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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This paper concerns with the changes of plasma amino acid (AA) concentrations of N. 10 ELBW infants receiving a regimen of partial parenteral nutrition including human serum albumin (HSA) as a protein supply. The plasma AA concentration has been compared with VLBW infants orally fed with human milk (HM) or human milk supplemented with human milk protein (HMP). As for the essential AA: in comparison to VLBW infants fed HM, the plasma concentration of VAL, PHE and LYS is significantly higher, that of THR, MET, LEU and HIS is similar, whereas that of ILE is significantly lower; in comparison to VLBW infants fed HMP, with the exception of PHE whose plasma concentration is higher, concentration of essential AA significantly lower; the percentage ratio between plasma concentration and intake is in the range of 1,4 to 3,3, except for LYS (= 0.83), indicating a good efficacy of the i.v. administered HSA as AA source, or a slow plasma clearance or a sustained flux of AA from body protein catabolism. Further researches are needed to investigate these aspects and the intermediate steps between i.v. infusion of HSA and the utilization of the component AA for body protein synthesis.
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PMID:[The partial parenteral nutrition of preterm infants with a body weight < 1000 g: the effects of an infusion of human albumin on plasma amino acid concentration]. 825 73

Four naturally occurring platelet-activating factor (PAF) analogs, 1-alk-1'-enyl-2-acetyl-sn-glycero-3-phosphocholine, 1-hexadecanoyl-2-acetyl-sn-glycero-3-phosphocholine, 1-octadecanoyl-2-acetyl-sn-glycero-3-phosphocholine, and 1-alkyl-2-acetyl-sn-glycero-3-phosphoethanolamine, stimulated human neutrophils (PMN) to mobilize Ca2+, degranulate, and produce superoxide anion. They were, respectively, 5-, 300-, 500-, and 4000-fold weaker than PAF in each assay; inhibited PMN-binding of [3H]PAF at concentrations paralleling their biological potencies; and showed sensitivity to the inhibitory effects of PAF antagonists. PAF and the analogs, moreover, desensitized PMN responses to each other but not to leukotriene B4 and actually increased (or primed) PMN responses to N-formyl-MET-LEU-PHE. Finally, 5-hydroxyeicosatetraenoate-enhanced PMN responses to PAF and the analogs without enhancing the actions of other stimuli. It stereospecifically raised each analog's potency by as much as 100-fold and converted a fifth natural analog, 1-alk-1'-enyl-2-acetyl-sn-glycero-3-phosphoethanolamine from inactive to a weak stimulator of PMN. PAF and its analogs thus represent a structurally diverse family of cell-derived phospholipids which can activate, prime, and desensitize neutrophils by using a common, apparently PAF receptor-dependent mechanism.
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PMID:Comparison of 1-O-alkyl-, 1-O-alk-1'-enyl-, and 1-O-acyl-2-acetyl-sn-glycero-3-phosphoethanolamines and -3-phosphocholines as agonists of the platelet-activating factor family. 828 Jul 72

The tyrosine kinase encoded by the MET proto-oncogene (p190MET) is the receptor for Hepatocyte Growth Factor/Scatter Factor (HGF/SF). Previous work has shown that autophosphorylation of p190MET enhances its enzymatic activity and that the major phosphorylation site is Tyr1235, located in the catalytic domain. This residue is part of a 'three tyrosine' motif, including Tyr1230, Tyr1234, and Tyr1235, conserved in several other receptor kinases. We studied the role of these tyrosines in the positive regulation of the p190MET kinase by site-directed mutagenesis. Substitution of either Tyr1235 or Tyr1234 with phenylalanine severely reduced the in vitro kinase activity toward exogenous substrates. Kinetic experiments showed that the residual activity of these mutants could still be enhanced by autophosphorylation. Phosphopeptide mapping indicated that, in the absence of Tyr1235, Tyr1234 is phosphorylated. Only the replacement of both Tyr1234 and Tyr1235 yielded a mutant which completely lost the ability to be activated by autophosphorylation. In stable transfectants expressing the HGF/SF receptor with single substitution of either Tyr1234 or Tyr1235 the response to HGF/SF was impaired. The ligand did not induce tyrosine phosphorylation of the receptor nor stimulated chemotaxis. These data show that Tyr1234 and Tyr1235 are critical for the activation of the HGF/SF receptor kinase both in vitro and in response to the ligand in intact cells.
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PMID:Tyrosines1234-1235 are critical for activation of the tyrosine kinase encoded by the MET proto-oncogene (HGF receptor). 830 3

