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Journal articles on the topic 'Dihydrofolate reductase'

Author: Grafiati

Published: 4 June 2021

Last updated: 25 January 2023

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1

Wilquet, Valérie, Mark Van de Casteele, Daniel Gigot, Christianne Legrain, and Nicolas Glansdorff. "Dihydropteridine Reductase as an Alternative to Dihydrofolate Reductase for Synthesis of Tetrahydrofolate in Thermus thermophilus." Journal of Bacteriology 186, no. 2 (January 15, 2004): 351–55. http://dx.doi.org/10.1128/jb.186.2.351-355.2004.

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ABSTRACT A strategy devised to isolate a gene coding for a dihydrofolate reductase from Thermus thermophilus DNA delivered only clones harboring instead a gene (the T. thermophilus dehydrogenase [DH Tt ] gene) coding for a dihydropteridine reductase which displays considerable dihydrofolate reductase activity (about 20% of the activity detected with 6,7-dimethyl-7,8-dihydropterine in the quinonoid form as a substrate). DH Tt appears to account for the synthesis of tetrahydrofolate in this bacterium, since a classical dihydrofolate reductase gene could not be found in the recently determined genome nucleotide sequence (A. Henne, personal communication). The derived amino acid sequence displays most of the highly conserved cofactor and active-site residues present in enzymes of the short-chain dehydrogenase/reductase family. The enzyme has no pteridine-independent oxidoreductase activity, in contrast to Escherichia coli dihydropteridine reductase, and thus appears more similar to mammalian dihydropteridine reductases, which do not contain a flavin prosthetic group. We suggest that bifunctional dihydropteridine reductases may be responsible for the synthesis of tetrahydrofolate in other bacteria, as well as archaea, that have been reported to lack a classical dihydrofolate reductase but for which possible substitutes have not yet been identified.

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2

Dedhar, S., D. Hartley, D. Fitz-Gibbons, G. Phillips, and J. H. Goldie. "Heterogeneity in the specific activity and methotrexate sensitivity of dihydrofolate reductase from blast cells of acute myelogenous leukemia patients." Journal of Clinical Oncology 3, no. 11 (November 1985): 1545–52. http://dx.doi.org/10.1200/jco.1985.3.11.1545.

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Dihydrofolate reductase activity was found to be highly heterogeneous in terms of its specific activity and methotrexate sensitivity in the blast cells of patients with acute myelogenous leukemia. None of the patients had previously been treated with methotrexate (MTX). The blast cells of four of 12 patients studied contained methotrexate-insensitive forms of dihydrofolate reductase, and the blast cells of three (distinct from the four mentioned previously) of the 12 had significantly higher dihydrofolate reductase activities than the rest. The presence of MTX-insensitive dihydrofolate reductases and high levels of enzyme activity represent intrinsic mechanisms of resistance and may explain the apparent clinical resistance of acute myelogenous leukemia to methotrexate.

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3

Young, H. K., R. A. Skurray, and S. G. B. Amyes. "Plasmid-mediated trimethoprim-resistance in Staphylococcus aureus. Characterization of the first gram-positive plasmid dihydrofolate reductase (type S1)." Biochemical Journal 243, no. 1 (April 1, 1987): 309–12. http://dx.doi.org/10.1042/bj2430309.

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The trimethoprim-resistance gene located on plasmid pSK1, originally identified in a multi-resistant Staphylococcus aureus from Australia, encodes the production of a dihydrofolate reductase (type S1), which confers a high degree of resistance to its host and is quite unlike any plasmid-encoded dihydrofolate reductase hitherto described. It has a low Mr (19,700) and has a higher specific activity than the constitutive Gram-negative plasmid dihydrofolate reductases. The type S1 enzyme is heat-stable and has a relatively low affinity for the substrate, dihydrofolate (Km 10.8 microM). It is moderately resistant to trimethoprim, and is competitively inhibited by this drug with an inhibitor-binding constant of 11.6 microM. This is the first identification and characterization of a plasmid-encoded trimethoprim-resistant dihydrofolate reductase derived from a Gram-positive species.

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4

Hammond, S. J., B. Birdsall, M. S. Searle, G. C. K. Roberts, and J. Feeney. "Dihydrofolate reductase." Journal of Molecular Biology 188, no. 1 (March 1986): 81–97. http://dx.doi.org/10.1016/0022-2836(86)90483-3.

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5

Adrian, P. V., and K. P. Klugman. "Mutations in the dihydrofolate reductase gene of trimethoprim-resistant isolates of Streptococcus pneumoniae." Antimicrobial Agents and Chemotherapy 41, no. 11 (November 1997): 2406–13. http://dx.doi.org/10.1128/aac.41.11.2406.

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Streptococcus pneumoniae isolates resistant to several antimicrobial agent classes including trimethoprim-sulfamethoxazole have been reported with increasing frequency throughout the world. The MICs of trimethoprim, sulfamethoxazole, and trimethoprim-sulfamethoxazole (1:19) for 259 clinical isolates from South Africa were determined, and 166 of these 259 (64%) isolates were resistant to trimethoprim-sulfamethoxazole (MICs > or =20 mg/liter). Trimethoprim resistance was found to be more strongly correlated with trimethoprim-sulfamethoxazole resistance (correlation coefficient, 0.744) than was sulfamethoxazole resistance (correlation coefficient, 0.441). The dihydrofolate reductase genes from 11 trimethoprim-resistant (MICs, 64 to 512 microg/ml) clinical isolates of Streptococcus pneumoniae were amplified by PCR, and the nucleotide sequences were determined. Two main groups of mutations to the dihydrofolate reductase gene were found. Both groups shared six amino acid changes (Glu20-Asp, Pro70-Ser, Gln81-His, Asp92-Ala, Ile100-Leu, and Leu135-Phe). The first group included two extra changes (Lys60-Gln and Pro111-Ser), and the second group was characterized by six additional amino acid changes (Glu14-Asp, Ile74-Leu, Gln91-His, Glu94-Asp, Phe147-Ser, and Ala149-Thr). Chromosomal DNA from resistant isolates and cloned PCR products of the genes encoding resistant dihydrofolate reductases were capable of transforming a susceptible strain of S. pneumoniae to trimethoprim resistance. The inhibitor profiles of recombinant dihydrofolate reductase from resistant and susceptible isolates revealed that the dihydrofolate reductase from trimethoprim-resistant isolates was 50-fold more resistant (50% inhibitory doses [ID50s], 3.9 to 7.3 microM) than that from susceptible strains (ID50s, 0.15 microM). Site-directed mutagenesis experiments revealed that one mutation, Ile100-Leu, resulted in a 50-fold increase in the ID50 of trimethoprim. The resistant dihydrofolate reductases were characterized by highly conserved redundant changes in the nucleotide sequence, suggesting that the genes encoding resistant dihydrofolate reductases may have evolved as a result of inter- or intraspecies recombination by transformation.

