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)

An ip injection of a Lactobacillus casei dihydrofolate reductase preparation into rats and mice given a single lethal dose of methotrexate (MTX) caused a marked lowering of free MTX in the blood. Alternatives to citrovorum factor as agents for reversing MTX toxicity were explored in mice. dl, L-5-Methyltetrahydrofolate, dl,L-5,10-methylenetetrahydrofolate, l,L-5,10-methylenetetrahydrofolate, and dihydrofolate were also effective MTX antagonists; d,L-5,10-methylenetetrahydrofolate was inert.
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PMID:Aspects of the reversal of methotrexate toxicity in rodents. 30 79

A rapid radiometric assay for the folate antagonist MTX, based on the inhibition of chicken liver dihydrofolate reductase activity, has been developed. In the system the inhibition by MTX of the reduction of tritiated FH2 is standardized and used to quantitate this antagonist in plasma of subjects receiving high-dose MTX therapy. The assay permits the detection of plasma MTX levels to 5 X 10(-9)M with a coefficient of variation of 15%. The predominating circulating folate, 5 methyltetrahydrofolate, or the rescue agent leucovorin (5 formyltetrahydrofolate) do not significantly interfere with the assay at concentrations attainable with current rescue programs. Analyses of multiple plasma samples with the present assay show close agreement with the competitive protein-binding assay.
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PMID:A simple radiometric assay for methotrexate and other folate antagonists. 31 1

The role of folate metabolism in growth control in monolayer and suspension cell cultures was studied in three related cell lines: BHK-21, polyoma-transformed BHK-21 (PyBHK), and an aminopterin-resistant derivative of BHK-21 (A5). BHK-21 cells had extremely low levels of dihydrofolate reductase, PyBHK had higher levels, and A5 had extremely high levels. Hypoxanthine and thymidine together, but not individually, induced BHK-21 to grow in agar, and stimulated its growth in agarose and monolayer culture. PyBHK and A5 grew spontaneously in agar, and hypoxanthine plus thymidine had little or no effect on their growth either in suspension or in monolayer cultures. We found that exogenous folinic acid, a derivative of folate metabolism that bypasses the function of dihydrofolate reductase, mimicked the growth-stimulatory effects of exogenous hypoxanthine plus thymidine BHK-21. We conclude that the growth limitation of BHK-21 in suspension culture is due, in part, to a deficiency of dihydrofolate reductase. This enzyme deficiency limits nucleoside synthesis and can be overcome by supplying end products of this pathway.
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PMID:Growth limitation of BHK-21 cells and its relation to folate metabolism. 31 16

At present, in countries of tropical Africa, chemotherapy is the main and often the only operationally, administratively, and financially feasible method of malaria control. This applies particularly in rural areas. This article reviews experience with chemotherapy in Africa since the late 1940s with mepacrine, proguanil, pyrimethamine, chloroquine, amodiaquine, and sulfones and sulfonamides in combination with dihydrofolate reductase inhibitors. Chloroquine has proved to be the most effective compound and it is the drug of choice as long as malarial parasites remain susceptible to it. Because of reports from East Africa of strains of Plasmodium falciparum resistant to 4-aminoquinolines, it is essential that national and regional policies be developed for the rational use of antimalarials.In most of the countries, the scope of activities is still limited to the administration of antimalarial drugs to sick persons through a limited network of health institutions. In some countries, however, attempts have been made to extend the coverage of drug administration by involving voluntary collaborators or through the provision of suppressive treatment to vulnerable groups of the population (such as infants, young children, pregnant women, nursing mothers, and schoolchildren) but the efficacy of such methods depends on the degree of involvement of voluntary collaborators, primary health workers, and communities.
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PMID:Use of drugs for malaria control in tropical Africa. 31 34

A quantitative structure-activity relationship (QSAR) for the inhibition of dihydrofolate reductase from S. faecium by quinazolines has been formulated. This is compared with a QSAR for inhibition of E. coli dihydrofolate reductase by 2,4-diamino-5-benzylpyrimidines. The QSAR for inhibition of bacterial enzyme is compared with QSAR for mammalian enzyme inhibition. A QSAR has been formulated for the antimalarial action of quinazolines against P. berghei in mice. The antimalarial QSAR is consistent with that of the in vitro bacterial study.
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PMID:Quantitative structure-activity relationships of antimalarial and dihydrofolate reductase inhibition by quinazolines and 5-substituted benzyl-2,4-diaminopyrimidines. 31 34

