Disease relevance of C00415

• As 7-hydroxy-MTX is a 200 fold less potent dihydrofolic acid reductase inhibitor compared with MTX decreased production of the metabolite may lead to enhanced clinical toxicity which may not be predictable monitoring MTX serum levels alone [1].

High impact information on C00415

• One of the origins, oriS14, is located within or adjacent to the coding sequence for ribosomal protein S14 on chromosome 2q, and the other, ori-beta, is approximately 17 kbp downstream of the dhfr (dihydrofolic acid reductase) locus on chromosome 2p [2].
• Isolation and characterization of dihydrofolic acid reductase from methotrexate-sensitive and -resistant human cell lines [3].
• The human dihydrofolic acid reductase has an apparent molecular weight of 21,000 to 22,000, a Km for folic acid of 6.1 to 7.6 X 10(-6) M and a Km for TPNH of 1.6 to 1.7 X 10(-4) M, turnover numbers of about 500 and 65 mol/min/mol of enzyme for the dihydrofolic acid reductase and the folic acid reductase activity, respectively [3].
• The available evidence indicates that this increased dihydrofolic acid reductase content results from a hyperproduction of an enzyme identical or similar to that of the sensitive cells, presumably due to a selective dihydrofolic acid reductase gene amplification, as previously reported for other cell lines of rodent origin [3].
• Substitution of the GTG codon by an AG codon using in vitro mutagenesis overcomes this block; cells transfected with the modified vector synthesize a functional prokaryotic protein that sustains the growth of these cells in the presence of dihydrofolic acid in the culture media [4].

Biological context of C00415

• The nucleotide sequence of the cDNA coding for the human dihydrofolic acid reductase [5].

Anatomical context of C00415

• Similarly, 5-formyltetrahydrofolic acid (FTHF) produced a marked hypermotility response after bilateral injection into the nucleus accumbens (2.5-25 micrograms), while dihydrofolic acid, tetrahydrofolic acid, and 5-methyltetrahydrofolic acid were ineffective [6].

Associations of C00415 with other chemical compounds

• The standard assay for P. carinii dihydrofolate reductase contained 0.12 mM NADPH and 92 microM dihydrofolic acid [7].
• In the presence of dihydrofolate reductase (EC 1.5.1.3), dihydrofolic acid is converted to tetrahydrofolate [8].
• These findings suggest that TMP produces some degree of inhibition of dihydrofolic acid reductase in mammalian cells and can potentially influence the effects of chemotherapy on tumour and/or host cells [9].
• Although pyrimethamine did not show laboratory evidence of potentiation with atovaquone, it was chosen as an alternative inhibitor of dihydrofolic acid reductase with a longer half-life than proguanil [10].

Gene context of C00415

• Thymidylate synthetase and dihydrofolic acid reductase in the stimulated human lymphocyte [11].
• The enzyme from the resistant cells can be protected against heat inactivation by either dihydrofolic acid or NADPH, or both [12].
• A study was undertaken to ascertain whether dihydrofolic acid is produced in the complex formed with 5,10-methylenetetrahydrofolate, 5-fluorodeoxyuridylate and thymidylate synthetase, as suggested by ultraviolet difference spectral studies [13].
• Similarly dihydrofolic acid microinfused into the same area produced an intense pattern of stereotyped movements, circling and high voltage electrocortical spikes, sharp waves and other abnormalities similar is those occurring in human epilepsy [14].

Analytical, diagnostic and therapeutic context of C00415

• 5. Addition by dihydrofolic acid or methotrexate prior to the isoelectric focusing did not change the behavior of the enzymes [15].

References