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)

DNA sequences corresponding to specific genes may be prepared by chemical synthesis, isolation of naturally occurring DNA, or reverse transcription. Such DNA may then be inserted into vectors such as plasmids or bacteriophages which carry the DNA into bacterial cells. Although significant differences exist in the basic molecular biology of eucaryotic and procaryotic organisms, these differences do not constitute absolute barriers to the expression of eucaryotic genes in bacteria. Several eucaryotic proteins, including insulin, growth hormone, ovalbumin, dihydrofolate reductase and somatostatin have been produced in bacteria. The use of chimeric microorganisms harboring recombinant DNA offers a completely new approach to the production of biologically useful polypeptides.
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PMID:Use of recombinant DNA technology for the production of polypeptides. 9 11

Levels of methotrexate (MTX) measured by both 3H radioactivity and dihydrofolate reductase assays were determined in cerebrospinal fluid (CSF), plasma, urine, and both neural and non-neural tissues at varying times after a single intraventricular injection into Cynomolgus monkeys (Macaca fascicularis). Clearance of the MTX from CSF was rapid after injection. A relatively constant level of 3HMTX was reached in plasma 2 1/2 hours after injection, and about 30% of the 3HMTX dose was excreted in the urine within 4 hours after injection. Maximum levels in CNS tissues were obtained by 4 hours after injection, and average concentrations of 10(-6) M MTX (moles/kg wet weight) were maintained in CSF for up to 12 hours and in brain for up to 24 hours after injection. Conversion of MTX to non-MTX products was detected in CSF between 4 and 12 hours, and in brain tissue between 12 and 24 hours after injection, and the amount of these products increased with time. Regional distribution studies in the cerebrum showed a U-shaped distribution curve for 3HMTX up to 12 hours after injection, which closely followed the 14C inulin distribution. Thus, the levels in deep cerebral tissue were less than the average level for brain, and this suggests that treatment of CNS tumors by intraventricular injection may have variable results, partly due to complex tissue distribution patterns.
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PMID:Direct administration of methotrexate into the central nervous system of primates. Part 1: Distribution and degradation of methotrexate in nervous and systemic tissue after intraventricular injection. 9 28

The complete amino acid sequence of dihydrofolate reductase from an amethopterin-resistant strain of Lactobacillus casei has been determined by sequence analysis of peptides produced by cleavage with cyanogen bromide, trypsin, staphylococcal protease, and myxobacter protease. Comparison of this sequence with those of reductases from other bacterial sources shows that the enzymes are homologous. The Lactobacillus casei reductase sequences shows a 29% sequence identity with that of the Escherichia coli enzyme and a 34% identity with the sequence of the enzyme from Streptococcus faecium. The NH2-terminal 68 residues of the L. casei reductase show a 54% sequence identity with that of the enzyme from S. faecium.
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PMID:Dihydrofolate reductase from amethopterin-resistant Lactobacillus casei. Sequences of the cyanogen bromide peptides and complete sequences of the enzyme. 9 27

Several independent, spontaneous rifampin-resistant mutants of Bacillus subtilis were isolated and found to have an increased resistance to trimethoprim, an inhibitor of dihydrofolate reductase. This increased resistance in the rif mutants was the result of a specific threefold increase in the activity of dihydrofolate reductase, since six other enzymes examined remained unchanged. This increased level of dihydrofolate reductase and the trimethoprim resistance were cotransformed (100%) with the rif marker. These results suggest that the RNA polymerase is altered in its recognition of the gene that specifies dihydrofolate reductase.
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PMID:Increased levels of dihydrofolate reductase in rifampin-resistant mutants of Bacillus subtilis. 10 41

The synthesis of 11-thiohomofolic acid (2) has been accomplished by an unambiguous procedure. Reaction of 1-chloro-4-[p-(carbomethoxy)thiophenoxy]-2-butanone (10) with hydroxylamine under carefully controlled conditions gave the corresponding oxime 33. Conversion of this oxime to 1-phthalimido-4-[p-(carbomethoxy)thiophenoxy]-2-butanone oxime (4) was carried out by its reaction with potassium phthalimide using crown 18 ether as a catalyst. Hydrazinolysis of compound 4 gave 1-amino-4-[p-(carbomethoxy)thiophenoxy]-2-butanone oxime (5), which was used for the construction of the title compound 2 by modification of the Boon and Leigh procedure. An alternate synthesis utilizing 1-hydroxy-4-[p-(carbomethoxy)thiophenoxy]-2-butanone (11) and 4-hydroxy-2,5,6-triaminopyrimidine has also been carried out. Compound 2 did not exhibit any antifolate activity against Lactobacillus casei or Streptococcus faecium. The dithionite reduction product, 7,8-dihydro-11-thiohomofolic acid, was able to function as a substrate of L. casei dihydrofolate reductase. The catalytic reduction product of 2, consisting of a mixture of diastereomers, exhibited powerful antifolate activity against both these organisms.
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PMID:Folate analogues altered in the C9-N10 bridge region: 11-thiohomofolic acid. 10 15

