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:3.4.23.5 (cathepsin D)
4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ADP-ribosylation site of histone H1 from calf thymus by purified hen liver nuclear ADP-ribosyltransferase was determined and effects of the ADP-ribose X histone-H1 adduct on cAMP-dependent phosphorylation of the histone H1 were investigated. ADP-ribosylated histone H1 was prepared by incubation of histone H1, 1 mM [adenylate-32P]NAD and the purified ADP-ribosyltransferase. N-Bromosuccinimide-directed bisection of ADP-ribosylated histone H1 showed that the NH2-terminal fragment (Mr = 6000) was modified and contained serine residue 38, the site of phosphorylation by cAMP-dependent protein kinase. Digestion of the NH2-terminal fragment with cathepsin D and trypsin, and purification of this fragment, using high-performance liquid chromatography, yielded a radiolabelled single peptide corresponding to residues 29-34 of histone H1, containing the arginine residue as the ADP-ribosylation site. These results indicate that ADP-ribosylation of histone H1 occurs at the arginine residue 34, sequenced at the NH2-terminal side of the phosphate-accepting serine residue 38. Phosphorylation of histone H1 from calf thymus by cAMP-dependent protein kinase was markedly reduced when histone H1 was ADP-ribosylated. Kinetic studies of phosphorylation revealed that ADP-ribosylated histone H1 was a linear competitive inhibitor of histone H1 and a linear non-competitive inhibitor of ATP.
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PMID:Amino acid sequence of histone H1 at the ADP-ribose-accepting site and ADP-ribose X histone-H1 adduct as an inhibitor of cyclic-AMP-dependent phosphorylation. 299 55

We have identified a system in human lymphocytes which proteolytically cleaves poly(ADPribose) polymerase to specific fragments of molecular weight 96 000, 79 000 and 62 000-60 000. This proteolytic processing is dependent on two different classes of proteinase. One of these proteinases is a serine proteinase, since the processing is inhibited by phenylmethylsulfonyl fluoride, antipain, soybean trypsin inhibitor and diisopropylfluorophosphate, the other is a cathepsin D-like proteinase, since processing is also inhibited by pepstatin A. The processing that occurs in permeabilized cells can be simulated in vitro by treating purified poly(ADPribose) polymerase with trypsin, but not by treating the polymerase with cathepsin D. Since processing at the cellular level is blocked by inhibitors of either of the two proteinases, but only trypsin could cleave the purified polymerase, this suggests that in the cell the action of the cathepsin D-like proteinase is a prerequisite for cleavage of poly(ADPribose) polymerase by the serine proteinase. Thus, a pathway involving sequential action of these proteinases may exist. Proteolysis in permeabilized human lymphocytes is stimulated by nucleotides containing a pyrophosphate group, such as 5',5'''-P1,P4-tetraphosphate and ATP, or by pyrophosphate itself. In contrast, nucleotides containing only a single phosphate, such as AMP and cyclic AMP, or inorganic sodium phosphate, do not show this stimulation of proteolysis. These results suggest that a pyrophosphate linkage is the minimum molecular requirement for stimulation of proteolytic processing of poly(ADPribose) polymerase. Proteolytic processing of poly(ADPribose) polymerase is independent of ADPribosylation. Following proteolysis, specific fragments of the polymerase, particularly the 62 000-60 000 molecular weight fragment(s), are still capable of being ADPribosylated.
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PMID:Proteolysis of poly(ADPribose) polymerase by a pyrophosphate- and nucleotide-stimulated system dependent on two different classes of proteinase. 299 8

The amino acid sequences at the "proteolytic processing regions" of cathepsin Ds have been determined for the enzymes from cows, pigs, and rats in order to deduce the sites of cleavage as well as the function of the proteolytic processing of cathepsin D. For bovine cathepsin D, the "processing region" sequence was determined from a peptide isolated from the single-chain enzyme. The COOH-terminal sequence of the light chain and the NH2-terminal sequence of the heavy chain were also determined. The processing region sequence of porcine cathepsin D was determined from its cDNA structure, and the same structure from rat cathepsin D was determined from the peptide sequence of the single-chain rat enzyme. From sequence homology to other aspartic proteases whose x-ray crystallographic structures are known, such as pepsinogen and penicillopepsin, it is clear that the processing regions are insertions to form an extended beta-hairpin loop between residues 91 and 92 (porcine pepsin numbers). However, the sizes of the processing regions of cathepsin Ds from different species are considerably different. For the enzymes from rats, cows, pigs, and human, the sizes of the processing regions are 6, 9, 9, and 11 amino acid residues, respectively. The amino acid sequences within the processing regions are considerably different. In addition, the proteolytic processing sites were found to be completely different in the bovine and porcine cathepsin Ds. While in the porcine enzyme, an Asn-Ser bond and a Gly-Val bond are cleaved to release 5 residues as a consequence of the processing; in the bovine enzyme, two Ser-Ser bonds are cleaved to release 2 serine residues. These findings would argue that the in vivo proteolytic processing of the cathepsin D single chain is probably not carried out by a specific "processing protease." Model building of the cathepsin D processing region conformation was conducted utilizing the homology between procathepsin D and porcine pepsinogen. The beta-hairpin structure of the processing region was found to (i) interact with the activation peptide of the procathepsin D in a beta-structure and (ii) place the Cys residue in the processing region within disulfide linkage distance to Cys-27 of cathepsin D light chain. These observations support the view that the processing region of cathepsin D may function to stabilize the conformation of procathepsin D and may play a role in its activation.
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PMID:Structures at the proteolytic processing region of cathepsin D. 318

