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)

Ammonium is a nitrogen source supporting growth of yeast cells at an optimal rate. We recently reported the first characterization of an NH4+ transport protein (Mep1p) in Saccharomyces cerevisiae. Here we describe the characterization of two additional NH4+ transporters, Mep2p and Mep3p, both of which are highly similar to Mep1p. The Mep2 protein displays the highest affinity for NH4+ (Km, 1 to 2 microM), followed closely by Mep1p (Km, 5 to 10 microM) and finally by Mep3p, whose affinity is much lower (Km, approximately 1.4 to 2.1 mM). A strain lacking all three MEP genes cannot grow on media containing less than 5 mM NH4+ as the sole nitrogen source, while the presence of individual NH4+ transporters enables growth on these media. Yet, the three Mep proteins are not essential for growth on NH4+ at high concentrations (>20 mM). Feeding experiments further indicate that the Mep transporters are also required to retain NH4+ inside cells during growth on at least some nitrogen sources other than NH4+. The MEP genes are subject to nitrogen control. In the presence of a good nitrogen source, all three MEP genes are repressed. On a poor nitrogen source, MEP2 expression is much higher than MEP1 and MEP3 expression. High-level MEP2 transcription requires at least one of the two GATA family factors Gln3p and Nil1p, which are involved in transcriptional activation of many other nitrogen-regulated genes. In contrast, expression of either MEP1 or MEP3 requires only Gln3p and is unexpectedly down-regulated in a Nil1p-dependent manner. Analysis of databases suggests that families of NH4+ transporters exist in other organisms as well.
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PMID:A family of ammonium transporters in Saccharomyces cerevisiae. 923 85

Exposures to volatile nitrosamines were measured at 24 rubber manufacturing plants from 1992 to 1995. A total of 709 exposure measurements were taken in general areas or personal breathing zones to estimate exposure according to production types (seals, joints, tyres, gloves, etc.) and production steps, from mixing to storage. Five different nitrosamines were identified. N-Nitrosodimethylamine is the most frequently encountered nitrosamine and represents the most important fraction of the total nitrosamine concentration measured in a given sample. This fact is consistent with the use of rubber additives containing corresponding amine precursors. One hundred and forty-one of the 709 values exceeded the German target value (TRK) of 2.5 micrograms/m3 for all nitrosamines present from rubber vulcanisation, the only available standard for occupational nitrosamine exposures. The salt bath curing process generates particularly high nitrosamine levels, 90% of the 96 measurements being over the TRK, with many values exceeding 20 micrograms/m3. The reasons why the TRK is exceeded are generally well identified. To reduce nitrosamine emission levels it would be advisable to eliminate nitrogen oxide sources, principally by using a process other than salt bath curing, and to develop different rubber stocks that do not contain secondary aliphatic amine functional groups ("safe amines").
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PMID:Assessment of exposure to carcinogenic N-nitrosamines in the rubber industry. 934 27

Extracellular signal-regulated protein kinase (ERK, or mitogen-activated protein kinase [MAPK]) regulatory cascades in fungi turn on transcription factors that control developmental processes, stress responses, and cell wall integrity. CEK1 encodes a Candida albicans MAPK homolog (Cek1p), isolated by its ability to interfere with the Saccharomyces cerevisiae MAPK mating pathway. C. albicans cells with a deletion of the CEK1 gene are defective in shifting from a unicellular budding colonial growth mode to an agar-invasive hyphal growth mode when nutrients become limiting on solid medium with mannitol as a carbon source or on glucose when nitrogen is severely limited. The same phenotype is seen in C. albicans mutants in which the homologs (CST20, HST7, and CPH1) of the S. cerevisiae STE20, STE7, and STE12 genes are disrupted. In S. cerevisiae, the products of these genes function as part of a MAPK cascade required for mating and invasiveness of haploid cells and for pseudohyphal development of diploid cells. Epistasis studies revealed that the C. albicans CST20, HST7, CEK1, and CPH1 gene products lie in an equivalent, canonical, MAPK cascade. While Cek1p acts as part of the MAPK cascade involved in starvation-specific hyphal development, it may also play independent roles in C. albicans. In contrast to disruptions of the HST7 and CPH1 genes, disruption of the CEK1 gene adversely affects the growth of serum-induced mycelial colonies and attenuates virulence in a mouse model for systemic candidiasis.
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PMID:Roles of the Candida albicans mitogen-activated protein kinase homolog, Cek1p, in hyphal development and systemic candidiasis. 959 38

Serum stem cell factor (SCF) and soluble KIT (sKIT) levels were estimated in patients with chronic renal failure (CRF) and anaemia, and compared with clinical parameters of blood cells and renal function. Serum SCF levels in CRF patients were 5-fold higher than those in healthy controls. However, serum sKIT levels in haemodialysis (HD)-CRF patients were only slightly higher than those of healthy controls. In untreated CRF patients and healthy controls, serum SCF levels were significantly correlated with blood urea nitrogen (BUN), creatinine. haemoglobin, red blood cell (RBC) count and sKIT. In untreated CRF patients, serum SCF levels were significantly correlated with BUN, creatinine, and sKIT. These results suggest that serum SCF levels increased with the deterioration of renal function and might be related to erythropoiesis.
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PMID:Elevated SCF levels in the serum of patients with chronic renal failure. 975 36

