Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasmodium falciparum digestive vacuoles containing ferric oxide granules were purified from parasite homogenates by centrifugation on discontinuous sucrose gradients. Digestive vacuole membranes prepared by osmotic lysis and washed with KCl showed no detectable contamination by erythrocyte membrane proteins and only minimal contamination by non-vacuolar parasite proteins. Purified vacuolar membranes were 2.6-fold enriched in total parasite membrane ATPase activity. This ATPase was optimally active at pH 7 in the presence of at least 2 mM Mg2+. Ca2+ and Mn2+ were approximately 80-90% as effective as Mg2+, and Zn2+, Co2+ and Fe2+ also exerted some stimulatory effect. The vacuolar membrane also hydrolyzed GTP, UTP, CTP and ADP, but AMP and 3',5'-cyclic AMP were hydrolyzed only one-tenth as effectively as ATP. The ATPase was unaffected by vanadate, ouabain or oligomycin but was significantly inhibited by the proton pump inhibitors NEM and NBD-Cl. Of 6 antimalarial drugs tested, quinine and quinacrine were the most effective inhibitors and mefloquine was the least effective.
Mol Biochem Parasitol 1988 Oct
PMID:Purification of Plasmodium falciparum digestive vacuoles and partial characterization of the vacuolar membrane ATPase. 297 31

The effects of inhibitors of poly(ADP-ribose) synthesis on cell growth and several parameters of nucleotide metabolism have been determined. At concentrations which produced similar inhibitions of poly(ADP-ribose) synthesis, 3-acetylaminobenzamide (1 mM) had no effect on L1210 cell growth, 3-aminobenzamide (5mM) was slightly inhibitory and 3-methoxybenzamide (5 mM) was a potent inhibitor of growth. During a 2-h incubation, none of the inhibitors affected ribo- or deoxyribonucleotide concentrations in cells treated with or without N-methyl-N-nitrosourea; however, N-methyl-N-nitrosourea treatment reduced dCTP concentrations by 50%. During a 24-hr incubation, 3-aminobenzamide and 3-acetylaminobenzamide did not lower ribonucleotide concentrations in cells grown with either undialyzed or dialyzed serum. In contrast, 3-methoxybenzamide caused a depletion of UTP in cells grown with undialyzed serum and caused a depletion of all purine and pyrimidine ribonucleotides in cells grown with dialyzed serum. 3-Aminobenzamide and 3-acetylaminobenzamide had no effect on the conversion of hypoxanthine to ATP and GTP but did slightly inhibit incorporation of formate into ATP and GTP. 3-Methoxybenzamide inhibited incorporation of both hypoxanthine and formate into purine ribonucleotides. 3-Aminobenzamide, 3-acetylaminobenzamide, and 3-methoxybenzamide all inhibited glycine incorporation into ATP and GTP and reduced both the incorporation of thymidine into DNA and the apparent specific activity of the dTTP pool. We conclude that inhibition of poly(ADP-ribose) synthesis causes little or no growth inhibition and has no effect on purine or pyrimidine nucleotide synthesis de novo. The effect of all the inhibitors on glycine and formate metabolism may be related to an inhibition of ADP-ribose synthesis or may be a secondary effect of the inhibitors. The growth inhibition and the reduction in nucleotide concentration caused by 3-methoxybenzamide are apparently secondary effects of this drug and may result from an inhibition of phosphoribosyl pyrophosphate synthesis.
Mol Pharmacol 1985 Aug
PMID:Specificity of inhibitors of poly(ADP-ribose) synthesis. Effects on nucleotide metabolism in cultured cells. 299 39

Studies were performed to verify the physiological significance of attenuation in the life cycle of simian virus 40 and the role of agnoprotein in this process. For these purposes, nuclei were isolated at various times after infection and incubated in vitro in the presence of [alpha-32P]UTP under the standard conditions which lead to attenuation. Attenuation was evident by the production of a 94-nucleotide attenuator RNA, revealed by gel electrophoresis. In parallel, the synthesis of agnoprotein was studied at various times after infection by labeling the cells for 3 h with [14C]arginine, lysing them, and analyzing the labeled proteins by gel electrophoresis. Both attenuation and the synthesis of agnoprotein were predominant towards the end of the infectious cycle. At earlier times, there was almost no attenuation and no synthesis of agnoprotein. Moreover, there was almost no attenuation even at the latest times after infection in nuclei isolated from cells infected with simian virus 40 deletion mutants that do not synthesize agnoprotein. Finally, analysis by dot blot hybridization showed higher amounts of cytoplasmic viral RNA in cells infected with an agnoprotein gene insertion mutant, delta 79, that does not produce agnoprotein, compared with cells infected with wild-type virus. The present studies indicate that attenuation is temporally regulated and suggest that agnoprotein enhances attenuation in isolated nuclei and that may also enhance it in vivo.
Mol Cell Biol 1985 Jun
PMID:Attenuation of late simian virus 40 mRNA synthesis is enhanced by the agnoprotein and is temporally regulated in isolated nuclear systems. 299 60