Neutral endopeptidase 24.11 (NEP/CALLA/CD10), an enzyme expressed on early lymphoid progenitors, neutrophils, and various other cell types, inactivates many biologically active peptides, including the bacterial chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (fMLP). Inhibition of CD10/NEP on the surface of human neutrophils (PMNs) in vitro inhibits migration toward this chemotaxin, suggesting that enzymatic inactivation by NEP regulates the neutrophil response to fMLP. Because PMNs in inflammatory sites are exposed to various cytokines, we evaluated the effects of selected cytokines on CD10/NEP activity in vitro. Of five cytokines tested--interleukin-1 (IL-1), IL-6, and IL-8, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor (GM-CSF)--GM-CSF provided the most consistent increase in surface NEP activity. Low concentrations (10(-9)-10(-7) M) of GM-CSF increased NEP activity in a time- and concentration-dependent manner to more than 225% that of control (phosphate-buffered saline-treated) cells. Cytofluorometry of cells stained with a fluorescent antibody to CD10 indicated that GM-CSF increased expression of surface CD10/NEP antigen in a similar manner. The effect of GM-CSF on NEP activity was enhanced still further by simultaneous exposure to IL-1, suggesting that combinations of cytokines may direct and regulate the neutrophil response within an inflammatory site. Rapid upregulation of CD10/NEP underscores the importance of this enzyme for control of peptide mediators of inflammation.
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PMID:Up-regulation of neutral endopeptidase (CALLA) in human neutrophils by granulocyte-macrophage colony-stimulating factor. 831 51

Mutant epidermal growth factor (EGF) receptors in which the five known tyrosine autophosphorylation sites (tyrosines 992, 1068, 1086, 1148, and 1173) were replaced with phenylalanine residues were expressed in NIH-3T3 cells (5F-EGFR) and transmembrane signaling parameters compared with cells expressing wild-type EGF receptor (WT-EGFR). Mutant and wild-type clones were chosen expressing similar numbers of receptors and Scatchard analysis of 125I-EGF binding showed high and low affinity binding of equal affinities for both receptor types. EGF stimulated tyrosine phosphorylation of proteins to a much lesser degree in cells expressing 5F-EGFR relative to cells expressing WT-EGFR. Tyrosine phosphorylation of the 5F-EGFR was 2-4% of WT-EGFR. Surprisingly, cells expressing WT-EGFR or 5F-EGFR showed little difference in dose response of EGF-stimulated [3H]thymidine incorporation or EGF stimulation of mitogen-activated protein kinase activity. However, EGF did not induce anchorage-independent growth of cells expressing 5F-EGFR to the same extent as it did for cells expressing WT-EGFR. EGF treatment of 5F-EGFR cells failed to elicit an increase in phosphatidylinositol 3-kinase activity or to stimulate hydrolysis of phosphoinositides or tyrosine phosphorylation of phospholipase C-gamma 1. These data suggest that a significant proportion of EGF receptor signaling can occur through receptors with altered capacity to interact with src homology 2 domain-containing proteins.
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PMID:Transmembrane signaling by epidermal growth factor receptors lacking autophosphorylation sites. 838 84