Epidermal proteinases, which may be involved in proteolysis of Mr greater than 300k histidine-rich protein in epidermis, were studied by SDS-PAGE analysis. Mr greater than 300k histidine-rich protein was extracted from granular cells of 2-day-old rats in citric acid-sucrose solution and separated from proteinases and smaller Mr proteins by Sephacryl S-300 column chromatography. The proteinase-free histidine-rich protein was stable in pH 3.5-9 at 37 degrees C for 12 h. Proteinases were partially purified from rat epidermis and inhibitor spectrum determined for each enzyme. Limited hydrolysis of Mr greater than 300k histidine-rich protein yielded a derivative of Mr 56k with cathepsin D at pH 3.5-7.5 and a serine proteinase at pH 7-9. Further proteolysis of Mr 56k protein to Mr 44k and a doublet of Mr 45k and 47k also was detected with cathepsin D at pH 3.5 and 7.5, respectively, while the serine proteinase degraded Mr 56k protein to a number of protein bands. Cathepsins B and L degraded Mr greater than 300k protein but no specific predominant product was identified. We suggest that cathepsin D and the serine proteinase may play a role in in situ processing of histidine-rich protein during cornification.
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PMID:Limited proteolysis of high molecular weight histidine-rich protein of rat epidermis by epidermal proteinases. 328 79

Proteolytic activity was estimated in lymphocyte lysates of cattle in normal state and in chronic lympholeukosis using 3H-acetylated casein (pH 7.4) and 3H-acetylated hemoglobin (pH 4.0) as substrates. Distinct individual variations in the enzymatic activity were observed either in neutral or slightly-acid media in the animal groups studied. In chronic lympholeukosis specific proteolytic activity, calculated per a cell, was decreased, while it was increased in calculation per a mg of protein. The lower content of protein (about 2.4-fold) was found in lysates of lymphocytes in chronic lympholeukosis as compared with normal state. An increase in proteolytic activity in lymphocyte lysates correlated with elevation of blood leukocytosis if chronic lympholeukosis developed in individual animals. Effects of a number of proteinase inhibitors and activators were studied in the cell lysates; the spectrum of proteinases in chronic lympholeukosis was dissimilar to that of normal state. Pepstatin inhibited quite completely the proteolytic activity at pH 4.0 in lymphocytes of healthy animals and hence cathepsin D was responsible for the activity; in chronic lympholeukosis, except of cathepsin D, thiol-dependent proteinase was also detected. Activity of proteinases at neutral pH value in lymphocytes of healthy and impaired animals was inhibited by phenylmethionine fluorosulfate and p-chloromercuribenzoate, thus suggesting that serine and thiol-dependent proteinases were present; the level of these enzymes was distinctly higher in chronic lympholeukosis as compared with normal state.
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PMID:[Comparative characteristics of lymphocyte proteolytic enzymes in normal conditions and in chronic lymphoid leukemia]. 353 48

The activity of chymase was markedly inhibited by phosphoglycerides such as phosphatidic acid, phosphatidylserine, and phosphatidylinositol, but was not affected by acylglycerides, phosphoglyceroserine, serine, inositol, or glycerol. These results suggest that both the nonpolar hydrophobic hydrocarbon tails and the polar hydrophilic head are essential for the inhibitory effects of phosphoglycerides. Binding of a primary amine to an anionic polar head of phosphatidic acid, such as in phosphatidylserine and phosphatidylethanolamine, slightly decreased the inhibitory effect of phosphatidic acid and, conversely, binding of a strong cation to the head, such as in phosphatidylcholine, resulted in its activation of chymase. Phosphatidic acid containing an unsaturated fatty acid, such as dioleoyl phosphatidic acid, caused the same extent of inhibition as natural phosphatidic acid from bovine brain, but was 20 times more inhibitory than phosphatidic acid containing a saturated fatty acid, such as distearoyl phosphatidic acid. The inhibition by phosphatidylserine was noncompetitive and pseudoirreversible, and the Ki value was 0.54 microM. The inhibition of chymase by phosphatidylserine was pH dependent, being strong at pH 8.5 to 9.5 but weak below pH 7.5. Phosphatidylserine specifically inhibited chymase and elastase; it did not inhibit the other chymotrypsin-type serine endopeptidases tested, trypsin, papain, collagenase, carboxypeptidase A, or cathepsin D.
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PMID:Inhibition of chymase activity by phosphoglycerides. 388 53

