| 词条 | Dihydrofolate reductase |
| 释义 |
| Name = Dihydrofolate reductase | EC_number = 1.5.1.3 | CAS_number = 9002-03-3 | IUBMB_EC_number = 1/5/1/3 | GO_code = 0004146 | image = PDB 8dfr EBI.jpg | width = | caption = Crystal structure of chicken liver dihydrofolate reductase. PDB entry {{PDBe|8dfr}} }}{{Infobox protein family | Symbol = DHFR_1 | Name = Dihydrofolate reductase | image = | width = | caption = | Pfam = PF00186 | Pfam_clan = CL0387 | InterPro = IPR001796 | SMART = | PROSITE = PDOC00072 | MEROPS = | SCOP = 1dhi | TCDB = | OPM family = | OPM protein = | CAZy = | CDD = }}{{Infobox protein family | Symbol = DHFR_2 | Name = R67 dihydrofolate reductase | image = PDB 2gqv EBI.jpg | width = | caption = High-resolution structure of a plasmid-encoded dihydrofolate reductase from E.coli. PDB entry {{PDBe|2gqv}} | Pfam = PF06442 | Pfam_clan = | InterPro = IPR009159 | SMART = | PROSITE = | MEROPS = | SCOP = 1vif | TCDB = | OPM family = | OPM protein = | CAZy = | CDD = }}{{Infobox_gene}}Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry. In humans, the DHFR enzyme is encoded by the DHFR gene.[1][2] It is found in the q11→q22 region of chromosome 5.[3] Bacterial species possess distinct DHFR enzymes (based on their pattern of binding diaminoheterocyclic molecules), but mammalian DHFRs are highly similar.[4] StructureA central eight-stranded beta-pleated sheet makes up the main feature of the polypeptide backbone folding of DHFR.[5] Seven of these strands are parallel and the eighth runs antiparallel. Four alpha helices connect successive beta strands.[6] Residues 9 – 24 are termed "Met20" or "loop 1" and, along with other loops, are part of the major subdomain that surround the active site.[7] The active site is situated in the N-terminal half of the sequence, which includes a conserved Pro-Trp dipeptide; the tryptophan has been shown to be involved in the binding of substrate by the enzyme.[8] {{Gallery| width=312 | height = 351 | Image:DHFRfolateNADPH.png|Human DHFR with bound dihydrofolate and NADPH }} FunctionDihydrofolate reductase converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidylic acid, and certain amino acids. While the functional dihydrofolate reductase gene has been mapped to chromosome 5, multiple intronless processed pseudogenes or dihydrofolate reductase-like genes have been identified on separate chromosomes.[9] {{Gallery| width=400 | Image:DHFR rxn.svg|Reaction catalyzed by DHFR. | Image:THFsynthesispathway.png|Tetrahydrofolate synthesis pathway. }} Found in all organisms, DHFR has a critical role in regulating the amount of tetrahydrofolate in the cell. Tetrahydrofolate and its derivatives are essential for purine and thymidylate synthesis, which are important for cell proliferation and cell growth.[10] DHFR plays a central role in the synthesis of nucleic acid precursors, and it has been shown that mutant cells that completely lack DHFR require glycine, an amino acid, and thymidine to grow.[11] DHFR has also been demonstrated as an enzyme involved in the salvage of tetrahydrobiopterin from dihydrobiopterin[12] MechanismGeneral mechanismDHFR catalyzes the transfer of a hydride from NADPH to dihydrofolate with an accompanying protonation to produce tetrahydrofolate.[10] In the end, dihydrofolate is reduced to tetrahydrofolate and NADPH is oxidized to NADP+. The high flexibility of Met20 and other loops near the active site play a role in promoting the release of the product, tetrahydrofolate. In particular the Met20 loop helps stabilize the nicotinamide ring of the NADPH to promote the transfer of the hydride from NADPH to dihydrofolate.[7] The mechanism of this enzyme is stepwise and steady-state random. Specifically, the catalytic reaction begins with the NADPH and the substrate attaching to the binding site of the enzyme, followed by the protonation and the hydride transfer from the cofactor NADPH to the substrate. However, two latter steps do not take place simultaneously in a same transition state.