Human neutrophils express several distinct guanine nucleotide binding (G)-protein-coupled receptors that mediate their responsiveness to chemoattractants. Phosphorylation by receptor-specific and second messenger-activated protein kinases is a common mechanism for regulation of G-protein-coupled receptors. To explore the possibility that chemoattractant receptors are regulated by unique receptor kinases, we utilized PCR to identify receptor kinases in human neutrophils. Here, we report the isolation of three G-protein-coupled-receptor-kinase (GPRK)-like sequences termed GPRK5, GPRK6, and GPRK7 in addition to the beta-adrenergic receptor kinase (beta ARK) 1 and 2 isoforms (beta ARK1 and beta ARK2). Two, GPRK5 and GPRK6, showed high homology at the amino acid level to the recently identified receptor-kinase-like sequence localized close to the Huntington disease locus. GPRK7 is of interest in that it contains a DLG (Asp-Leu-Gly) amino acid motif of receptor kinases preceded by a DFD (Asp-Phe-Asp) motif. We isolated cDNAs corresponding to GPRK6; the complete sequence shows > 66% identity and 81% similarity at the amino acid level to the GPRK from the Huntington disease locus. The GPRK6 cDNA probe hybridizes to two mRNAs of 2.9 and 2.1 kb that were expressed in all the tested human tissues including HL-60 cells and neutrophils. Genomic Southern blot analysis and chromosome mapping showed that GPRK6 hybridizes to two closely related genes located on chromosomes 5 and 13 and are, therefore, distinct from the GPRK located near the Huntington disease locus on chromosome 4. The identification herein of three putative receptor kinases indicates that in addition to beta ARK and rhodopsin kinase subfamilies, there are other receptor-kinase subfamilies that regulate the broad spectrum of G-protein-coupled receptors.
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PMID:Identification of additional members of human G-protein-coupled receptor kinase multigene family. 841 12

Replacement of Met31 by (N-Me)Nle in CCK8 or CCK4 has been shown to improve the affinity and selectivity for CCK-B receptors. In order to obtain molecules with enhanced bioavailability, two novel series of protected tetrapeptides of the general formula Boc-Trp30-X-Asp-Y33 have been developed. Introduction of (N-Me)Nle and the bulky, aromatic naphthylalaninamide (Nal-NH2) in positions X and Y, respectively, does not greatly modify the affinity for guinea pig brain CCK-B receptors. In contrast, incorporation of hindering N-methyl amino acids such as (N-Me)Phe, (N-Me)Phg, or (N-Me)Chg, but not their non-methylated counterparts, in position X induced a large decrease in affinity for the CCK-B binding sites. Among the various peptides synthesized, Boc-[(N-Me)Nle31,1Nal-NH2(33)]CCK4 (2) (KI = 2.8 nM), Boc-[Phg31,1Nal-NH2(33)]CCK4 (15) (KI = 14 nM), and Boc-[Phg31,1Nal-N(CH3)2(33)]CCK4 (17) (KI = 39 nM) displayed good affinities for brain CCK-B receptors and had good selectivity ratios. These pseudopeptides, in which the presence of unnatural and hydrophobic residues is expected to improve their penetration of the central nervous system, were shown to be very resistant to brain peptidases. Interestingly, whereas compounds 2 and 15 proved to be full agonists for rat hippocampal CCK-B receptors when measured in an electrophysiological assay, compound 17 behaved as a potent antagonist in the same test and displayed a good affinity in rat brain KI(CCK-B) = 51 nM as compared to the Merck antagonist L365,260,KI(CCK-B) = 12 nM. This illustrates a simple means to obtain CCK-B antagonists and suggests that the free, CONH2 group plays a critical role in the recognition of the agonist state of brain CCK-B receptors.
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PMID:CCK-B agonist or antagonist activities of structurally hindered and peptidase-resistant Boc-CCK4 derivatives. 842 Dec 83

Neutral endopeptidase 24.11 (EC 3.4.24.11; NEP) is a membrane-bound Zn-metalloendopeptidase with a catalytic activity and a specificity very similar to that of thermolysin, a bacterial zinc-endoprotease. NEP can be inactivated by reaction with diethylpyrocarbonate, due to the modification of a histidine residue present in the active site of the enzyme. This histidine residue was proposed to be analogous to His231 in thermolysin, which is involved in the stabilization of the tetrahedral intermediate during the transition state. Using site-directed mutagenesis of the cDNA encoding rabbit NEP, we have created two mutants of NEP where His711 was replaced by either Gln or Phe (NEP-Gln711 and NEP-Phe711). Determination of kinetic parameters showed that both mutants had Km values very similar to that of the non-mutated enzyme but that their kcat values were 25-fold lower. The calculated difference in free energy needed to form the transition state complex was increased by 2.2 kcal/mol for both mutants. These observations strongly suggest that His711 is involved in the stabilization of the transition state by forming an hydrogen bond with the oxyanion of the tetrahedral intermediate.
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PMID:Kinetic evidence that His-711 of neutral endopeptidase 24.11 is involved in stabilization of the transition state. 844 Mar 86