Methotrexate analogues, in which an additional nitrogen atom is inserted between the phenyl ring and the carbonyl group of the side chain, were prepared by photochemical methods. The compounds were less inhibitory toward dihydrofolate reductase and thymidylate synthetase derived from Lactobacillus casei than was methotrexate. They were also less cytotoxic against human lymphoblastic leukemia cells (CCRF-CEM). In vivo against L-1210 leukemia in mice, the aza homologue of methotrexate showed significant antitumor activity (%ILS = 55%) compared to methotrexate (%ILS = 88%).
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PMID:Methotrexate analogues. 12. Synthesis and biological properties of some aza homologues. 10 16

Folic acid analogues containing an additional nitrogen atom between the phenyl ring and the carbonyl group of the side chain were synthesized. None of the compounds showed significant inhibitory activity against human lymphoblastic leukemia cells (CCRF-CEM) in culture or against Lactobacillus casei (ATCC 7469) growth. Against L1210 leukemia in mice, the aza homologue of folic acid, 4, and the aspartic acid analogue, 14, showed no increase in life span over control animals. These compounds were more toxic in vivo than the corresponding methotrexate analogues. Compound 4 supported the growth of Streptococcus faecium (ATCC 8043), and its tetrahydro derivative supported the growth of Pediococcus cerevisiae (ATCC 8081). These results strongly suggest that 4 can substitute for folate derivatives as cofactors for serine transhydroxymethylase, thymidylate synthetase, and dihydrofolate reductase.
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PMID:Synthesis of aza homologues of folic acid. 10 17

Quantitative structure-activity relationships (QSAR) have been established for the inhibition of dihydrofolate reductase and thymidylate synthetase by 2,4-diaminoquinazoline-glutamic acid analogues. For dihydrofolate reductase from both human acute lymphocytic leukemia cells and murine L1210R cells, QSAR's obtained with 50 quinazolines were similar. On the other hand, for the inhibition of thymidylate synthetase from murine L1210S cells and from Lactobacillus casei, QSAR's formulated on the basis of data measured with 33 compounds were different, indicating that the two enzymes are dissimilar. The use of multivariate statistics including cluster analysis, factor analysis, and discriminant analysis is shown to facilitate the formulation of a satisfactory correlation equation. The procedure is demonstrated by the development of QSAR for the inhibition of thymidylate synthetase.
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PMID:Multivariate analysis and quantitative structure-activity relationships. Inhibition of dihydrofolate reductase and thymidylate synthetase by quinazolines. 11 Sep 30

A series of 6-substituted and 6,7-disubstituted pyrimido[4,5-b][1,4]oxazines (8-oxadihydropteridines) was synthesized through the condensation of an alpha-halo ketone and 2,5-diamino-4,6-pyrimidinediol. The resulting 8-oxadihydropteridines were assayed as potential antifolates in a dihydrofolate reductase enzyme system. The 2-amino-4-hydroxyoxa-dihydropteridines were found to possess greater biological activity than the corresponding 2,4-diamino compounds. The pteroic acid homeostere 2-amino-4-hydroxy-6-phenethyl-8-oxadihydropteridine was the most potent of the compounds tested.
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PMID:Synthesis and biological activity of 8-oxadihydropteridines. 11 Sep 34

Members of the genus Neisseria are relatively nonsusceptible to trimethoprim, an inhibitor of dihydrofolate reductase. For example, the minimal inhibitory concentration (MIC) of trimethoprim for N. gonorrhoeae ranges from 2 to 70 mug/ml, whereas the MIC for Escherichia coli is 0.2 mug/ml or less. In an effort to understand this difference, dihydrofolate reductase was partially purified from five Neisseria species and compared with the enzyme from E. coli. N. gonorrhoeae dihydrofolate reductase was similar to that from E. coli in molecular weight (18,000) and affinity for the substrates reduced nicotinamide adenine dinucleotide phosphate and dihydrofolate (K(m) = 13 and 8 muM, respectively). However, the gonococcal enzyme had a decreased affinity for trimethoprim, with an apparent K(i) of 45 x 10(-9) M, some 30-fold greater than the E. coli value of 1.2 x 10(-9) M. These enzymes also differed in their isoelectric points and pH activity profiles. Within the genus Neisseria, the dihydrofolate reductase isolated from N. meningitidis and N. lactamica resembled the N. gonorrhoeae enzyme, and only small differences were detected for the N. flavescens and Branhamella catarrhalis dihydrofolate reductases. These data indicate that the relatively poor affinity of trimethoprim for the dihydrofolate reductase from these organisms may be largely responsible for the relative nonsusceptibility of Neisseria sp. to trimethoprim. The contribution of other resistance mechanisms to the overall nonsusceptibility was assessed. Strains of N. gonorrhoeae with altered cell envelope permeability had MIC values less than twofold different from those of isogenic wild-type strains. Also, a direct relationship was observed between the affinity of trimethoprim analogs for gonococcal dihydrofolate reductase and the MIC of these compounds for the gonococcus. These observations suggest that the cell envelope of N. gonorrhoeae is not impermeable to trimethoprim. Changes in the amount of dihydrofolate reductase activity could cause alterations in the susceptibility of the gonococcus to trimethoprim, as demonstrated with N. gonorrhoeae strains selected for trimethoprim resistance after chemical mutagenesis. However, the level of dihydrofolate reductase activity in wild-type N. gonorrhoeae was similar to that of E. coli, indicating that the difference in the susceptibility of these organisms is not due to greater amounts of enzyme in N. gonorrhoeae.
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PMID:Dihydrofolate reductase from Neisseria sp. 11 11


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