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6

Al-Rubeai, M., and J. W. Dale. "Purification and characterization of dihydrofolate reductase from Mycobacterium phlei." Biochemical Journal 235, no. 1 (April 1, 1986): 301–3. http://dx.doi.org/10.1042/bj2350301.

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The dihydrofolate reductase from Mycobacterium phlei was purified and characterized; it has an Mr of 15 000 and a pI of 4.8. It is competitively inhibited by both methotrexate and trimethoprim, although the affinity is less than for other bacterial dihydrofolate reductases.

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7

Strehl, Elke, Ingrid Schneider, and Erich F. Elstner. "Inhibition of Dihydrofolate Reductase by Mofebutazon." Zeitschrift für Naturforschung C 48, no. 9-10 (October 1, 1993): 815–17. http://dx.doi.org/10.1515/znc-1993-9-1022.

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Abstract Mofebutazon, Dihydrofolate Reductase, Non-Steroidal Antiinflammatory Drugs (NSAIDs) Mofebutazon, in contrast to phenylbutazon, inhibits dihydrofolate reductase in a concentration-dependent manner. An apparent for mofebutazon and dihydrofolate reductase in the presence of NADPH as electron donor and dihydrofolate as electron acceptor of approximately 0.2 mM was calculated.

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8

Kehrenberg, Corinna, and Stefan Schwarz. "dfrA20, a Novel Trimethoprim Resistance Gene from Pasteurella multocida." Antimicrobial Agents and Chemotherapy 49, no. 1 (January 2005): 414–17. http://dx.doi.org/10.1128/aac.49.1.414-417.2005.

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ABSTRACT A novel trimethoprim resistance gene, designated dfrA20, was detected on the 11-kb plasmid pCCK154 from Pasteurella multocida. The dfrA20 gene codes for a dihydrofolate reductase of 169 amino acids. Sequence comparisons revealed that the DfrA20 protein differed distinctly from all dihydrofolate reductases known so far.

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9

Farnham, P. J., and R. T. Schimke. "Murine dihydrofolate reductase transcripts through the cell cycle." Molecular and Cellular Biology 6, no. 2 (February 1986): 365–71. http://dx.doi.org/10.1128/mcb.6.2.365-371.1986.

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The murine dihydrofolate reductase gene codes for mRNAs that differ in the length of their 3' untranslated region as well as in the length of their 5' leader sequence. In addition, the dihydrofolate reductase promoter functions bidirectionally, producing a series of RNAs from the opposite strand than the dihydrofolate reductase mRNAs. We have examined the production of these RNAs and their heterogeneous 5' and 3' termini as mouse 3T6 cells progress through a physiologically continuous cell cycle. We found that all of the transcripts traverse the cell cycle in a similar manner, increasing at the G1/S boundary without significantly changing their ratios relative to one another. We conclude that cell-cycle regulation of dihydrofolate reductase is achieved without recruiting new transcription initiation sites and without a change in polyadenylation sites. It appears that the mechanism responsible for the transcriptional cell-cycle regulation of the dihydrofolate reductase gene is manifested only by transiently increasing the efficiency of transcription at the dihydrofolate reductase promoter.

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10

Farnham, P. J., and R. T. Schimke. "Murine dihydrofolate reductase transcripts through the cell cycle." Molecular and Cellular Biology 6, no. 2 (February 1986): 365–71. http://dx.doi.org/10.1128/mcb.6.2.365.

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The murine dihydrofolate reductase gene codes for mRNAs that differ in the length of their 3' untranslated region as well as in the length of their 5' leader sequence. In addition, the dihydrofolate reductase promoter functions bidirectionally, producing a series of RNAs from the opposite strand than the dihydrofolate reductase mRNAs. We have examined the production of these RNAs and their heterogeneous 5' and 3' termini as mouse 3T6 cells progress through a physiologically continuous cell cycle. We found that all of the transcripts traverse the cell cycle in a similar manner, increasing at the G1/S boundary without significantly changing their ratios relative to one another. We conclude that cell-cycle regulation of dihydrofolate reductase is achieved without recruiting new transcription initiation sites and without a change in polyadenylation sites. It appears that the mechanism responsible for the transcriptional cell-cycle regulation of the dihydrofolate reductase gene is manifested only by transiently increasing the efficiency of transcription at the dihydrofolate reductase promoter.

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11

Kadlec, Kristina, and Stefan Schwarz. "Identification of a Novel Trimethoprim Resistance Gene, dfrK, in a Methicillin-Resistant Staphylococcus aureus ST398 Strain and Its Physical Linkage to the Tetracycline Resistance Gene tet(L)." Antimicrobial Agents and Chemotherapy 53, no. 2 (November 17, 2008): 776–78. http://dx.doi.org/10.1128/aac.01128-08.

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ABSTRACT A novel trimethoprim resistance gene, designated dfrK, was detected in close proximity to the tetracycline resistance gene tet(L) on the ca. 40-kb plasmid pKKS2187 in a porcine methicillin (meticillin)-resistant Staphylococcus aureus isolate of sequence type 398. The dfrK gene encodes a 163-amino-acid dihydrofolate reductase that differs from all so-far-known dihydrofolate reductases.

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12

Rod, Thomas H., and Charles L. Brooks. "How Dihydrofolate Reductase Facilitates Protonation of Dihydrofolate." Journal of the American Chemical Society 125, no. 29 (July 2003): 8718–19. http://dx.doi.org/10.1021/ja035272r.