The determination of the amino acid sequence of the dihydrofolate reductase from Escherichia coli RT500 is described. The sequence, comprising 159 residues, has been derived from automatic sequencing of the intact protein in conjunction with manual sequencing of lysine-blocked tryptic peptides, Staphylococcus aureus protease peptides, and alpha-lytic protease peptides. Comparison of the sequence with that of the dihydrofolate reductase from a methotrexate-resistant strain of E. coli (MB1428) shows that 145 of the residues are identical. The distribution of the differences along the length of the molecule is discussed.
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PMID:The amino-acid sequence of the dihydrofolate reductase of a trimethoprim-resistant strain of Escherichia coli. 32 5

A method for the high-voltage electrophoresis of dihydrofolate reductase from Escherichia coli W 3110 is described. Dihydrofolate reductase catalyses the reduction of dihydrofolic acid to tetrahydrofolic acid. By addition of a tetrazolium salt, tetrahydrofolic acid reacts by formation of a violet water insoluble formazane which is an indicator for the enzyme. Besides several unspecific bands, two isoenzymes of the dihydrofolate reductase from Escherichia coli W 3110 are found which are specificially inhibited by the folate antagonists methotrexate and trimethoprime in a concentration of 0, 1muM, 1 muM respectively.
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PMID:[High-voltage electrophoresis of dihydrofolate reductase from Escherichia coli W 3110 (author's transl)]. 32 Jun 38

Three spontaneous fol regulatory mutants contain dihydrofolate reductase molecules which differ in physical properties from enzymes of their parent strains. The enzymes were purified over 100-fold by affinity chromatography and were shown to differ in vitro in thermolability and in affinity for trimethoprim, a competitive inhibitor of the enzyme. These results indicate that some fol regulatroy mutations occur in the structural gene for dihydrofolate reductase.
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PMID:Altered dihydrofolate reductase in fol regulatroy mutants of Escherichia coli K12. 32 67

This paper is concerned with the physiological role(s) of T4 phage-coded dihydrofolate reductase, which functions both in DNA precursor metabolism and as a virion protein. (i) We have detected enzyme activity in noninfectious particles produced under restrictive conditions by gene 11 mutants. This supports the conclusion of Kozloff et al. (J. Virol. 16:1401-1408, 1975) that the protein lies in the baseplate, covered by the gene 11 protein. (ii) We have obtained further evidence for virion dihydrofolate reductase as the target for neutralizing activity of T4 dihydrofolate reductase antiserum and as a determinant of the heat lability of the virion. This derives from our observation that the reductases specified by T4B and T4D differ in several properties. (iii) We have investigated several anomalous properties of T4 mutants bearing deletions that reportedly extend into or through the frd gene, which codes for dihydrofolate reductase. Evidence is presented that the deletions in fact do not extend through frd. These strains direct the synthesis of material that cross-reacts with antiserum to homogeneous dihydrofolate reductase. Moreover, they are all quite sensitive to the phage-neutralizing effects of this antiserum. In addition, they are restricted by several of the hospital strains, wild-type strains of Escherichia coli supplied by the California Institute of Technology group. (iv) We have attempted to detect dihydrofolate reductase among early-synthesized proteins present in T4 tails. Two such proteins are seen, one of which is evidently the gene 25 product and one that is a bacterial protein. Quantitation of our electrophoretic technique has allowed determination of the number of molecules of some T4 tail components present per virion. (v) Finally, we have compared the T4 dihydrofolate reductase with the corresponding enzyme specified by two plasmids conferring resistance to trimethoprim (Skold and Widh, J. Biol. Chem. 249:4324-4325, 1974). Although the enzymes are similar in some properties, they differ in several important respects, including immunological activity.
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PMID:Bacteriophage T4 virion dihydrofolate reductase: approaches to quantitation and assessment of function. 33 Aug 80

The determination of the amino acid sequence of the enzyme dihydrofolate reductase (5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase, EC 1.5.1.3) from a mutant of Escherichia coli B is described. The 159 residues were positioned by automatic Edman degradation of the whole protein, of the reduced and alkylated cyanogen bromide fragments, and of selected tryptic, chymotryptic, and thermolytic digestion products. An N-bromosuccinimide produced fragment of the largest cyanogen bromide peptide was also used in the sequence determination.
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PMID:Dihydrofolate reductase: the amino acid sequence of the enzyme from a methotrexate-resistant mutant of Escherichia coli. 35 Feb 68


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