the cysteine proteinases is comparable to the enzyme's substrate specificity.
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PMID:Novel N-peptidyl-O-acyl hydroxamates: selective inhibitors of cysteine proteinases. 839 90


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