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13

Farnham, P. J., and R. T. Schimke. "In vitro transcription and delimitation of promoter elements of the murine dihydrofolate reductase gene." Molecular and Cellular Biology 6, no. 7 (July 1986): 2392–401. http://dx.doi.org/10.1128/mcb.6.7.2392-2401.1986.

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We have developed an in vitro transcription system for the murine dihydrofolate reductase gene. Although transcription in vitro from a linearized template was initiated at the same start sites as in vivo, the correct ratios were more closely approximated when a supercoiled template was used. In addition, whereas the dihydrofolate reductase promoter functions bidirectionally in vivo, the initiation signals directed unidirectional transcription in this in vitro system. The dihydrofolate reductase gene does not have a typical TATA box, but has four GGGCGG hexanucleotides within 300 base pairs 5' of the AUG codon. Deletion analysis suggested that, although sequences surrounding each of the GC boxes could specify initiation approximately 40 to 50 nucleotides downstream, three of the four GC boxes could be removed without changing the accuracy or efficiency of initiation at the major in vivo site. The dihydrofolate reductase promoter initiated transcription very rapidly in vitro, with transcripts visible by 1 min and almost maximal by 2 min at 30 degrees C with no preincubation. Nuclear extracts prepared from cells blocked in the S phase by aphidicolin or from adenovirus-infected cells at 16 h postinfection had enhanced dihydrofolate reductase transcriptional activity. This increased in vitro transcription mimicked the increase in dihydrofolate reductase mRNA seen in S-phase cells and suggested the presence of a cell-cycle-specific factor(s) which stimulated transcription from the dihydrofolate reductase gene.

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14

Farnham, P. J., and R. T. Schimke. "In vitro transcription and delimitation of promoter elements of the murine dihydrofolate reductase gene." Molecular and Cellular Biology 6, no. 7 (July 1986): 2392–401. http://dx.doi.org/10.1128/mcb.6.7.2392.

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We have developed an in vitro transcription system for the murine dihydrofolate reductase gene. Although transcription in vitro from a linearized template was initiated at the same start sites as in vivo, the correct ratios were more closely approximated when a supercoiled template was used. In addition, whereas the dihydrofolate reductase promoter functions bidirectionally in vivo, the initiation signals directed unidirectional transcription in this in vitro system. The dihydrofolate reductase gene does not have a typical TATA box, but has four GGGCGG hexanucleotides within 300 base pairs 5' of the AUG codon. Deletion analysis suggested that, although sequences surrounding each of the GC boxes could specify initiation approximately 40 to 50 nucleotides downstream, three of the four GC boxes could be removed without changing the accuracy or efficiency of initiation at the major in vivo site. The dihydrofolate reductase promoter initiated transcription very rapidly in vitro, with transcripts visible by 1 min and almost maximal by 2 min at 30 degrees C with no preincubation. Nuclear extracts prepared from cells blocked in the S phase by aphidicolin or from adenovirus-infected cells at 16 h postinfection had enhanced dihydrofolate reductase transcriptional activity. This increased in vitro transcription mimicked the increase in dihydrofolate reductase mRNA seen in S-phase cells and suggested the presence of a cell-cycle-specific factor(s) which stimulated transcription from the dihydrofolate reductase gene.

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15

Adrian, P. V., C. J. Thomson, K. P. Klugman, and S. G. B. Amyes. "Prevalence and genetic location of non-transferable trimethoprim resistant dihydrofolate reductase genes in South African commensal faecal isolates." Epidemiology and Infection 115, no. 2 (October 1995): 255–67. http://dx.doi.org/10.1017/s0950268800058386.

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SummaryIn a recent survey of trimethoprim resistance. 357 Gram-negative aerobic organisms were isolated from healthy volunteers from rural and urban populations in South Africa. Trimethoprim resistance did not transfer to anEscherichia coliJ62–2 recipient strain by conjugation in a liquid mating in 161 (45·1%) of the isolates. These isolates which did not transfer their resistance were probed with intragenic oligonucleotide probes for the types Ia. Ib. IIIa. V. VI. VII. VIII. IX. X and XII dihydrofolate reductase genes. Contrary to all previous data, the most prevalent dihydrofolate reductase gene in this group of non-transferable isolates which hybridized, was the type VII (38%) followed by the type Ia (25%). Ib (12%). V (1·7%) and VIII (1·2%). None of the strains hybridized to the types IIIa. VI. XI. X and the XII dihydrofolate reductase probes. Southern blots of plasmid and chromosomal DNA from selective isolates revealed that the type VII dihydrofolate reductase genes were located on the chromosome and were associated with the integrase gene of Tn21. However, the type Ib and V dihydrofolate reductase genes were all found on plasmids which could not be mobilized. The type Ia dihydrofolate reductase genes were found on both non-transferable plasmids and on the chromosome. The nature of the genetic structures associated with a dihydrofolate reductase gene strongly affects the means of spread of the gene in a population.

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16

Miller, A. D., M. F. Law, and I. M. Verma. "Generation of helper-free amphotropic retroviruses that transduce a dominant-acting, methotrexate-resistant dihydrofolate reductase gene." Molecular and Cellular Biology 5, no. 3 (March 1985): 431–37. http://dx.doi.org/10.1128/mcb.5.3.431-437.1985.

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We constructed several retroviruses which transduced a mutant dihydrofolate reductase gene that was resistant to methotrexate inhibition and functioned as a dominant selectable marker. The titer of dihydrofolate reductase-transducing virus produced by virus-producing cells could be increased to very high levels by selection of the cells in increasing concentrations of methotrexate. Helper virus-free dihydrofolate reductase-transducing virus was also generated by using a broad-host-range amphotropic retroviral packaging system. Cell lines producing helper-free dihydrofolate reductase-transducing virus with a titer of 4 X 10(6) per ml were generated. These retroviral vectors should have general utility for high-efficiency transduction of genes in cultured cells and in animals.

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17

Miller, A. D., M. F. Law, and I. M. Verma. "Generation of helper-free amphotropic retroviruses that transduce a dominant-acting, methotrexate-resistant dihydrofolate reductase gene." Molecular and Cellular Biology 5, no. 3 (March 1985): 431–37. http://dx.doi.org/10.1128/mcb.5.3.431.