[15][13] In a study using computational and experimental approaches, Liu et al conclude that the protonation step precedes the hydride transfer.[14] DHFR's enzymatic mechanism is shown to be pH dependent, particularly the hydride transfer step, since pH changes are shown to have remarkable influence on the electrostatics of the active site and the ionization state of its residues.[14] The acidity of the targeted nitrogen on the substrate is important in the binding of the substrate to the enzyme's binding site which is proved to be hydrophobic even though it has direct contact to water.[15][15] Asp27 is the only charged hydrophilic residue in the binding site, and neutralization of the charge on Asp27 may alter the pKa of the enzyme. Asp27 plays a critical role in the catalytic mechanism by helping with protonation of the substrate and restraining the substrate in the conformation favorable for the hydride transfer.[21][15][15] The protonation step is shown to be associated with enol tautomerization even though this conversion is not considered favorable for the proton donation.[13] A water molecule is proved to be involved in the protonation step.[16][26][17] Entry of the water molecule to the active site of the enzyme is facilitated by the Met20 loop.[18] Conformational changes of DHFRThe catalytic cycle of the reaction catalyzed by DHFR incorporates five important intermediate: holoenzyme (E:NADPH), Michaelis complex (E:NADPH:DHF), ternary product complex (E:NADP+:THF), tetrahydrofolate binary complex (E:THF), and THF‚NADPH complex (E:NADPH:THF). The product (THF) dissociation step from E:NADPH:THF to E:NADPH is the rate determining step during steady-state turnover.[19] Conformational changes are critical in DHFR's catalytic mechanism.[20] The Met20 loop of DHFR is able to open, close or occlude the active site.[21][22] Correspondingly, three different conformations classified as the opened, closed and occluded states are assigned to Met20. In addition, an extra distorted conformation of Met20 was defined due to its indistinct characterization results.[21] The Met20 loop is observed in its occluded conformation in the three product ligating intermediates, where the nicotinamide ring is occluded from the active site. This conformational feature accounts for the fact that the substitution of NADP+ by NADPH is prior to product dissociation. Thus, the next round of reaction can occur upon the binding of substrate.[19] R67 DHFRDue to its unique structure and catalytic features, R67 DHFR is widely studied. R67 DHFR is a type II R-plasmid-encoded DHFR without genetically and structurally relation to the E. coli chromosomal DHFR. It is a homotetramer that possesses the 222 symmetry with a single active site pore that is exposed to solvent[null .][23] This symmetry of active site results in the different binding mode of the enzyme: It can bind with two dihydrofolate (DHF) molecules with positive cooperativity or two NADPH molecules with negative cooperativity, or one substrate plus one, but only the latter one has the catalytical activity.[24] Compare with E. coli chromosomal DHFR, it has higher Km in binding dihydrofolate (DHF) and NADPH. The much lower catalytical kinetics show that hydride transfer is the rate determine step rather than product (THF) release.[25] In the R67 DHFR structure, the homotetramer forms an active site pore. In the catalytical process, DHF and NADPH enters into the pore from opposite position. The π-π stacking interaction between NADPH's nicotinamide ring and DHF's pteridine ring tightly connect two reactants in the active site. However, the flexibility of p-aminobenzoylglutamate tail of DHF was observed upon binding which can promote the formation of the transition state.[26] Clinical significanceDihydrofolate reductase deficiency has been linked to megaloblastic anemia.