A 273 bp DNA fragment containing the attenuator of the pyrBI operon was inserted into a synthetic cloning site early in the lacZ gene on a plasmid. By this operation the first few codons of lacZ were joined through a linker to the last 39 codons of the open reading frame for the putative pyrB leader peptide. In addition a gene fusion encoding a hybrid protein with beta-galactosidase activity was formed between the pyrB start and the rest of lacZ. This gene fusion is expressed from the lac promoter and the transcript is subject to facultative termination at the pyrBI attenuator. Different variants of the lacZ start were used that either contained a stop codon or directed the translation toward the attenuator in any of the alternative reading frames. The following results were obtained. No significant read-through of transcription over the pyrB attenuator was seen when the leader translation ended 49 nucleotide residues, or more, upstream of the attenuator symmetry, but a UTP-modulated attenuation was established if the leader translation was allowed to proceed across the attenuator as for the putative leader peptide or in a frame-shifted version. The regulation, however, was not as great as for the native pyrB gene. This is probably because the substitution of the normal start of the leader peptide by the start of lacZ alters the coupling between transcription and translation and thereby the attenuation frequency. It cannot, however, be ruled out that the pyrBI operon is regulated at the promoters in addition to the control by attenuation.
Mol Gen Genet 1985
PMID:Role of translation in the UTP-modulated attenuation at the pyrBI operon of Escherichia coli. 300 27

Kinetic and physical parameters of UDP-glucose pyrophosphorylase were determined in Meriones unguiculatus infected with Echinococcus multilocularis metacestodes (cestoda). Studies were carried out on parasite cysts, and on livers from control and infected animals after purification of the enzyme by affinity chromatography on UTP-agarose. The enzyme from infected and control livers had km values for UTP of 0.01 mM and 0.5 mM, respectively; for glucose-1-phosphate values were 0.46 mM and 0.07 mM, respectively. On the other hand the enzyme from cysts was found to have a higher Km for UTP (1 mM) and for glucose-1-phosphate (1.5 mM) than from infected or non-infected livers. Physical characteristics (pI = 6 and Mr = 160,000) of UDP-glucopyrophosphorylases were the same in controls and infected host livers but were different from the cyst enzyme (pI = 7 and Mr = 251,000). These results provide evidence for the existence of significant differences between parasitic and host enzymes, which could possibly be exploited in chemotherapy.
Mol Biochem Parasitol 1987 Feb
PMID:A comparative study of UTP-D-glucose-1-phosphate uridylyl transferase in the cysts of Echinococcus multilocularis and the livers of infected and control Meriones unguiculatus. 303 98

8-oxy-GTP was obtained via reaction of GTP with ascorbic acid and addition of hydrogen peroxide. 8-oxy-GTP is recognized and displays substrate properties of UTP on substitution of 8-oxy-GTP for UTP in polynucleotide synthesis catalyzed by E. coli RNA polymerase on a poly[d(A-T)].poly[d(A-T)] template. Such incorporation does not take place at equimolar quantities of GTP and 8-Br-GTP. The incorporation of 8-oxy-GTP instead of UTP, is 2.5-3 times higher upon replacement of Mg2+ by Mn2+ ions. The dinucleotide ApU serving as an initiator rises the incorporation level of 8-oxy-GTP both for Mg2+ and Mn2+ ions. 8-oxy-GTP slightly inhibits poly[r(A-U)] synthesis, but UTP strongly inhibits the incorporation of 8-oxy-GTP. [alpha-32P] 8-oxy-GTP is incorporated mainly instead of UTP, but it can be incorporated also during the substitution of 8-oxy-GTP for ATP.
Mol Biol (Mosk)
PMID:[Display of 8-hydroxy-GTP substrate properties of UTP in the reaction of polynucleotide synthesis catalyzed by RNA-polymerase from Escherichia coli in the presence of poly[d(AT).d(AT)] template]. 305 96