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We constructed several retroviruses which transduced a mutant dihydrofolate reductase gene that was resistant to methotrexate inhibition and functioned as a dominant selectable marker. The titer of dihydrofolate reductase-transducing virus produced by virus-producing cells could be increased to very high levels by selection of the cells in increasing concentrations of methotrexate. Helper virus-free dihydrofolate reductase-transducing virus was also generated by using a broad-host-range amphotropic retroviral packaging system. Cell lines producing helper-free dihydrofolate reductase-transducing virus with a titer of 4 X 10(6) per ml were generated. These retroviral vectors should have general utility for high-efficiency transduction of genes in cultured cells and in animals.

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18

Sutton, Cari, R. Scott McIvor, Micki Vagt, Barbara Doggett, and Raj P. Kapur. "Methotrexate-Resistant Form of Dihydrofolate Reductase Protects Transgenic Murine Embryos from Teratogenic Effects of Methotrexate." Pediatric and Developmental Pathology 1, no. 6 (November 1998): 503–12. http://dx.doi.org/10.1007/s100249900069.

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Methotrexate, a potent inhibitor of the ubiquitously expressed enzyme dihydrofolate reductase, induces limb and facial anomalies that resemble vascular disruptions in their evolution and final outcome. Previous studies suggest that inhibition of dihydrofolate reductase is responsible for methotrexate-induced embryopathy, although specific sites of methotrexate activity have not been well defined. In this report, we show that constitutive expression of a methotrexate-resistant form of dihydrofolate reductase in transgenic embryos and their placentas ameliorates methotrexate teratogenicity. However, expression of the transgene in maternal tissues had no significant protective effect. The results confirm the role of dihydrofolate reductase inhibition in the pathogenesis of methotrexate-induced birth defects and provide a foundation for future studies of targeted transgene expression in select embryonic or placental cell populations.

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19

KLINGENBERG, Olav, and Sjur OLSNES. "Ability of methotrexate to inhibit translocation to the cytosol of dihydrofolate reductase fused to diphtheria toxin." Biochemical Journal 313, no. 2 (January 15, 1996): 647–53. http://dx.doi.org/10.1042/bj3130647.

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A fusion protein consisting of dihydrofolate reductase and diphtheria toxin A-fragment was made by genetically linking cDNA for the two proteins followed by in vitro transcription and translation in a rabbit reticulocyte lysate system. The dihydrofolate reductase in the fusion protein exhibited enzyme activity and, in the presence of methotrexate which imposes a tight structure on dihydrofolate reductase, it was trypsin resistant, indicating that it was correctly folded. When reconstituted with diphtheria toxin B-fragment, it bound specifically to diphtheria toxin receptors and was translocated into cells upon exposure to low pH. Methotrexate prevented the translocation. Protein synthesis was inhibited in cells incubated with the reconstituted fusion protein, but the inhibition was reduced in the presence of methotrexate. We also made a fusion protein containing a mutated dihydrofolate reductase with much lower affinity to methotrexate. Methotrexate did not prevent translocation of this protein. The data indicate that methotrexate prevents translocation of the fusion protein containing wild-type dihydrofolate reductase by imposing a tight structure on to the enzyme.

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20

Schilling, L. J., and P. J. Farnham. "Identification of a new promoter upstream of the murine dihydrofolate reductase gene." Molecular and Cellular Biology 9, no. 10 (October 1989): 4568–70. http://dx.doi.org/10.1128/mcb.9.10.4568-4570.1989.

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In vitro reactions identified a transcription initiation site located 740 nucleotides upstream of the dihydrofolate reductase translational start. Transcription from this site proceeded in the direction opposite to that of dihydrofolate reductase mRNA. Deletion mapping indicated that this new promoter can be separated from the dihydrofolate reductase promoter and that separation increased transcription at -740. Transcripts that initiate at -740 were also detected in cellular RNA, indicating that this is a bona fide transcription initiation site in vivo.

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21

Schilling, L. J., and P. J. Farnham. "Identification of a new promoter upstream of the murine dihydrofolate reductase gene." Molecular and Cellular Biology 9, no. 10 (October 1989): 4568–70. http://dx.doi.org/10.1128/mcb.9.10.4568.

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In vitro reactions identified a transcription initiation site located 740 nucleotides upstream of the dihydrofolate reductase translational start. Transcription from this site proceeded in the direction opposite to that of dihydrofolate reductase mRNA. Deletion mapping indicated that this new promoter can be separated from the dihydrofolate reductase promoter and that separation increased transcription at -740. Transcripts that initiate at -740 were also detected in cellular RNA, indicating that this is a bona fide transcription initiation site in vivo.

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22

Duff, Michael R., Shaileja Chopra, Michael Brad Strader, Pratul K. Agarwal, and Elizabeth E. Howell. "Tales of Dihydrofolate Binding to R67 Dihydrofolate Reductase." Biochemistry 55, no. 1 (December 21, 2015): 133–45. http://dx.doi.org/10.1021/acs.biochem.5b00981.

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23

Deng, Hua, and Robert Callender. "Structure of Dihydrofolate When Bound to Dihydrofolate Reductase." Journal of the American Chemical Society 120, no. 31 (August 1998): 7730–37. http://dx.doi.org/10.1021/ja9814974.

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24

Matherly, LH, JW Taub, Y. Ravindranath, SA Proefke, SC Wong, P. Gimotty, S. Buck, JE Wright, and A. Rosowsky. "Elevated dihydrofolate reductase and impaired methotrexate transport as elements in methotrexate resistance in childhood acute lymphoblastic leukemia." Blood 85, no. 2 (January 15, 1995): 500–509. http://dx.doi.org/10.1182/blood.v85.2.500.500.

