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)

Inhibition of tyrosine kinases is a possible approach for the treatment of cancer. We have investigated the catalytic mechanism of the epidermal growth factor receptor tyrosine kinase (EGF-RTK) in order to obtain information for use in structure-based searching for inhibitors. Initial rate studies imply that EGF-RTK forms a ternary complex together with ATP and peptide substrate. Investigation of pH and temperature dependence suggests that the kinase reaction requires the ionised form of a carboxylate (pK = 6.3) and the protonated form of another group (pK = 9.1). These characteristics are consistent with a mechanism where the carboxylate of Asp813(pK = 6.3) facilitates deprotonation of the tyrosyl hydroxyl of the peptide substrate, activating it as a nucleophile to attack the gamma-phosphorus of ATP which interacts with a protonated enzyme side-chain (pK = 9.1), possibly the guanidinium group of Arg817. This proposed catalytic mechanism was used to define a query when searching for inhibitors in a database of predicted three-dimensional structures. The procedure involved searching for compounds that mimic the ATP gamma-phosphate, tyrosyl hydroxyl and the tyrosyl aromatic ring, all of which seem to interact strongly with the enzyme during catalysis. This search allowed identification of inhibitors of EGF-RTK which were used to define queries for two-dimensional searching of a larger database, leading to the discovery of 4-(3-chloroanilino)quinazoline (CAQ) which is a potent inhibitor (Ki = 16 nM) of the enzyme. The compound is believed to be the first representative from a new structural class of anilinoquinazoline tyrosine kinase inhibitors. It follows competitive kinetics with respect to ATP and noncompetitive kinetics when the peptide is varied, implying that it functions as an analogue of ATP. CAQ is a novel and potent lead in the search for tyrosine kinase inhibitors as potential agents for the treatment of cancer.
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PMID:Epidermal growth factor receptor tyrosine kinase. Investigation of catalytic mechanism, structure-based searching and discovery of a potent inhibitor. 808 Apr 38

We have purified SP-22, a substrate protein for mitochondrial ATP-dependent protease in bovine adrenal cortex. Native SP-22 showed an M(r) of 350,000 +/- 20,000, and was composed of more than 10 molecules of an M(r) 21,600 subunit. Subcellular and submitochondrial fractionation of adrenocortical tissues revealed that SP-22 was localized in the mitochondrial matrix, suggesting that SP-22 is a natural substrate for ATP-dependent protease, a matrix enzyme. The concentration of SP-22 in adrenocortical mitochondrial fractions was 16 +/- 3 micrograms/mg proteins (mean +/- SD, n = 6) as determined by radioimmunoassay using specific anti-SP-22 antibody. Adrenal cortex showed the highest concentration among the 15 bovine tissues tested, followed by liver, renal cortex, adrenal medulla, heart, and renal medulla. We determined the amino acid sequence of SP-22, which is composed of 195 amino acids. Amino acid 47 was not identified by the sequencer. FAB-mass spectrometry of AA47-AA55 fragment revealed that AA47 was cysteine-sulfinic acid (Cys-SO2H). By a homology search in the NBRF-PIR data base, SP-22 was found to be 91% homologous to murine erythroleukemia cell MER-5 protein, which may have an important role in the induction of differentiation. SP-22 was also homologous to the C22 component of alkyl hydroperoxide reductase in Salmonella typhimurium, thiol-specific antioxidant in Saccharomyces cerevisiae, and some other proteins. Since a segment around AA47 was highly conserved, this residue may be important for the biochemical functions of SP-22.
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PMID:Purification and characterization of a substrate protein for mitochondrial ATP-dependent protease in bovine adrenal cortex. 808 78