Depletion of the putrescine and spermidine content of Ehrlich ascites tumor cells by alpha-difluoromethylornithine (DFMO) treatment results in at least a 1 500-fold increase in the decarboxylated S-adenosylmethionine (deSAM) content. The accumulation of this adenine nucleoside occurs because of the absence of putrescine and spermidine to act as aminopropyl group acceptors in the spermidine and spermine synthase reactions and because of an increase in S-adenosylmethionine decarboxylase activity. The fact that the synthesis of deSAM continues in DFMO-treated cells makes the pathway an adenine trap. This prompted a study of the adenine nucleotide pools. High-performance liquid chromatographic analysis showed that the total adenine nucleotide pool increased, rather than decreased, as a result of DFMO treatment; the major contributors to the increase being ATP and ADP, which increased 2.6 and 1.9 times, respectively. The cellular content of other ribonucleotides increased as well, particularly that of UTP and CTP. When putrescine was added together with DFMO, the increases in cellular ribonucleotide contents were prevented, showing that they were indeed caused by polyamine depletion.
Mol Cell Biochem 1986 Apr
PMID:Polyamine depletion increases cellular ribonucleotide levels. 308 9

A kinetic analysis of inhibition of synthesis of dinucleotide pppApU catalyzed by Escherichia coli RNA-polymerase on A1 promoter of the DNA from T7 delta DIII phage mutant by 8-oxy-ATP under the conditions of the coupled synthesis of pppApU and pppApUpC and in the presence of an incomplete set of substrates, namely ATP, UTP, CTP, has been performed. It was found that 8-oxy-ATP is an unproductive analog of both ATP and CTP. A comparative analysis of the dissociation constants shows that 8-oxy-ATP binds at ATP center 3.3. times and at CTP center 540 times weaker than natural substrates. At the UTP center 8-oxy-ATP does not bind at all.
Mol Biol (Mosk)
PMID:[Kinetics of inhibition by 8-oxy-ATP of the dinucleotide pppApU synthesis catalyzed by Escherichia coli RNA-polymerase on the promoter A1 of phage T7 delta D111 DNA during coupled synthesis of di- and trinucleotides and a limited set of substrates]. 329 44

We have used the galK gene, minus its promoter, to quantitate transcription of the orfE--pyrE operon of Escherichia coli in front of and after the intercistronic attenuator. Expression of the hybrid genes was studied in a bacterium with mutations that permit changes in the UTP and GTP pools during exponential growth. It was found that the greater part of pyrE gene regulation by the nucleotides takes place at the intercistronic attenuator and that promoter control contributes only little, ca. twofold. When pools of both UTP and GTP were high only 5%-6% of the mRNA chains were continued into the pyrE gene. However, when the UTP pool was reduced (from 1.3 to 0.2 mumol/g dry weight) nearly 100% of transcription passed the attenuator. Likewise, a reduction in the GTP pool (from 3.2 to 0.8 mumol/g dry weight) resulted in 25%-30% escape of attenuation. Regulation by attenuation disappeared when a premature stop-codon was introduced near the end of orfE such that translational coupling to transcription was prevented in the attenuator area. Therefore, we attribute the modulation of attenuation to nucleotide-induced variations in the kinetics of mRNA chain elongation. In support for this it was found that an RNA polymerase mutant with reduced RNA chain growth rate transcribed past the pyrE attenuator at a high frequency in the presence of a high UTP pool, but only when coupling of translation to transcription was allowed at the end of orfE.
Mol Gen Genet 1987 Jun
PMID:Effect of UTP and GTP pools on attenuation at the pyrE gene of Escherichia coli. 330 6

The mixed disulfide of methyl mercaptan and L-homocysteine, S-(methylthio)-L-homocysteine (L-SMETH), inhibits the growth of L-1210 leukemia cells in culture at micromolar concentrations. The inhibition is markedly promoted by added cupric ion, but not by ions of other metals, is stereospecific, and is competitive with glutamine. For example, at 10 microM each of L-SMETH and Cu2+, almost complete growth inhibition was observed if cells were grown in 1 mM glutamine, 50% inhibition at 2 mM glutamine, and none at 4 mM glutamine. The inhibition is also completely relieved by cytidine in noncompetitive manner, but not by guanosine or uridine, indicating that the principal damage to the cellular economy resides in the amination of UTP to CTP. This was confirmed by high performance liquid chromatography analysis of cell extracts, which showed a marked decrease in CTP with increases in the levels of UTP, GTP, and ATP. A major swelling of cells leading to lysis accompanies the inhibition and increases in DNA and protein per cell confirms this unbalanced growth. The chemical basis for this biological interaction is presented.
Mol Pharmacol 1988 Sep
PMID:Evidence for a copper:S-(methylthio)-L-homocysteine complex as a glutamine antagonist of cytidine triphosphate synthesis in L1210 murine leukemia cells. 341 27


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