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Abstract A retrospective study of clinical resistance to methotrexate (MTX) was performed on 29 archival specimens of frozen lymphoblasts obtained from children with acute lymphoblastic leukemia (ALL), including 19 at initial presentation and 10 at first relapse. Blasts were assayed for dihydrofolate reductase and MTX transport by flow cytometry using the fluorescent methotrexate analog, PT430 (Rosowsky et al, J Biol Chem 257:14162, 1982). In contrast to tissue culture cells, patient blasts were often heterogeneous for dihydrofolate reductase content. Of the 19 specimens at initial diagnosis, 7 exhibited dual blast populations, characterized by threefold to 10-fold differences in relative dihydrofolate reductase; the dihydrofolate reductase-overproducing populations comprised 12% to 68% of the total blasts for these specimens. Remission duration intervals for patients exhibiting dual blast populations were notably shorter than for patients expressing a single blast population with lower dihydrofolate reductase ( < or = 9 months v > or = 15 months, respectively), a difference that was statistically significant (P = .045). There was no apparent correlation between expression of increased dihydrofolate reductase at diagnosis and known patient and disease prognostic features (immunophenotype, age, sex, and white blood count). For the relapsed patients, 4 of 10 exhibited dual lymphoblast populations with elevated dihydrofolate reductase. The majority of the patient lymphoblast specimens were entirely competent for MTX transport and, likewise, expressed immunoreactive reduced folate carriers by indirect immunofluorescence staining with specific antiserum to the transporter. Three patients (2 at relapse and 1 at diagnosis) exhibited heterogeneous expression of imparied MTX transport (14% to 73% of blasts). In only 1 of these patients did the majority of the lymphoblasts (73%) show impaired MTX transport and for this specimen, immunoreactive carrier proteins were virtually undetectable. These results suggest that heterogeneous expression of elevated dihydrofolate reductase and impaired MTX transport are important modes of resistance in childhood ALL patients undergoing chemotherapy with MTX and that these parameters may serve as predictive indices of clinical response to MTX.

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25

Matherly, LH, JW Taub, Y. Ravindranath, SA Proefke, SC Wong, P. Gimotty, S. Buck, JE Wright, and A. Rosowsky. "Elevated dihydrofolate reductase and impaired methotrexate transport as elements in methotrexate resistance in childhood acute lymphoblastic leukemia." Blood 85, no. 2 (January 15, 1995): 500–509. http://dx.doi.org/10.1182/blood.v85.2.500.bloodjournal852500.

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A retrospective study of clinical resistance to methotrexate (MTX) was performed on 29 archival specimens of frozen lymphoblasts obtained from children with acute lymphoblastic leukemia (ALL), including 19 at initial presentation and 10 at first relapse. Blasts were assayed for dihydrofolate reductase and MTX transport by flow cytometry using the fluorescent methotrexate analog, PT430 (Rosowsky et al, J Biol Chem 257:14162, 1982). In contrast to tissue culture cells, patient blasts were often heterogeneous for dihydrofolate reductase content. Of the 19 specimens at initial diagnosis, 7 exhibited dual blast populations, characterized by threefold to 10-fold differences in relative dihydrofolate reductase; the dihydrofolate reductase-overproducing populations comprised 12% to 68% of the total blasts for these specimens. Remission duration intervals for patients exhibiting dual blast populations were notably shorter than for patients expressing a single blast population with lower dihydrofolate reductase ( < or = 9 months v > or = 15 months, respectively), a difference that was statistically significant (P = .045). There was no apparent correlation between expression of increased dihydrofolate reductase at diagnosis and known patient and disease prognostic features (immunophenotype, age, sex, and white blood count). For the relapsed patients, 4 of 10 exhibited dual lymphoblast populations with elevated dihydrofolate reductase. The majority of the patient lymphoblast specimens were entirely competent for MTX transport and, likewise, expressed immunoreactive reduced folate carriers by indirect immunofluorescence staining with specific antiserum to the transporter. Three patients (2 at relapse and 1 at diagnosis) exhibited heterogeneous expression of imparied MTX transport (14% to 73% of blasts). In only 1 of these patients did the majority of the lymphoblasts (73%) show impaired MTX transport and for this specimen, immunoreactive carrier proteins were virtually undetectable. These results suggest that heterogeneous expression of elevated dihydrofolate reductase and impaired MTX transport are important modes of resistance in childhood ALL patients undergoing chemotherapy with MTX and that these parameters may serve as predictive indices of clinical response to MTX.

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26

VASUDEVAN, Subhash G., Bela PAAL, and Wilfred L. F. ARMAREGO. "Dihydropteridine Reductase fromEscherichia coliExhibits Dihydrofolate Reductase Activity." Biological Chemistry Hoppe-Seyler 373, no. 2 (January 1992): 1067–74. http://dx.doi.org/10.1515/bchm3.1992.373.2.1067.

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27

WU, Jia-Wei, Zhi-Xin WANG, and Jun-Mei ZHOU. "Inactivation kinetics of dihydrofolate reductase from Chinese hamster during urea denaturation." Biochemical Journal 324, no. 2 (June 1, 1997): 395–401. http://dx.doi.org/10.1042/bj3240395.

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The kinetic theory of substrate reaction during modification of enzyme activity has been applied to the study of inactivation kinetics of Chinese hamster dihydrofolate reductase by urea [Tsou (1988) Adv. Enzymol. Relat. Areas Mol. Biol. 61, 381–436]. On the basis of the kinetic equation of substrate reaction in the presence of urea, all microscopic kinetic constants for the free enzyme and enzyme–substrate binary and ternary complexes have been determined. The results of the present study indicate that the denaturation of dihydrofolate reductase by urea follows single-phase kinetics, and changes in enzyme activity and tertiary structure proceed simultaneously in the unfolding process. Both substrates, NADPH and 7,8-dihydrofolate, protect dihydrofolate reductase against inactivation, and enzyme–substrate complexes lose their activity less rapidly than the free enzyme.

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28

Deng, Hua, Robert Callender, and Elizabeth Howell. "Vibrational Structure of Dihydrofolate Bound to R67 Dihydrofolate Reductase." Journal of Biological Chemistry 276, no. 52 (October 25, 2001): 48956–60. http://dx.doi.org/10.1074/jbc.m105107200.