Intact bovine adrenal medullary chromaffin cells were preincubated with 32PO4, and the multiple-site phosphorylation of tyrosine hydroxylase (TH) was studied. Up to eight 32P-labeled peptides were produced by tryptic hydrolysis of TH; however, all of the tryptic phosphopeptides were derived from four phosphorylation sites--Ser8, Ser19, Ser31 and Ser40. In situ regulation of 32P incorporation into the latter three sites was demonstrated with a diverse set of pharmacological agents. 32P incorporation into Ser19 was preferentially increased by brief exposures to depolarizing secretagogues. Longer treatments also increased Ser31 and Ser40 phosphorylation. Nicotine, muscarine and vasoactive intestinal polypeptide--reflecting cholinergic and non-cholinergic components of sympatho-adrenal transmission--each produced different patterns of multiple-site phosphorylation of TH. Nicotine, bradykinin and histamine increased 32P incorporation at each of the three sites whereas muscarine, angiotensin II, endothelin III, prostaglandin E1, GABA and ATP selectively increased Ser31 phosphorylation. Nerve growth factor did not influence TH phosphorylation in chromaffin cells from adult adrenal glands but selectively increased Ser31 phosphorylation in chromaffin cells isolated from calf adrenal glands. 32P incorporation into Ser40 was selectively increased by forskolin and other cAMP-acting agents whereas vasoactive intestinal polypeptide increased Ser31 and Ser40 phosphorylation. Thus, the phosphorylation of TH in bovine chromaffin cells appears to be regulated at three sites by three separate intracellular signaling pathways--Ser19 via Ca2+/calmodulin-dependent protein kinase II; Ser31 via ERK (MAP2 kinases); and Ser40 via cAMP-dependent protein kinase. These signaling pathways, as well as the extracellular signals that were effective in stimulating them, are similar to those previously described for TH in rat pheochromocytoma cells. However, several of the pharmacological agents produced different patterns of multiple-site TH phosphorylation in the bovine chromaffin cells. These differences between tissues could be accounted for by differences in the coupling/access between the extracellular signal transduction systems and the intracellular signaling pathways as opposed to differences in the intracellular signaling pathways per se.
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PMID:Multiple signaling pathways in bovine chromaffin cells regulate tyrosine hydroxylase phosphorylation at Ser19, Ser31, and Ser40. 809 28

The HER2 (neu/erb-B2) proto-oncogene codes for a transmembrane receptor with tyrosine kinase activity and with high homology to the EGF receptor (HER1). The high incidence of HER2 overexpression in breast and ovary carcinomas prompted us to synthesize protein tyrosine kinase inhibitors (tyrphostins) which selectively inhibit the HER2 kinase activity. Two groups of tyrphostins were developed: one highly selective in inhibiting HER1 as opposed to HER2, the other highly selective in inhibiting HER2. Both the HER1 and the HER2 selective blockers were competitive with ATP binding. This suggests that even though the kinase domains of the respective receptors show an 80% degree of homology it is possible to design small molecules capable of discriminating between them. These results also show that the two kinases differ in their ATP binding sites. Mitogenic signaling induced by EGF in NIH3T3 cells overexpressing either HER1 or HER1-2 (possessing the HER2 kinase domain) was blocked identically by the agents that discriminate between the two in vitro. This paradox was further explored and elucidated. We propose that high intracellular ATP levels prevent inhibitor binding to the receptor. The antiproliferative action of the two distinct selective tyrphostins observed may result from the inhibition of a downstream element, presumably a tyrosine kinase, which mediates mitogenic signaling.
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PMID:Selective inhibition of the epidermal growth factor and HER2/neu receptors by tyrphostins. 809 9

Almost all atypical epithelial lesions of the stomach consist of atypical cells in the superficial part of the glands and nonatypical cells in the deeper portion of the glands. A transition zone was formed between the superficial atypical gland cells and the deeper nonatypical gland cells. Positive cells were widely demonstrated with immunohistochemical stains for PCNA in the superficial atypical glands and transition zone. The rate of PCNA positivity was 37.7%. However, a small number of positive cells for EGFR (8.5%), c-erbB-2(11.3%), p53(11.3%) and c-K-ras(1.7%) were found in ATP. The incidence of positivity for these factors was low compared with that for carcinomas. The percentages of positive cells for EGFR(1.5%) and c-erbB-2(4.5%) were very low in intestinal metaplasia.
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PMID:[Immunohistochemical study for growth factor and oncogene on atypical epithelium of the stomach]. 810 26

The pharmacokinetics of atracurium are not altered by impaired hepatic function. The drug is therefore used widely in liver transplant patients. In previous work on the hepatotoxic effects of atracurium in an isolated, perfused rat liver model, we could not detect biochemical (release of lactate dehydrogenase or aspartate aminotransferase) or histological evidence of liver cell damage, except a reduction in hepatic tissue ATP content. In the present study, rat livers were reperfused with Krebs-Henseleit bicarbonate buffer with or without atracurium after 21 h of cold ischaemic storage in University of Wisconsin (UW), Bretschneider's HTK or Euro-Collins solution. UW-protected livers showed a complete restoration of ATP, total adenine nucleotides and energy charge during reperfusion, but the addition of atracurium diminished the regeneration capacity to about 50%. The energy charge (an index for determination of liver viability) was also reduced markedly.
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PMID:Administration of atracurium during reperfusion of rat livers after 21 h of cold ischaemic storage in different solutions. 811 May 59

