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:3.4.24.11 (CD10)
9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In addition to angiotensin I converting enzyme (ACE; EC 3.4.15.1) and carboxypeptidase N (CPN; EC 3.4.17.3), other peptidases contribute to bradykinin (BK) degradation in plasma. Rat plasma degraded BK by hydrolysis of the N-terminal Arg1-Pro2 bond, and the characteristics of hydrolysis are consistent with identification of aminopeptidase P (APP; EC 3.4.11.9) as the responsible enzyme. BK and BK[1-5] N-terminal hydrolysis was optimal at neutral pH, was inhibited by 2-mercaptoethanol, dithiothreitol, o-phenanthroline and EDTA, but was unaffected by the aminopeptidase inhibitors amastatin, puromycin and diprotin A, the endopeptidase-24.11 inhibitors phosphoramidon and ZINCOV, and the ACE and CPN inhibitors captopril and D,L-mercapto-methyl-3-guanidinoethylthiopropanoic acid (MERGETPA), respectively. Although kallidin (Lys-BK) was not metabolized directly by APP, conversion to BK by plasma aminopeptidase M (EC 3.4.11.2) resulted in subsequent degradation by APP. BK analogs containing N-terminal Arg1-Pro2 bonds, including [Tyr8-(OMe)] BK and [Phe8 psi(CH2NH)Arg9]BK (B2 agonists), des-Arg9-BK and [D-Phe8]des-Arg9-BK (B1 agonists), and [Leu8]des-Arg9-BK (B1 antagonist), were degraded by APP with Km and Vmax values comparable to those found for BK (Km = 19.7 +/- 2.6 microM; Vmax = 12.1 +/- 1.2 nmol/min/mL). In contrast, B2 antagonists containing D-Arg0 N-termini, including D-Arg[Hyp3,Thi5.8,D-Phe7]BK and D-Arg[Hyp3,D-Phe7,Phe8 psi(CH2NH)Arg9]BK, were resistant to APP-mediated hydrolysis. These data support a role for plasma aminopeptidase P in the degradation of circulating kinins, and a variety of B2 and B1 kinin agonists and antagonists. However, APP does not participate in the degradation of D-Arg0-containing antagonists.
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PMID:Metabolism of bradykinin agonists and antagonists by plasma aminopeptidase P. 165 Oct 78

Sequence analysis of aminopeptidase N has shown that this zinc exopeptidase contains a consensus sequence (Val-Xaa-Xaa-His-Glu-Xaa-Xaa-His), generally found at the active site of zinc endopeptidases [Jongeneel, C. V., Bouvier, J. and Bairoch, A. (1989) FEBS Lett. 242, 211-214]. This suggests that the active site of aminopeptidase N may be closer to that of a classical zinc endopeptidase, such as thermolysin, than to that of an exopeptidase, such as carboxypeptidase A, which does not contain the above sequence. However, the nature of the other amino acids involved in the enzymatic activity of the eukaryotic aminopeptidase N remains unknown. Chemical modifying agents have now been used to characterize the active site of aminopeptidase N further. The location of the modified residues was also determined by comparing the protection given by three competitive inhibitors which interact with different subsites of the active site. Aminopeptidase N was rapidly inactivated by 2,3-butanedione and diethylpyrocarbonate and partially inactivated by N-acetylimidazole, diazoacetamide and a soluble carbodiimide, suggesting the presence of functional arginyl, histidyl, tyrosyl and aspartyl/glutamyl residues. In each case the reaction kinetics showed that the inactivation could be correlated with modification of a single residue. The protection experiments indicated that the residues are at the active site of the enzyme and that the arginine and tyrosine are probably located in the S'1-S'2 subsites, histidine in the S1 subsite and the acidic residue near the zinc binding site and the S'1 subsite. Steady-state kinetics showed that the arginine, histidine and acidic residues are involved in substrate binding, while the tyrosine may play a role in the catalytic process. All these data support an endopeptidase-like structure for the active site of aminopeptidase N.
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PMID:Functional residues at the active site of aminopeptidase N. 167 19

We contrasted the effects of D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-DPhe-Thi-Arg-TFA (kinin receptor antagonist), of aprotinin (kallikrein inhibitor), and of combined treatment with captopril (kininase II inhibitor) and phosphoramidon (neutral endopeptidase 24.11 inhibitor) on renal function of rats with and without 14-day deoxycorticosterone pretreatment (DOC, 25 mg.kg-1.wk-1 sc). Neither the kinin antagonist nor aprotinin affected renal function in rats with and without DOC pretreatment. Combined treatment with captopril and phosphoramidon caused in rats with and without DOC pretreatment augmentation (P less than 0.05) of kinin excretion (50-64%), glomerular filtration rate (12-11%), and sodium excretion (46-48%). In DOC-pretreated rats undergoing infusion of captopril and phosphoramidon, the superimposed administration of either the kinin antagonist or aprotinin caused the lowering of renal plasma flow, glomerular filtration rate, and sodium excretion. These effects of the kinin antagonist and aprotinin in rats infused with kininase inhibitors may be the consequence of blockade, respectively, of the renal actions and synthesis of kinins that, when in excess, elicit renal vasodilation and increase glomerular filtration rate and sodium excretion. Collectively, these observations suggest regulatory influence of kinins during conditions featuring increased renal kinin levels.
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PMID:Effects of a kinin antagonist on renal function in rats. 169 May 17