[9] Treatment is with reduced forms of folic acid. Because tetrahydrofolate, the product of this reaction, is the active form of folate in humans, inhibition of DHFR can cause functional folate deficiency. DHFR is an attractive pharmaceutical target for inhibition due to its pivotal role in DNA precursor synthesis. Trimethoprim, an antibiotic, inhibits bacterial DHFR while methotrexate, a chemotherapy agent, inhibits mammalian DHFR. However, resistance has developed against some drugs, as a result of mutational changes in DHFR itself.[27]DHFR mutations cause a rare autosomal recessive inborn error of folate metabolism that results in megaloblastic anemia, pancytopenia and severe cerebral folate deficiency which can be corrected by folinic acid supplementation .[28][29] Therapeutic applications{{main article|Dihydrofolate reductase inhibitor}}Since folate is needed by rapidly dividing cells to make thymine, this effect may be used to therapeutic advantage. DHFR can be targeted in the treatment of cancer and as a potential target against bacterial infections. DHFR is responsible for the levels of tetrahydrofolate in a cell, and the inhibition of DHFR can limit the growth and proliferation of cells that are characteristic of cancer and bacterial infections. Methotrexate, a competitive inhibitor of DHFR, is one such anticancer drug that inhibits DHFR.[30] Other drugs include trimethoprim and pyrimethamine. These three are widely used as antitumor and antimicrobial agents.[31] Other classes of compounds that target DHFR in general, and bacterial DHFRs in particular, belong to the classes such as diaminopteridines, diaminotriazines, diaminopyrroloquinazolines, stilbenes, chalcones, deoxybenzoins, to name but a few.[32] Trimethoprim has shown to have activity against a variety of Gram-positive bacterial pathogens.[33] However, resistance to trimethoprim and other drugs aimed at DHFR can arise due to a variety of mechanisms, limiting the success of their therapeutical uses.[34][35][36] Resistance can arise from DHFR gene amplification, mutations in DHFR, decrease in the uptake of the drugs, among others. Regardless, trimethoprim and sulfamethoxazole in combination has been used as an antibacterial agent for decades.[33] Folate is necessary for growth,[37] and the pathway of the metabolism of folate is a target in developing treatments for cancer. DHFR is one such target. A regimen of fluorouracil, doxorubicin, and methotrexate was shown to prolong survival in patients with advanced gastric cancer.[38] Further studies into inhibitors of DHFR can lead to more ways to treat cancer. Bacteria also need DHFR to grow and multiply and hence inhibitors selective for bacterial DHFR have found application as antibacterial agents.[33] Classes of small-molecules employed as inhibitors of dihydrofolate reductase include diaminoquinazoline & diaminopyrroloquinazoline,[39] diaminopyrimidine, diaminopteridine and diaminotriazines.[40] Potential anthrax treatmentDihydrofolate reductase from Bacillus anthracis (BaDHFR) a validated drug target in the treatment of the infectious disease, anthrax. BaDHFR is less sensitive to trimethoprim analogs than is dihydrofolate reductase from other species such as Escherichia coli, Staphylococcus aureus, and Streptococcus pneumoniae. A structural alignment of dihydrofolate reductase from all four species shows that only BaDHFR has the combination phenylalanine and tyrosine in positions 96 and 102, respectively. BaDHFR's resistance to trimethoprim analogs is due to these two residues (F96 and Y102), which also confer improved kinetics and catalytic efficiency.[41] Current research uses active site mutants in BaDHFR to guide lead optimization for new antifolate inhibitors.[41] As a research toolDHFR has been used as a tool to detect protein–protein interactions in a protein-fragment complementation assay (PCA). CHO cellsDHFR lacking CHO cells are the most commonly used cell line for the production of recombinant proteins. These cells are transfected with a plasmid carrying the dhfr gene and the gene for the recombinant protein in a single expression system, and then subjected to selective conditions in thymidine-lacking medium. Only the cells with the exogenous DHFR gene along with the gene of interest survive. InteractionsDihydrofolate reductase has been shown to interact with GroEL[42] and Mdm2.