High energy phosphates (HEP: ATP & phosphocreatine (PCr)) are to be considered under qualitative (free energy of hydrolysis) and quantitative (concentration) aspects. Energy charge is also a (normalized) concentration related parameter. Owing to high turnover rates concentration (HEP stores) provides sufficient energy only for 10 to 20 s in the case of interruption of supply. Utilization (without immediate supply) leads to rapid drop of free energy which--owing to the CK reaction--is indicated by rapid drop of PCr and the respective ratios. Critical reduction of free energy appears to be prevented by various protective mechanisms reflected in phenomena of early hypoxic failure, hibernating and stunning.
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PMID:Meaning of energetic parameters. 811 44

Dianilinophthalimides represent a novel class of inhibitors of the EGF-receptor protein tyrosine kinase with a high degree of selectivity versus other tyrosine and serine/threonine kinases. Steady-state kinetic analysis of compound 3, which showed potent inhibitory activity, revealed competitive type kinetics relative to ATP. Despite a highly symmetrical structure of compound 3, X-ray studies revealed an unsymmetrical propeller-shaped conformation of the molecule which differs clearly from that of the constitutionally related staurosporine aglycons. These conformational differences may explain the reversal of the selectivity profile of compound 3 relative to the staurosporine aglycons. In cellular assays compounds 3 and 4 have been shown to inhibit EGF-induced receptor autophosphorylation, c-fos induction and EGF-dependent proliferation of Balb/c MK cells. This inhibition was selective as compounds had no effect on PDGF-induced receptor autophosphorylation and c-fos induction. Furthermore, compound 3 showed potent antitumor activity in vivo at well-tolerated doses.
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PMID:Dianilinophthalimides: potent and selective, ATP-competitive inhibitors of the EGF-receptor protein tyrosine kinase. 815 12

Abnormal hyperphosphorylation of the cytoskeletal protein TAU is seen in the characteristic paired helical filaments [neurofibrillary tangles] of Alzheimer's disease [AD]. A recently described protein kinase, PK40erk, (1) a member of the ERK family of kinases, can produce in vitro many of the properties of Alzheimer-like hyperphosphorylated TAU. cAMP-dependent protein kinase A [PKA] phosphorylates TAU to a lesser extent; however, the product is not like the hyperphosphorylated TAU of AD in several important respects. We now report that in vitro PK40erk, a candidate for the enzyme responsible for TAU hyperphosphorylation in AD, will further phosphorylate TAU that was previously saturated by protein kinase A, provided that the concentrations of free uncomplexed ATP are low. Interestingly, the actions of different kinases on TAU are not independent, but may depend on the order in which they work on TAU; i.e., prior phosphorylation by PKA partially inhibits the action of PK40erk.
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PMID:Hyperphosphorylation of human TAU by brain kinase PK40erk beyond phosphorylation by cAMP-dependent PKA: relation to Alzheimer's disease. 816 86

The kinetics of inhibition of the epidermal growth factor (EGF) receptor (EGFR) tyrosine kinase (TK) activity by erbstatin, tyrphostins, and lavendustin derivatives were studied in a system that employs poly(Glu6Ala3Tyr) (GAT) and ATP as substrates, after preactivation with EGF. All data were analyzed for computer best-fit curves by a program that was written for this purpose and is available upon request to those interested. The inhibition kinetics followed a sequential, Bi-Bi, rapid equilibrium, random mechanism, the mechanism of the EGFR-TK. Erbstatin and a few tyrphostins that contain a 3,4-dihydroxy-(cis)-cinnamonitrile [1-(3',4'-dihydroxyphenyl)-2-nitriloethene] group were found to be pure competitive inhibitors with respect to both substrates of the kinase reaction, i.e., GAT and ATP. Two tyrphostins, each containing an additional dihydroxyphenyl group in the alpha-position, were found to be pure competitive inhibitors with respect to GAT and noncompetitive (or mixed-competitive) inhibitors with respect to ATP. A lavendustin derivative with a 2,5-dihydroxyphenyl ring and a lavendustin derivative with a 3,4-dihydroyphenyl ring were also found to be competitive inhibitors with respect to both ATP and GAT. Various possible modes of binding at the EGFR-TK active center for the tyrphostins studied are proposed and the significance of the present findings, as well as the interpretations of computer analyses of kinetic data, is discussed.
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PMID:Kinetics of inhibition by tyrphostins of the tyrosine kinase activity of the epidermal growth factor receptor and analysis by a new computer program. 818 46


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