Dietary treatment of pediatric obesity is a challenge given the need for adequate nutrients to support the maintenance of lean tissue and growth. The primary purpose of this investigation was to assess the effects of reduced energy intake on protein turnover in obese children aged 8 to 10 years. Following a 2-week baseline period, 16 subjects reduced energy intake during a 6-week intervention period. At baseline and following the intervention, 15N-glycine methodology was used to measure nitrogen flux (Q), protein synthesis (PS), protein breakdown (PB), and net turnover ([NET] PS - PB). Other criterion measures included resting metabolic rate (RMR), fat mass (FM), fat-free mass (FFM), urinary creatinine to height ratio (Cr:Ht), and nitrogen balance (NB). On average, subjects lost 2.2 +/- 0.3 kg, of which greater than 85% was FM. Decreased Q (P = .03) indicated downregulation of protein turnover in response to diet-induced weight loss. While PB did not change, NET declined slightly (P = .06) as a consequence of reduced PS (P = .03). Reductions in FFM (P = .09), Cr:Ht (P = .02), and NB (P = .03) accompanied alterations in protein turnover, but there was no change in the RMR. In conclusion, while short-term therapy promoted the loss of FM and did not compromise RMR, practitioners must be cautious when prescribing diets, given the observed changes in protein utilization and somatic protein status. Longitudinal studies are needed to further characterize the metabolic responses of obese children to long-term diet therapy.
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PMID:Effects of reduced energy intake on protein utilization in obese children. 986 70

Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGFR protein tyrosine kinase together with published X-ray crystal data of quercetin (2) in complex with the Hck tyrosine kinase and of deschloroflavopiridol (3b) in complex with CDK2, a putative binding mode of the isoflavone genistein (1) was proposed. Then, based on literature data suggesting that a salicylic acid function, which is represented by the 5-hydroxy-4-keto motif in 1, could serve as a pharmacophore replacement of a pyrimidine ring, superposition of 1 onto the potent EGFR tyrosine kinase inhibitor 4-(3'-chlorophenylamino)-6, 7-dimethoxyquinazoline (4) led to 3'-chloro-5,7-dihydroxyisoflavone (6) as a target structure which in fact was 10 times more potent than 1. The putative binding mode of 6 suggests a sulfur-aromatic interaction of the m-chlorophenyl moiety with Cys 773 in the "sugar pocket" of the EGFR kinase model. Replacement of the oxygen in the chromenone ring of 6 by a nitrogen atom further improved the inhibitory activity against the EGFR kinase. With IC50 values of 38 and 8 nM, respectively, the quinolones 11 and 12 were the most potent compounds of the series. N-Alkylation of 11 did not further improve enzyme inhibitory activity but led to derivatives with cellular activity in the lower micromolar range.
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PMID:Use of a pharmacophore model for the design of EGFR tyrosine kinase inhibitors: isoflavones and 3-phenyl-4(1H)-quinolones. 1009 Jul 85

Ammonium uptake in the yeast Saccharomyces cerevisiae involves three membrane transporters (Mep1, -2 and -3) belonging to an evolutionarily conserved protein family that also includes the rhesus (Rh) blood group polypeptides of erythrocytes. We show here that, in the 26972c mutant defective in NH4+ transport, the Mep1 protein carrying an amino acid substitution in its cytoplasmic C-terminus trans-inhibits the closely related Mep3 protein. The same mutation introduced into Mep3 leads to loss of transport activity and this inactive form also trans-inhibits native Mep3. Inhibition of Mep3 is post-translational and can be overcome by overexpression. These results are consistent with a direct interaction between Mep proteins, as is the case for the Rh polypeptides. The soybean GmSAT1 gene, recently cloned for its ability to complement the NH4+ transport defect of strain 26972c, has been described as an NH4+ channel protein involved in the transfer of fixed nitrogen from the bacteroid to the host plant. We show here that GmSAT1 contains a sequence homologous to the DNA-binding domain of basic helix-loop-helix (bHLH) transcription factors. We also show that GmSAT1 restores NH4+ uptake in the yeast mutant by interfering with the inhibition of Mep3. Our results are not consistent with a direct role of GmSAT1 in ammonium transport.
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PMID:Cross-talk between ammonium transporters in yeast and interference by the soybean SAT1 protein. 1065 98