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29

Giladi, Moshe, Neta Altman-Price, Itay Levin, Liat Levy, and Moshe Mevarech. "FolM, A New Chromosomally Encoded Dihydrofolate Reductase in Escherichia coli." Journal of Bacteriology 185, no. 23 (December 1, 2003): 7015–18. http://dx.doi.org/10.1128/jb.185.23.7015-7018.2003.

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ABSTRACT Escherichia coli (thyA ΔfolA) mutants are viable and can grow in minimal medium when supplemented with thymidine alone. Here we present evidence from in vivo and in vitro studies that the ydgB gene determines an alternative dihydrofolate reductase that is related to the trypanosomatid pteridine reductases. We propose to rename this gene folM.

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30

Montoya-Zavala, M., and J. L. Hamlin. "Similar 150-kilobase DNA sequences are amplified in independently derived methotrexate-resistant Chinese hamster cells." Molecular and Cellular Biology 5, no. 4 (April 1985): 619–27. http://dx.doi.org/10.1128/mcb.5.4.619-627.1985.

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We have isolated overlapping recombinant cosmids that represent 150 kilobases of contiguous DNA sequence from the amplified dihydrofolate reductase domain of a methotrexate-resistant Chinese hamster ovary cell line (CHOC 400). This sequence includes the 25-kilobase dihydrofolate reductase gene and an origin of DNA synthesis. Eight cosmids that span this domain have been utilized as radioactive hybridization probes to analyze the similarities among the dihydrofolate reductase amplicons in four independently derived methotrexate-resistant Chinese hamster cell lines. We have observed no significant differences among the four cell lines within the 150-kilobase DNA sequence that we have examined, except for polymorphisms that result from the amplification of one or the other of two possible alleles of the dihydrofolate reductase domain. We also show that the restriction patterns of the amplicons in these four resistant cell lines are virtually identical to that of the corresponding, unamplified sequence in drug-susceptible parental cells. Furthermore, measurements of the relative copy numbers of fragments from widely separated regions of the amplicon suggest that all fragments in this 150-kilobase region may be amplified in unison. Our data show that in methotrexate-resistant Chinese hamster cells, the amplified unit is large relative to the dihydrofolate reductase gene itself. Furthermore, within the 150-kilobase amplified consensus sequence that we have examined, significant rearrangements do not seem to occur during the amplification process.

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31

Montoya-Zavala, M., and J. L. Hamlin. "Similar 150-kilobase DNA sequences are amplified in independently derived methotrexate-resistant Chinese hamster cells." Molecular and Cellular Biology 5, no. 4 (April 1985): 619–27. http://dx.doi.org/10.1128/mcb.5.4.619.

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We have isolated overlapping recombinant cosmids that represent 150 kilobases of contiguous DNA sequence from the amplified dihydrofolate reductase domain of a methotrexate-resistant Chinese hamster ovary cell line (CHOC 400). This sequence includes the 25-kilobase dihydrofolate reductase gene and an origin of DNA synthesis. Eight cosmids that span this domain have been utilized as radioactive hybridization probes to analyze the similarities among the dihydrofolate reductase amplicons in four independently derived methotrexate-resistant Chinese hamster cell lines. We have observed no significant differences among the four cell lines within the 150-kilobase DNA sequence that we have examined, except for polymorphisms that result from the amplification of one or the other of two possible alleles of the dihydrofolate reductase domain. We also show that the restriction patterns of the amplicons in these four resistant cell lines are virtually identical to that of the corresponding, unamplified sequence in drug-susceptible parental cells. Furthermore, measurements of the relative copy numbers of fragments from widely separated regions of the amplicon suggest that all fragments in this 150-kilobase region may be amplified in unison. Our data show that in methotrexate-resistant Chinese hamster cells, the amplified unit is large relative to the dihydrofolate reductase gene itself. Furthermore, within the 150-kilobase amplified consensus sequence that we have examined, significant rearrangements do not seem to occur during the amplification process.

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32

Navarro-Martínez, María Dolores, Enma Navarro-Perán, Juan Cabezas-Herrera, Joaquín Ruiz-Gómez, Francisco García-Cánovas, and José Neptuno Rodríguez-López. "Antifolate Activity of Epigallocatechin Gallate against Stenotrophomonas maltophilia." Antimicrobial Agents and Chemotherapy 49, no. 7 (July 2005): 2914–20. http://dx.doi.org/10.1128/aac.49.7.2914-2920.2005.

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ABSTRACT The catechin epigallocatechin gallate, one of the main constituents of green tea, showed strong antibiotic activity against 18 isolates of Stenotrophomonas maltophilia (MIC range, 4 to 256 μg/ml). In elucidating its mechanism of action, we have shown that epigallocatechin gallate is an efficient inhibitor of S. maltophilia dihydrofolate reductase, a strategic enzyme that is considered an attractive target for the development of antibacterial agents. The inhibition of S. maltophilia dihydrofolate reductase by this tea compound was studied and compared with the mechanism of a nonclassical antifolate compound, trimethoprim. Investigation of dihydrofolate reductase was undertaken with both a trimethoprim-susceptible S. maltophilia isolate and an isolate with a high level of resistance. The enzymes were purified using ammonium sulfate precipitation, gel filtration, and methotrexate affinity chromatography. The two isolates showed similar levels of dihydrofolate reductase expression and similar substrate kinetics. However, the dihydrofolate reductase from the trimethoprim-resistant isolate demonstrated decreased susceptibility to inhibition by trimethoprim and epigallocatechin gallate. As with other antifolates, the action of epigallocatechin gallate was synergistic with that of sulfamethoxazole, a drug that blocks folic acid metabolism in bacteria, and the inhibition of bacterial growth was attenuated by including leucovorin in the growth medium. We conclude that the mechanism of action of epigallocatechin gallate on S. maltophilia is related to its antifolate activity.

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33

Takahashi, H., M. Ozawa, C. Yamane, and M. Iwakura. "Mutation Analysis of Dihydrofolate Reductase." Seibutsu Butsuri 41, supplement (2001): S96. http://dx.doi.org/10.2142/biophys.41.s96_1.

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34

Villafranca, J. E., E. E. Howell, S. J. Oatley, M. S. Warren, C. David, J. Hirai, and J. Kraut. "Structures of engineered dihydrofolate reductase." Acta Crystallographica Section A Foundations of Crystallography 43, a1 (August 12, 1987): C320. http://dx.doi.org/10.1107/s0108767387076839.