Enzymes that hydrolyze kinins are known under the collective term of "kininases." This short review surveys kininase I- and II-type enzymes. For the sake of simplicity, we call carboxypeptidases that remove the C-terminal arginine of kinins kininase I-type enzymes. Plasma carboxypeptidase N and the cell membrane-bound carboxypeptidase M belong here. Kininase II enzymes release the C-terminal dipeptide Phe-Arg; angiotensin I-converting enzyme and neutral endopeptidase 24.11 (enkephalinase) are prominent members of this subgroup of proteins. The primary sequence of five proteins of the four human kininases (including the catalytic and regulatory subunits of carboxypeptidase N) were deduced from the nucleotide sequence of their cDNAs. The structure and properties of these enzymes are briefly discussed.
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PMID:Some old and some new ideas on kinin metabolism. 169 56

The effects of inhaled bradykinin (BK), substance P (SP), and neurokinin A (NKA) on pulmonary resistance and airway responsiveness to carbachol were studied in conscious allergic sheep. Inhaled BK (20 breaths, 0.1 to 5.0 mg.ml-1) caused dose-dependent increases in pulmonary resistance. Neither inhaled SP nor NKA (20 breaths, 0.1 to 1.0 mg.ml-1) produced significant bronchoconstriction in allergic sheep. However, the response to SP could be enhanced (p less than 0.05) by pretreatment with the neutral endopeptidase inhibitor, thiorphan (40 breaths, 1 mg.ml-1). Sheep that were allergic to Ascaris suum antigen were 5.9 times (p less than 0.05) more sensitive to the constrictor effects of BK than nonallergic sheep. BK-induced bronchoconstriction was blocked in a dose-dependent fashion by the BK beta 2-receptor antagonist, NPC 567 (D-arginine[hydroxyproline3,D-phenylalanine7]BK). Atropine (0.2 mg.kg-1, intravenously) and nedocromil sodium (1 mg.kg-1 in 3 ml of saline, aerosolized) significantly inhibited the BK-induced bronchoconstriction by 97% and 43%, respectively. Chlorpheniramine (2 mg.kg-1, intravenously) had no effect. NKA caused a transient increase in airway responsiveness in allergic sheep, producing a mean 1.9-fold leftward shift in dose-response curves to aerosolized carbachol (p less than 0.05). This hyperresponsiveness was not evident 24 hours after NKA challenge. Neither SP nor BK changed airway responsiveness. Thus, in allergic sheep, inhaled BK caused a more pronounced bronchoconstriction than that observed in nonallergic sheep. The bronchoconstriction was blocked by a BK-receptor antagonist and appeared to be partially mediated via cholinergic reflexes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Airway effects of inhaled bradykinin, substance P, and neurokinin A in sheep. 170 88

Neuropeptides containing the carboxylterminal sequence Arg-Phe-NH2 are found throughout the animal kingdom and are important substances mediating neuronal communication. Here, we have cloned the cDNA coding for the precursor protein of the sea anemone neuropeptide (Antho-RFamide) less than Glu-Gly-Arg-Phe-NH2. This precursor is 334 amino acids in length and contains 19 copies of unprocessed Antho-RFamide (Gln-Gly-Arg-Phe-Gly), which are tandemly arranged in the C-terminal part of the protein. Paired basic residues (Lys-Arg) or single basic residues (Arg) occur at the C-terminal side of each Antho-RFamide sequence. These are likely signals for posttranslational cleavage. The processing signals at the N-terminal side of each Antho-RFamide sequence, however, include acidic residues. Processing at these amino acids must involve either an amino- or an endopeptidase that cleaves C-terminally of aspartic acid or glutamic acid residues. Such processing is, to our knowledge, hitherto unknown for peptidergic neurons. The Antho-RFamide precursor also contains two copies of the putative Antho-RFamide-related peptide Phe-Gln-Gly-Arg-Phe-NH2 and one copy of Tyr-Val-Pro-Gly-Arg-Tyr-NH2. In addition, the precursor protein harbors four other putative neuropeptides that are much less related to Antho-RFamide. This report shows that the biosynthetic machinery for neuropeptides in coelenterates, the lowest animal group having a nervous system, is already very efficient and similar to that of higher invertebrates, such as mollusks and insects, and vertebrates.
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PMID:Primary structure of the precursor for the sea anemone neuropeptide Antho-RFamide (less than Glu-Gly-Arg-Phe-NH2). 170 27