The objectives of this investigation were to characterize neuropeptide-degrading enzymes on the surface of gastric muscle cells and to determine their physiological function. Neutral endopeptidase (NEP, EC 3.4.24.11) activity was measured using the fluorogenic substrate glutaryl-Ala-Ala-Phe-4-methoxy-2-naphthylamine. The NEP inhibitors phosphoramidon and DL-thiorphan (1 microM) inhibited degradation of the substrate by gastric muscle membranes by 100% and by freshly dispersed gastric muscle cells by 55-60%. The phosphoramidon or DL-thiorphan-inhibitable activity, attributed to NEP, of membranes was 112 +/- 4.0 pmol h-1 (micrograms protein)-1 and of cells was 4.2 +/- 0.8 nmol h-1 (10(6) cells)-1. This activity was associated with membranes prepared from cells and was not detected in the cytoplasm or in the cell incubation solution. Gastric muscle membranes were fractionated by electrophoresis and analysed by Western blotting using two NEP antisera. Both antisera recognized a protein in membranes with an electrophoretic mobility identical to that of recombinant human NEP and an apparent molecular mass of approximately 95 kDa. Neuropeptides were degraded by membranes with specific activities in the order of [Leu5]enkephalin > [Met5]enkephalin > gastrin-releasing peptide-10 (GRP-10) > [D-Ala2][Leu5]enkephalin > somatostatin-14. Phosphoramidon and DL-thiorphan similarly inhibited the degradation of GRP-10 (mean of 35% inhibition), somatostatin-14 (57%) and the aminopeptidase-resistant analogue, [D-Ala2][Leu5]enkephalin (75%). When aminopeptidases were inhibited with amastatin (10 microM) phosphoramidon inhibited degradation of [Leu5]enkephalin (54%) and [Met5]enkephalin (100%). Phosphoramidon increased the potency of the contractile effects of neuropeptides on muscle cells by > 280-fold for somatostatin-14, 17-fold for GRP-10, 18-fold for [Met5]enkephalin and 14-fold for [Leu5]enkephalin. The results show that an NEP-like enzyme on the surface of gastric muscle cells degrades and inactivates enkephalins, GRP-10 and somatostatin-14 and acts in a manner analogous to that of acetylcholinesterase in the neuromuscular junction of skeletal muscle.
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PMID:Neutral endopeptidase (EC 3.4.24.11) modulates the contractile effects of neuropeptides on muscle cells from the guinea-pig stomach. 844 12

The distribution of neutral endopeptidase (NEP; EC 3.4.24.11) was examined in the alimentary tract of the rat. Immunoreactive NEP and NEP mRNA were localized to epithelial cells of the small intestine and to muscle cells in the stomach, small intestine, and colon by immunohistochemistry and in situ hybridization histochemistry. NEP antisera recognized a protein on Western blots of membranes from gastric, jejunal, and colonic mucosa and gastric muscle with an electrophoretic mobility identical to that of recombinant human NEP (approximately 95 kDa). An antisense cRNA probe to NEP hybridized to RNA of approximately 3.5 kb and approximately 6.5 kb, corresponding to the primary transcripts of rat NEP, on Northern blots of total RNA from the jejunal mucosa. NEP message was detected in mRNA from jejunal and colonic mucosa and gastric, jejunal, and colonic muscle using a ribonuclease protection assay. NEP enzymatic activity, assessed by DL-thiorphan-inhibitable degradation of glutaryl-Ala-Ala-Phe-4-methoxy-2-naphthylamine, was highest in homogenates of jejunal mucosa (868 +/- 98 pmol.h-1 x micrograms protein-1) and was between 49- and 413-fold lower in other gastrointestinal tissues. The cellular origin of NEP in the gastric and colonic mucosa could not be determined.
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PMID:Distribution and abundance of neutral endopeptidase (EC 3.4.24.11) in the alimentary tract of the rat. 846 Jul 3


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