Extracts of rheumatoid synovial tissue obtained at surgical synovectomy contained neutral proteinases as well as cathepsin D. The neutral proteinase activity was particle-bound but could be solubilized by 1 M MgCl2. About half of the solubilized activity adsorbed to aproptinin-Sepharose at pH 7.5 and was desorbed at pH 3.3. This activity was shown to be due to leukocyte elastase and cathepsin G by enzymological and immunological criteria. The neutral proteinase activity that did not adsorb to aprotinin-Sepharose was not due to elastase or cathepsin G. It was able to hydrolyse proteoglycan and was inhibited by diisopropylfluorophosphate, soybean and lima bean trypsin inhibitors. It was, therefore, a serine proteinase. Its inhibition characteristics were different from those of plasmin, kallikrein or thrombin. All of the neutral proteinase activity of synovial extracts was attributable to serine proteinases, no evidence of metallo-proteinases was found. The possible role of the neutral proteinases in the degradation of the matrix of cartilage is discussed. A simple procedure for purifying leukocyte elastase and cathepsin G is described as well as the raising of specific antisera to these enzymes.
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PMID:Identification of proteinases in rheumatoid synovium. Detection of leukocyte elastase cathepsin G and another serine proteinase. 615 6

The human leucocyte migration in the leucocyte migration under agarose technique ( LMAT ) was investigated with specific inhibitors of aspartic, sulphhydryl , metallo- and serine proteinases. The general aspartic proteinase inhibitor pepstatin and the highly specific competitive cathepsin D inhibitor, N-gly-glu-gly-phe-leu-gly-D-phe-leu suppressed leucocyte migration at concentrations of 20-200 mumol/l and 30-59 mumol/l, respectively. The suphhydryl enzyme inactivator, N-ethylmaleimide suppressed leucocyte migration at concentrations of 100-200 mumol/l. Several inhibitors of serine- and metallo enzymes were tested, but none had any effect on leucocyte mobility, although the metal binding agent 8-hydroxyquinoline was strongly inhibitory to cell migration, the significance of which is discussed.
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PMID:Leucocyte migration inhibition in vitro with inhibitors of aspartic and sulphhydryl proteinases. 620 30

There are two types of enzymes in tissues leading to angiotensin formation: a) those resulting in the formation of angiotensin I, such as renin and cathepsin D, the presence of which is now well established for brain tissue and b) Those leading to the direct formation of angiotensin II without the angiotensin I step, such as cathepsin G and tonin. Recent findings concerning tonin, a serine protease, are described: a) 80% of its amino acid sequence, b) its different characteristics from other serine proteases, from renin, cathepsin D and the angiotensin I converting enzyme, c) the activation of inactive renin, d) its involvement in the 1K-1C hypertensive rats, e) the demonstration of its presence in the distal tubular cells of the rat kidney, and finally, f) its presence in urine and the influence of age and of sodium intake on its urinary excretion.
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PMID:Extrarenal angiotensin-forming enzymes. 631 65

A synthetic tetradecapeptide, H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Ser-OH, which corresponds to the 13 amino terminal residues of human angiotensinogen plus a carboxy terminal serine to replace a suggested site of carbohydrate attachment, has been shown to be a good substrate for human kidney renin. At pH 7.2 and 37 degrees C the KM or Michaelis constant was 8.4 +/- 2.9 microM, and the VM or velocity at infinite tetradecapeptide concentration was 11.3 +/- 2.4 mumol angiotensin I made per hour per milligram renin. The tetradecapeptide was highly resistant to cleavage by mouse submaxillary renin. The tetradecapeptide was also slowly cleaved by human liver cathepsin D, by rabbit lung angiotensin-converting enzyme, and by reconstituted human serum, but did not yield angiotensin I. Thus, this synthetic renin substrate should permit more specific measurement of human kidney renin activity.
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PMID:Renin cleavage of a human kidney renin substrate analogous to human angiotensinogen, H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Ser-OH, that is human renin specific and is resistant to cathepsin D. 638 71


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