A soluble 80-kDa endopeptidase has been isolated from Trypanosoma brucei brucei. The enzyme, which has a pI 5.1, is optimally active at about pH 8.2 and has apparent pKa values of 6.0 and greater than or equal to 10. It is inhibited by the serine protease inhibitor diisopropylfluorophosphate and by the serine protease mechanism-based inhibitor 3,4-dichloroisocoumarin. Unexpectedly, the enzyme is inhibited by the cysteine protease inhibitor benzyloxycarbonyl-Leu-Lys-CHN2 but not by the related diazomethane, butoxycarbonyl-Val-Leu-Gly-Lys-CHN2, nor by other cysteine protease specific compounds. Specificity studies with a variety of amidomethylcoumaryl (AMC) derivatives of small peptides show that the enzyme has a highly restricted trypsin-like specificity. The best substrate, based on the magnitude of kcat/Km, was benzyloxycarbonyl-Arg-Arg-AMC; other good substrates were benzyloxycarbonyl-Phe-Arg-AMC, benzoyl-Arg-AMC, and compounds with Arg at P1 and Ala or Gly at P2. The hydrolysis of most substrates obeyed classical Michaelis-Menton kinetics but several exhibited pronounced substrate inhibition. The enzyme did not activate plasminogen nor decrease blood clotting time; it was inhibited by aprotinin but not by chicken ovomucoid. We conclude that the enzyme is a trypsin-like serine endopeptidase with unusually restricted subsite specificities.
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PMID:Characterization of an endopeptidase of Trypanosoma brucei brucei. 173 36

Recombinant platelet-derived growth factor (PDGF)-BB was expressed and secreted from yeast in order to study the structure-function relationships of this mitogen. A simple purification scheme has been developed which yields greater than 95% pure PDGF-BB. Analysis of this recombinant PDGF-BB shows partial proteolysis after arginine-32. Substitution of this arginine residue, or arginine-28 [a potential KEX2 (lysine-arginine endopeptidase) cleavage site], prevents or reduces cleavage of PDGF-BB respectively. These mutations result in a 5-fold increase in expression levels of PDGF-BB, and the resulting mutant proteins show higher activity in a number of biological assays than the cleaved wildtype PDGF-BB. These data are in accord with previous work by Giese, LaRochelle, May-Siroff, Robbins & Aaronson [(1990) Mol. Cell Biol. 10, 5496-5501] suggesting that the region isoleucine-25-phenylalanine-37 is involved in PDGF-receptor binding.
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PMID:Purification and analysis of proteinase-resistant mutants of recombinant platelet-derived growth factor-BB exhibiting improved biological activity. 173 68

Intact cells of Streptococcus sanguis ATCC 10556 possessed arylaminopeptidases exhibiting activity toward the nitroanilide (NA) derivatives of leucine, alanine, methionine, arginine, or lysine. Weak hydrolytic activity was observed in assays with the NA derivatives of valine, proline, glycine, or glutamic acid. Subcellular localization studies revealed that arylaminopeptidase activities were located in both the cell membrane and cytoplasm. Arylaminopeptidases exhibiting activity toward the leucine, alanine, or methionine NA substrates appeared to be more predominantly associated with the membrane, whereas enzymes exhibiting activity toward arginyl-NA or lysyl-NA were more prevalently located in the cytoplasm. Several results from this study suggest that the membrane-assocaited arginyl and lysyl arylaminopeptidases were located in such a way that their expression was restricted in the intact cell. The addition of 0.5 mol/L NaCl to protoplast preparations derived from mutanolysin-treated cells resulted in an almost complete solubilization of membrane-associated arylaminopeptidase activities. These observations support the conclusion that the association of arylaminopeptidases with the cell membrane may involve hydrophobic or electrostatic interactions, or both. S. sanguis ATCC 10556 also possessed at least one caseinolytic endopeptidase activity. This activity is most likely located near the membrane surface, as no association with the cell wall was evident. The location of membrane-associated endopeptidase and arylaminopeptidase activities, together with intracellular peptidases, is suggested to provide an efficient mechanism for the hydrolysis and subsequent utilization of polypeptide and oligopeptide substrates as sources of amino acids for growth by this microorganism.
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PMID:Studies on the subcellular localization of protease and arylaminopeptidase activities in Streptococcus sanguis ATCC 10556. 177 82

Human MSEL-neurophysin has been dissected into two halves by endopeptidase Lys-C, taking advantage of a peculiar Lys59-Ala60 bond. Two sub-domains, N-terminal (1-59) and C-terminal (60-93), have been separated. These sub-domains have been purified by reverse-phase high pressure liquid chromatography and identified by their N-terminal sequences. The N-terminal fragment comprises two chains 1-18 and 19-59, because of the presence of a second lysine residue in position 18, whereas the C-terminal fragment (60-93) is a single chain. Hormone-binding experiments have been carried out using vasopressin or vasopressinyl-Gly-Lys-Arg and testing the ability of the hormone-neurophysin complex to precipitate at pH 3.9 with 10% NaCl. The N-terminal sub-domain precipitates in presence of vasopressin in the same way as native neurophysin whereas the C-terminal sub-domain does not. It can be concluded that the hormone-binding site is located in the 1-59 region of neurophysin.
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PMID:The hormone-binding site of neurophysins: binding of vasopressin to the N-terminal sub-domain dissected from human MSEL-neurophysin through endopeptidase Lys-C. 181 3


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