Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.5.1.3 (dihydrofolate reductase)
 5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1-Acyl- and 1,2-diacyl-1,2,4-triazolidine-3,5-diones were found to be potent cytotoxic agents in murine and human cancer cell lines, e.g. L1210, P388, Tmolt3, colon adenocarcinoma, Hela cells and glioma. In vivo activity was demonstrated at 8 mg/kg/day against Ehrlich ascites carcinoma growth. In L1210 cells, 1-acetyl-4-phenyl-1,2,4-triazolidine-3,5-dione, 41, reduced DNA synthesis significantly with moderate reduction in RNA synthesis. Enzyme sites in L1210 cells which were markedly affected were m- and r-RNA polymerase, PRPP amidotransferase, IMP dehydrogenase, dihydrofolate reductase, thymidine, TMP and TDP kinases. Kinetic studies suggest the inhibition of rate limiting enzymes in the purine pathway by 41 was responsible for its cytotoxicity. Acute toxicity studies in mice indicated 41 was safe for therapeutic use at 20, 50, and 100 mg/ky/day.
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PMID:Antineoplastic activities and cytotoxicity of 1-acyl and 1,2-diacyl-1,2,4-triazolidine-3,5-diones in murine and human tissue culture cells. 144 91

Trimethoprim-resistance genes of Shigella dysenteriae 1 strains, isolated from a different location of six different countries of Asia over a 5-year period were characterized by using three different dihydrofolate reductase (DHFR) gene probes. The trimethoprim-resistant (TMPR) strains hybridized only with the type I DHFR gene probe by colony hybridization. None of the strains hybridized with types II and III DHFR gene probes. Southern blot experiments using plasmid DNA extracted from these resistant strains indicated that the type I DHFR genes were either on a 20 MDa plasmid or might be located on the chromosome. None of the other plasmids present in S. dysenteriae 1 strains hybridized with the probe. This indicates that the TMP resistance in these S. dysenteriae 1 strains are mediated by type I DHFR enzyme, and there may be transposition of this type I DHFR gene occurs between the 20 MDa plasmid and the chromosome in this serotype of shigella.
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PMID:Trimethoprim resistance gene in Shigella dysenteriae 1 isolates obtained from widely scattered locations of Asia. 218 27

Metabolic inhibitors which act in the process of pyrimidine salvage influenced on the uracil incorporation into nucleic acids of Toxoplasma. Inhibitors of dihydrofolate reductase, pyrimethamine and methotrexate, and inhibitors of thymidylate synthase, fluoro-uridine, fluoro-dUMP and fluoro-uracil, diminished isotopic uracil uptake in dose-dependent manners. Azauridine which suppresses de novo pyrimidine biosynthesis did not affect the salvage even in a relatively high dose. These results suggested that the activation of uracil salvage should be closely related with the function of TMP biosynthetic enzymes. The pattern of thymidine uptake had no differences between control HL-60 cells and Toxoplasma infected cells, which did not reflect the specific proliferation of Toxoplasma. It can be exploited to characterize the effects of various compounds related with the proliferation of Toxoplasma, especially its DNA synthesis.
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PMID:Effects of pyrimidine salvage inhibitors on uracil incorporation of Toxoplasma gondii. 227 4

A child with dihydropteridine reductase (DHPR) deficiency developed signs of dopamine insufficiency after being given trimethoprim-sulfamethoxazole (TMP-SMX). She recovered function after the antibiotic was stopped, which suggests that it adversely influenced dopamine metabolism in the CNS. The authors speculate that TMP, a dihydrofolate reductase inhibitor, was the major cause of the patient's deterioration, and suggest that it and other dihydrofolate inhibitors, notably methotrexate, are contra-indicated for patients with DHPR deficiency.
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PMID:Adverse effects of trimethoprim-sulfamethoxazole in a child with dihydropteridine reductase deficiency. 239 Oct 14