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35

Münzel, Thomas, and Andreas Daiber. "Redox Regulation of Dihydrofolate Reductase." Arteriosclerosis, Thrombosis, and Vascular Biology 35, no. 11 (November 2015): 2261–62. http://dx.doi.org/10.1161/atvbaha.115.306556.

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36

Myllykallio, Hannu, Damien Leduc, Jonathan Filee, and Ursula Liebl. "Life without dihydrofolate reductase FolA." Trends in Microbiology 11, no. 5 (May 2003): 220–23. http://dx.doi.org/10.1016/s0966-842x(03)00101-x.

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37

Beard, W. A., J. R. Appleman, T. J. Delcamp, J. H. Freisheim, and R. L. Blakley. "Hydride Transfer by Dihydrofolate Reductase." Journal of Biological Chemistry 264, no. 16 (June 1989): 9391–99. http://dx.doi.org/10.1016/s0021-9258(18)60544-7.

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38

Hitchings, George H. "Selective inhibitors of dihydrofolate reductase." In Vitro Cellular & Developmental Biology 25, no. 4 (April 1989): 303–10. http://dx.doi.org/10.1007/bf02624591.

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39

Hamlin, Joyce L., and Chi Ma. "The mammalian dihydrofolate reductase locus." Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression 1087, no. 2 (October 1990): 107–25. http://dx.doi.org/10.1016/0167-4781(90)90195-8.

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40

Huennekens, F. M. "In search of dihydrofolate reductase." Protein Science 5, no. 6 (June 1996): 1201–8. http://dx.doi.org/10.1002/pro.5560050626.

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41

Chu, Edward, Chris H. Takimoto, Donna Voeller, Jean L. Grem, and Carmen J. Allegra. "Specific binding of human dihydrofolate reductase protein to dihydrofolate reductase messenger RNA in vitro." Biochemistry 32, no. 18 (May 11, 1993): 4756–60. http://dx.doi.org/10.1021/bi00069a009.

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42

Means, A. L., and P. J. Farnham. "Transcription initiation from the dihydrofolate reductase promoter is positioned by HIP1 binding at the initiation site." Molecular and Cellular Biology 10, no. 2 (February 1990): 653–61. http://dx.doi.org/10.1128/mcb.10.2.653-661.1990.

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We have identified a sequence element that specifies the position of transcription initiation for the dihydrofolate reductase gene. Unlike the functionally analogous TATA box that directs RNA polymerase II to initiate transcription 30 nucleotides downstream, the positioning element of the dihydrofolate reductase promoter is located directly at the site of transcription initiation. By using DNase I footprint analysis, we have shown that a protein binds to this initiator element. Transcription initiated at the dihydrofolate reductase initiator element when 28 nucleotides were inserted between it and all other upstream sequences, or when it was placed on either side of the DNA helix, suggesting that there is no strict spatial requirement between the initiator and an upstream element. Although neither a single Sp1-binding site nor a single initiator element was sufficient for transcriptional activity, the combination of one Sp1-binding site and the dihydrofolate reductase initiator element cloned into a plasmid vector resulted in transcription starting at the initiator element. We have also shown that the simian virus 40 late major initiation site has striking sequence homology to the dihydrofolate reductase initiation site and that the same, or a similar, protein binds to both sites. Examination of the sequences at other RNA polymerase II initiation sites suggests that we have identified an element that is important in the transcription of other housekeeping genes. We have thus named the protein that binds to the initiator element HIP1 (Housekeeping Initiator Protein 1).

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43

Means, A. L., and P. J. Farnham. "Transcription initiation from the dihydrofolate reductase promoter is positioned by HIP1 binding at the initiation site." Molecular and Cellular Biology 10, no. 2 (February 1990): 653–61. http://dx.doi.org/10.1128/mcb.10.2.653.

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We have identified a sequence element that specifies the position of transcription initiation for the dihydrofolate reductase gene. Unlike the functionally analogous TATA box that directs RNA polymerase II to initiate transcription 30 nucleotides downstream, the positioning element of the dihydrofolate reductase promoter is located directly at the site of transcription initiation. By using DNase I footprint analysis, we have shown that a protein binds to this initiator element. Transcription initiated at the dihydrofolate reductase initiator element when 28 nucleotides were inserted between it and all other upstream sequences, or when it was placed on either side of the DNA helix, suggesting that there is no strict spatial requirement between the initiator and an upstream element. Although neither a single Sp1-binding site nor a single initiator element was sufficient for transcriptional activity, the combination of one Sp1-binding site and the dihydrofolate reductase initiator element cloned into a plasmid vector resulted in transcription starting at the initiator element. We have also shown that the simian virus 40 late major initiation site has striking sequence homology to the dihydrofolate reductase initiation site and that the same, or a similar, protein binds to both sites. Examination of the sequences at other RNA polymerase II initiation sites suggests that we have identified an element that is important in the transcription of other housekeeping genes. We have thus named the protein that binds to the initiator element HIP1 (Housekeeping Initiator Protein 1).

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44

Basco, Leonardo K., Rachida Tahar, and Pascal Ringwald. "Molecular Basis of In Vivo Resistance to Sulfadoxine-Pyrimethamine in African Adult Patients Infected withPlasmodium falciparum Malaria Parasites." Antimicrobial Agents and Chemotherapy 42, no. 7 (July 1, 1998): 1811–14. http://dx.doi.org/10.1128/aac.42.7.1811.