The effect of interaction with DNA and oligonucleotides on the photophysical properties of two thiazole orange (TO) derivatives, with different side chains (-(CH2)3-N+(CH3)3 and -(CH2)6-I)) linked to the nitrogen of the quinoline ring of the thiazole orange, is presented here. The first one called TO-PRO1 is a commercially available dye, whereas the second one called TO-MET has been specially synthesized for further covalent binding to oligonucleotides with the aim of being used for specific in situ detection of biomolecular interactions. Both photophysical measurements and molecular calculations have been done to assess their possible mode of interaction with DNA. When dissolved in buffered aqueous solutions both derivatives exhibit very low fluorescence quantum yields of 8 x 10(-5) and 2 x 10(-4), respectively. However, upon binding to double-stranded DNA, large spectroscopic changes result and the quantum yield of fluorescence is enhanced by four orders of magnitude, reaching values up to phi F = 0.2 and 0.3, respectively, as a result of an intercalation mechanism between DNA base pairs. A modulation of the quantum yield is observed as a function of the base sequence. The two derivatives also bind with single-stranded oligonucleotides, but the fluorescence quantum yield is not so great as that when bound to double-stranded samples. Typical fluorescence quantum yields of 7 x 10(-3) to 3 x 10(-2) are observed when the dyes interact with short oligonucleotides, whereas the fluorescence quantum yield remains below 10(-2) when interacting with single-stranded oligonucleotides. This slight but significant quantum-yield increase is interpreted as a folding of the single strand around the dye, which reduces the internal rotation of the two heterocycles around the central methine bridge that links the two moieties of the dye. From these properties, it is proposed to link monomer covalently to oligonucleotides for the subsequent detection of target sequences within cells.
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PMID:A theoretical and experimental study of two thiazole orange derivatives with single- and double-stranded oligonucleotides, polydeoxyribonucleotides and DNA. 1067 30

Protein tyrosine phosphatase 1B (PTP1B) displays a preference for peptides containing acidic as well as aromatic/aliphatic residues immediately NH(2)-terminal to phosphotyrosine. The structure of PTP1B bound with DADEpYL-NH(2) (EGFR(988)(-)(993)) offers a structural explanation for PTP1B's preference for acidic residues [Jia, Z., Barford, D., Flint, A. J., and Tonks, N. K. (1995) Science 268, 1754-1758]. We report here the crystal structures of PTP1B in complex with Ac-ELEFpYMDYE-NH(2) (PTP1B.Con) and Ac-DAD(Bpa)pYLIPQQG (PTP1B.Bpa) determined to 1.8 and 1.9 A resolution, respectively. A structural analysis of PTP1B.Con and PTP1B.Bpa shows how aromatic/aliphatic residues at the -1 and -3 positions of peptide substrates are accommodated by PTP1B. A comparison of the structures of PTP1B.Con and PTP1B.Bpa with that of PTP1B.EGFR(988)(-)(993) reveals the structural basis for the plasticity of PTP1B substrate recognition. PTP1B is able to bind phosphopeptides by utilizing common interactions involving the aromatic ring and phosphate moiety of phosphotyrosine itself, two conserved hydrogen bonds between the Asp48 carboxylate side chain and the main chain nitrogens of the pTyr and residue 1, and a third between the main chain nitrogen of Arg47 and the main chain carbonyl of residue -2. The ability of PTP1B to accommodate both acidic and hydrophobic residues immediately NH(2)-terminal to pTyr appears to be conferred upon PTP1B by a single residue, Arg47. Depending on the nature of the NH(2)-terminal amino acids, the side chain of Arg47 can adopt one of two different conformations, generating two sets of distinct peptide binding surfaces. When an acidic residue is positioned at position -1, a preference for a second acidic residue is also observed at position -2. However, when a large hydrophobic group occupies position -1, Arg47 adopts a new conformation so that it can participate in hydrophobic interactions with both positions -1 and -3.
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PMID:Structural basis of plasticity in protein tyrosine phosphatase 1B substrate recognition. 1088 23

Peroxynitrite is a potent oxidizing and nitrating species formed in a diffusion-limited reaction between nitrogen monoxide and superoxide. It induces apoptosis through unknown mechanisms and is believed to interfere with receptor tyrosine kinase signalling through nitration of tyrosine residues. One pathway emanating from receptor tyrosine kinases is that leading to activation of the anti-apoptotic kinase Akt. In the present study we provide evidence that peroxynitrite, administered to cells using two different delivery systems, results in the dose- and time-dependent activation of Akt. Akt activation is rapid and followed by phosphorylation of glycogen synthase kinase-3, an established substrate of Akt. Akt activation is inhibited in the presence of the phosphoinositide 3-kinase (PI-3K) inhibitors wortmannin and LY294002, and by treatment with the platelet-derived growth factor (PDGF) receptor (PDGFR) inhibitor AG1295, indicating a requirement for PDGFR and PI-3K in mediating peroxynitrite-induced Akt activation. Accordingly, the PDGFR-A and PDGFR-B isoforms were shown to undergo rapid tyrosine phosphorylation on treatment with peroxynitrite. Prior exposure of cells to peroxynitrite interferes with PDGF-induced Akt phosphorylation. Our findings suggest that Akt activation occurs as an acute response to peroxynitrite treatment and could play an important role in influencing cell survival and/or alter the cellular response to other growth regulatory signals.
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PMID:Peroxynitrite activates the phosphoinositide 3-kinase/Akt pathway in human skin primary fibroblasts. 1106 76


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