Between June and October 1982, Vibrio cholerae el tor Inaba phage type Russian 13, resistant to ampicillin (Ap), chloramphenicol (Cm), colistin, neomycin (Nm), kanamycin (Km), gentamicin (Gm), trimethoprim sulfamethoxazole (TMP-SMZ), and tetracycline (Tc), was isolated from 31 children with diarrhea at a hospital in Samutsakorn, Thailand. Thirty of these children were less than 2 years of age and were admitted to a single pediatric ward. Seventeen of the cases, infected with V. cholerae (MARV) resistant to several antibiotics, were admitted to the hospital for non-gastrointestinal illnesses; these children developed diarrhea and positive cultures for MARV 1-greater than 10 days after admission. The majority of cases occurred in September, when the attack rate in the patient population in 1 pediatric ward was 11.5%. During this period, MARV with the same characteristics was isolated from water used for bathing in a reservoir on the pediatric ward where most of the cases occurred. MARV was not isolated from adults with diarrhea at the hospital. No further MARV infections occurred at the hospital after the water reservoir had been drained and disinfected. V. cholerae isolates from children and water contained a conjugative incompatibility group C plasmid of 100 megadaltons (mDa) encoding resistance to Ap, Cm, Nm, Km, Gm, TMP-SMZ, and Tc. This plasmid hybridized with a DNA probe for genes encoding Type II dihydrofolate reductase (DHFR). As far as we know, this is the first report of MARV with V. cholerae that contained genes coding for Type II DHFR.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:An epidemic of Vibrio cholerae el tor Inaba resistant to several antibiotics with a conjugative group C plasmid coding for type II dihydrofolate reductase in Thailand. 264 46

The percentage of clinical isolates of several species of Enterobacteriaceae, particularly Escherichia coli and Klebsiella pneumoniae, resistant to trimethoprim (TMPR) has increased gradually at the Brigham and Women's Hospital (Boston) in recent years. Thirty-seven of 42 TMPR isolates from six species of gram-negative bacilli conjugally transferred TMP resistance to K12 E. coli. beta-Lactam resistance cotransferred from 21 of the 37 donors, and sulfamethoxazole (SMZ) resistance cotransferred from five of the 37 donors. Plasmids that encoded TMP resistance either alone or with SMZ resistance had a molecular size of approximately 52.5 kilobases, with identical restriction endonuclease-generated "fingerprints." Plasmids encoding beta-lactam-mediated resistance (beta R) were approximately four kilobases larger and had fragment patterns that were identical for all of the TMPR/beta R plasmids tested and had many restriction endonuclease-generated bands in common with TMPR plasmids. Radiolabeled dihydrofolate reductase (DHFR) probes identified the type II DHFR as the determinant of TMP resistance. In contrast with reports from Europe, TMP resistance in multiple species of Enterobacteriaceae was found to be spread in one hospital by a single, stable conjugative plasmid that has a wide host range and encodes the type II DHFR gene.
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PMID:Trimethoprim resistance in multiple genera of Enterobacteriaceae at a U.S. hospital: spread of the type II dihydrofolate reductase gene by a single plasmid. 298 9

Cooperativity in the binding of two substrates to an enzyme is a now well-established phenomenon. The x-ray crystallographic structure of the E. coli DHFR binary TMP complex compared with the ternary enzyme-NADPH-TMP complex suggests without too imaginative extrapolation, that the conformational changes resulting from the binding of one ligand aid in favorably positioning potential binding sites for the second ligand. Of greater importance is the fact that the extent to which inhibitor binding is enhanced by the binding of NADPH varies from species to species. To a significant extent, for example, the selectivity of TMP is enhanced by the increase in its binding to the E. coli enzyme when NADPH is present as compared with several mammalian enzymes. The reverse, negative cooperativity (a decrease in binding of a substance when moving from the binary to a ternary complex), is perhaps less common and certainly less well studied. The present paper deals with one such enzyme, the DHFR from C. albicans, and by reference to another, that from S. cerevisiae, where it is shown that the binding of substrates exhibit strong negative cooperativity. It was of interest also to determine the relationship between inhibitor/NADPH cooperativity and the relative insensitivity of N. gonorrhoeae to TMP. Equilibrium studies show that the binding of TMP in binary complex with this enzyme is exceedingly poor and that a 2,200-fold cooperative effect brings the gonococcal enzyme Ki within one order of magnitude of the E. coli enzyme Ki. Even so, it takes synergism of another sort (with sulfamethoxazole) and high doses to make co-trimoxazole therapy feasible for treating gonorrhoeae. The comparative results on the gonococcal enzyme for a family of near relatives of TMP are of interest also for the reason that the structure-activity relationships with this enzyme are quite different from those of the E. coli and other microbial enzymes. Finally, it should be pointed out that although the negative cooperativity found for the candida and saccharomyces enzymes is relatively large, it is the values of the substrate Michaelis constants that are physiologically relevant. The Km values of the yeast enzymes are within the range for other DHFR and therefore the intracellular activity of the enzymes should not be compromised.
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PMID:Substrate-inhibitor cooperative interactions with microbial dihydrofolate reductases. 331