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ABSTRACT In vitro sulfadoxine and pyrimethamine resistance has been associated with point mutations in the dihydropteroate synthase and dihydrofolate reductase domains, respectively, but the in vivo relevance of these point mutations has not been well established. To analyze the correlation between genotype and phenotype, 10 Cameroonian adult patients were treated with sulfadoxine-pyrimethamine and followed up for 28 days. After losses to follow-up (n = 1) or elimination of DNA samples due to mixed parasite populations with pyrimethamine-sensitive and pyrimethamine-resistant profiles (n = 3), parasite genomic DNA from day 0 blood samples of six patients were analyzed by DNA sequencing. Three patients who were cured had isolates characterized by a wild-type or mutant dihydrofolate reductase gene (with one or two mutations) and a wild-type dihydropteroate synthase gene. Three other patients who failed to respond to sulfadoxine-pyrimethamine treatment carried isolates with triple dihydrofolate reductase gene mutations and either a wild-type or a mutant dihydropteroate synthase gene. Three dihydrofolate reductase gene codons (51, 59, and 108) may be reliable genetic markers that can accurately predict the clinical outcome of sulfadoxine-pyrimethamine treatment in Africa.

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45

WU, Jia-Wei, and Zhi-Xin WANG. "Activation mechanism and modification kinetics of Chinese hamster dihydrofolate reductase by p-chloromercuribenzoate." Biochemical Journal 335, no. 1 (October 1, 1998): 181–89. http://dx.doi.org/10.1042/bj3350181.

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Substrate effects on the activation kinetics of Chinese hamster dihydrofolate reductase by p-chloromercuribenzoate (pCMB) have been studied. On the basis of the kinetic equation of substrate reaction in the presence of pCMB, all modification kinetic constants for the free enzyme and enzyme–substrate binary and ternary complexes have been determined. The results of the present study indicate that the modification of Chinese hamster dihydrofolate reductase by pCMB shows single-phase kinetics, and that changes in the enzyme activity and tertiary structure proceed simultaneously during the modification process. Both substrates, NADPH and 7,8-dihydrofolate, protect dihydrofolate reductase against modification by pCMB. In the presence of a saturating concentration of NADPH, the value of kcat for 7,8-dihydrofolate in the enzyme-catalysed reaction increased four-fold on modification of Cys-6, accompanied by a two-fold increase in Km for the modified enzyme. The utilization of the binding energy of a group to increase kcat rather than reduce Km implies that the full binding energy of the group is not realized in the formation of the enzyme–substrate complex, but is used to stabilize the enzyme–transition-state complex.

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46

Cody, Vivian, Qilong Mao, and Sherry F. Queener. "Recombinant bovine dihydrofolate reductase produced by mutagenesis and nested PCR of murine dihydrofolate reductase cDNA." Protein Expression and Purification 62, no. 1 (November 2008): 104–10. http://dx.doi.org/10.1016/j.pep.2008.07.001.

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47

Xu, Ying, Georges Feller, Charles Gerday, and Nicolas Glansdorff. "Moritella Cold-Active Dihydrofolate Reductase: Are There Natural Limits to Optimization of Catalytic Efficiency at Low Temperature?" Journal of Bacteriology 185, no. 18 (September 15, 2003): 5519–26. http://dx.doi.org/10.1128/jb.185.18.5519-5526.2003.

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ABSTRACT Adapting metabolic enzymes of microorganisms to low temperature environments may require a difficult compromise between velocity and affinity. We have investigated catalytic efficiency in a key metabolic enzyme (dihydrofolate reductase) of Moritella profunda sp. nov., a strictly psychrophilic bacterium with a maximal growth rate at 2°C or less. The enzyme is monomeric (M r = 18,291), 55% identical to its Escherichia coli counterpart, and displays Tm and denaturation enthalpy changes much lower than E. coli and Thermotoga maritima homologues. Its stability curve indicates a maximum stability above the temperature range of the organism, and predicts cold denaturation below 0°C. At mesophilic temperatures the apparent Km value for dihydrofolate is 50- to 80-fold higher than for E. coli, Lactobacillus casei, and T. maritima dihydrofolate reductases, whereas the apparent Km value for NADPH, though higher, remains in the same order of magnitude. At 5°C these values are not significantly modified. The enzyme is also much less sensitive than its E. coli counterpart to the inhibitors methotrexate and trimethoprim. The catalytic efficiency (k cat /Km ) with respect to dihydrofolate is thus much lower than in the other three bacteria. The higher affinity for NADPH could have been maintained by selection since NADPH assists the release of the product tetrahydrofolate. Dihydrofolate reductase adaptation to low temperature thus appears to have entailed a pronounced trade-off between affinity and catalytic velocity. The kinetic features of this psychrophilic protein suggest that enzyme adaptation to low temperature may be constrained by natural limits to optimization of catalytic efficiency.

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48

Herrington, Muriel B., and Neema T. Chirwa. "Growth properties of afolAnull mutant ofEscherichia coliK12." Canadian Journal of Microbiology 45, no. 3 (March 1, 1999): 191–200. http://dx.doi.org/10.1139/w98-229.

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In Escherichia coli, dihydrofolate reductase is required for both the de novo synthesis of tetrahydrofolate and the recycling of dihydrofolate produced during the synthesis of thymidylate. The coding region of the dihydrofolate reductase gene, folA, was replaced with a kanamycin resistance determinant. Unlike earlier deletions, this mutation did not disrupt flanking genes. When the mutation was transferred into a wild-type strain and a thymidine- (thy) requiring strain, the resulting strains were viable but slow growing on rich medium. Both synthesized less folate than their parents, as judged by the incorporation of radioactive para-aminobenzoic acid. The derivative of the wild-type strain did not grow on any defined minimal media tested. In contrast, the derivative of the thy-requiring strain grew slowly on minimal medium with thy but exhibited auxotrophies on some combinations of supplements. These results suggest that when folates are limited, they can be distributed appropriately to folate-dependent biosynthetic reactions only under some conditions. Key words: dihydrofolate reductase, Escherichia coli, biosynthesis, folates, one-carbon metabolism.

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49

Katayanagi, K., Y. Kamiya, T. Sato, E. Ohmae, and K. Gekko. "Crystal structure of dihydrofolate reductase mutants." Seibutsu Butsuri 40, supplement (2000): S122. http://dx.doi.org/10.2142/biophys.40.s122_1.

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50

IQBAL, M. PERWAIZ, N. MEHBOOBALI, M. ANWAR WAQAR, and HINA S. ZUBERI. "Dihydrofolate reductase from a reptile, uromastix." Biochemical Society Transactions 19, no. 2 (April 1, 1991): 193S. http://dx.doi.org/10.1042/bst019193s.

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