The term "high molecular weight substances" used in this paper implies mostly nucleic acids of certain molecular weight and protein, and the genetic aspects of anti-cancer chemotherapy were discussed. Studies on the mechanism of action of 5-FU have been focused on the inhibition of DNA synthesis, and it has been reported that 5-FU inhibits the growth of thymidylate synthesis deleted FM3A Thy 21 cells even in the presence of thymidine, and that the level of TTP is equal to that in control cells. On the other hand, the active metabolite of 5-FU, FdUMP, is known to bind to synthesized thymidylate and 5, 10-methylene-tetrahydrofolic acid to form a ternary complex. Recently, the cytocidal effect of 5-FU was observed in thymidylate synthetase-deficient cells in the presence of a sufficient amount of thymidine, suggesting that the cytocidal effect of 5-FU might be caused by inhibition of the RNA pathway. In this laboratory, the effect of 5-FU on polysomal patterns and the incorporation of 3H-UR into polysomes was studied in L1210 cells, but no significant difference was observed between normal and 5-FU-treated cells. Ribosomal RNA extracted from the polysomes of 5-FU treated cells appeared to contain a smaller 28S rRNA in comparison to 18S rRNA, indicating that the processing might be inhibited. Expression of mouse H-2Dd mRNA was not influenced by 5-FU at 10(-5) M up to 6 h. Methotrexate (MTX) has a chemical structure similar to folic acid, and is known to bind to DHFR (dihydrofolate reductase), and inhibit the synthesis of TMP. The cellular PRPP content is known to be increased by MTX, which inhibits purine synthesis. The level of PRPP content was found to be increased approximately 25 fold at 3 h after 10(-6) M MTX although normal bone marrow cells showed no increase even after MTX. This increased level of PRPP thus obtained in cancer cells was thought to be used for the phosphorylation of 5-FU. Clinically, sequential chemotherapy using MTX and 5-FU was employed successfully for solid tumors on the basis of the experimental evidence. In order to minimize the adverse effects of anti-cancer drugs, a technique involving the incorporation of the drug-resistant gene into normal bone marrow cells has been designed in this laboratory, and the MTX-resistant cells thus obtained are transplanted into the tumor-bearing mice.
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PMID:[The metabolism of high-molecular-weight substances in cells and the effect of anticancer drugs]. 356 94

Trichomonas vaginalis is incapable of de novo pyrimidine biosynthesis because it cannot incorporate bicarbonate, aspartate or orotate into its pyrimidine nucleotides or nucleic acids. The organism can salvage exogenous cytidine greater than uridine greater than uracil and thymidine, and incorporate them into the nucleotide pool. A portion of cytidine is converted to CMP, CDP and CTP by cytidine phosphotransferase and nucleotide kinases. Some cytidine and most of uracil are, however, converted first to uridine by cytidine deaminase and uridine phosphorylase respectively; uridine is then incorporated into UMP, UDP and UTP by uridine phosphotransferase and nucleotide kinases. The two phosphotransferases, found mainly in the non-sedimentable fraction of T. vaginalis, provide the main avenue of pyrimidine salvage. No significant levels of pyrimidine phosphoribosyl transferase or nucleoside kinases can be detected in the extract. T. vaginalis has no appreciable dihydrofolate reductase or thymidylate synthetase; it grows normally in millimolar concentrations of methotrexate, pyrimethamine, or trimethoprim, and cannot incorporate labels from exogenous uracil or uridine into DNA. It has an enzyme thymidine phosphotransferase in the sedimentable fraction which converts thymidine to TMP. Thymidine salvage in T. vaginalis is thus totally isolated from the rest of the pyrimidine salvage.
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PMID:Salvage of pyrimidine nucleosides by Trichomonas vaginalis. 619 66

The anaerobic parasitic protozoa Tritrichomonas foetus is found incapable of de novo pyrimidine biosynthesis by its failure to incorporate bicarbonate, aspartate, or orotate into pyrimidine nucleotides or nucleic acids. Uracil phosphoribosyltransferase in the cytoplasm provides the major pyrimidine salvage for the parasite. Exogenous uridine and cytidine are mostly converted to uracil by uridine phosphorylase and cytidine deaminase in T. foetus prior to incorporation. T. foetus cannot incorporate labels from exogenous uracil or uridine into DNA; it has no detectable dihydrofolate reductase or thymidylate synthetase and is resistant to methotrexate, pyrimethamine, trimethoprim, and 5-bromovinyldeoxyuridine at millimolar concentrations. It has an enzyme thymidine phosphotransferase in cellular fraction pelleting at 100,000 X g that can convert exogenous thymidine to TMP via a phosphate donor such as p-nitrophenyl phosphate or nucleoside 5'-monophosphate. Thymidine salvage in T. foetus is thus totally dissociated from other pyrimidine salvage.
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PMID:Pyrimidine metabolism in Tritrichomonas foetus. 657 72


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