[43] Interactive pathway map{{FluoropyrimidineActivity WP1601|highlight=Dihydrofolate_reductase}}References1. ^{{cite journal | vauthors = Chen MJ, Shimada T, Moulton AD, Harrison M, Nienhuis AW | title = Intronless human dihydrofolate reductase genes are derived from processed RNA molecules | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 79 | issue = 23 | pages = 7435–9 | date = December 1982 | pmid = 6961421 | pmc = 347354 | doi = 10.1073/pnas.79.23.7435 }} 2. ^{{cite journal | vauthors = Chen MJ, Shimada T, Moulton AD, Cline A, Humphries RK, Maizel J, Nienhuis AW | title = The functional human dihydrofolate reductase gene | journal = The Journal of Biological Chemistry | volume = 259 | issue = 6 | pages = 3933–43 | date = March 1984 | pmid = 6323448 | doi = | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=6323448 }} 3. ^{{cite journal | vauthors = Funanage VL, Myoda TT, Moses PA, Cowell HR | title = Assignment of the human dihydrofolate reductase gene to the q11----q22 region of chromosome 5 | journal = Molecular and Cellular Biology | volume = 4 | issue = 10 | pages = 2010–6 | date = October 1984 | pmid = 6504041 | pmc = 369017 | doi = 10.1128/mcb.4.10.2010 }} 4. ^{{cite journal | vauthors = Smith SL, Patrick P, Stone D, Phillips AW, Burchall JJ | title = Porcine liver dihydrofolate reductase. Purification, properties, and amino acid sequence | journal = The Journal of Biological Chemistry | volume = 254 | issue = 22 | pages = 11475–84 | date = November 1979 | pmid = 500653 | doi = }} 5. ^{{cite journal | vauthors = Matthews DA, Alden RA, Bolin JT, Freer ST, Hamlin R, Xuong N, Kraut J, Poe M, Williams M, Hoogsteen K | title = Dihydrofolate reductase: x-ray structure of the binary complex with methotrexate | journal = Science | volume = 197 | issue = 4302 | pages = 452–5 | date = July 1977 | pmid = 17920 | doi = 10.1126/science.17920 }} 6. ^{{cite journal | vauthors = Filman DJ, Bolin JT, Matthews DA, Kraut J | title = Crystal structures of Escherichia coli and Lactobacillus casei dihydrofolate reductase refined at 1.7 A resolution. II. Environment of bound NADPH and implications for catalysis | journal = The Journal of Biological Chemistry | volume = 257 | issue = 22 | pages = 13663–72 | date = November 1982 | pmid = 6815179 }} 7. ^1 {{cite journal|authorlink4=Jane Dyson | vauthors = Osborne MJ, Schnell J, Benkovic SJ, Dyson HJ, Wright PE | title = Backbone dynamics in dihydrofolate reductase complexes: role of loop flexibility in the catalytic mechanism | journal = Biochemistry | volume = 40 | issue = 33 | pages = 9846–59 | date = August 2001 | pmid = 11502178 | doi = 10.1021/bi010621k }} 8. ^{{cite journal | vauthors = Bolin JT, Filman DJ, Matthews DA, Hamlin RC, Kraut J | title = Crystal structures of Escherichia coli and Lactobacillus casei dihydrofolate reductase refined at 1.7 A resolution. I. General features and binding of methotrexate | journal = The Journal of Biological Chemistry | volume = 257 | issue = 22 | pages = 13650–62 | date = November 1982 | pmid = 6815178 | doi = }} 9. ^1 {{cite web | title = Entrez Gene: DHFR dihydrofolate reductase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1719| accessdate = }} 10. ^1 {{cite journal | vauthors = Schnell JR, Dyson HJ, Wright PE | title = Structure, dynamics, and catalytic function of dihydrofolate reductase | journal = Annual Review of Biophysics and Biomolecular Structure | volume = 33 | issue = 1 | pages = 119–40 | year = 2004 | pmid = 15139807 | doi = 10.1146/annurev.biophys.33.110502.133613 }} 11. ^{{cite journal | vauthors = Urlaub G, Chasin LA | title = Isolation of Chinese hamster cell mutants deficient in dihydrofolate reductase activity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 77 | issue = 7 | pages = 4216–20 | date = July 1980 | pmid = 6933469 | pmc = 349802 | doi = 10.1073/pnas.77.7.4216 }} 12. ^{{cite journal | vauthors = Crabtree MJ, Tatham AL, Hale AB, Alp NJ, Channon KM | title = Critical role for tetrahydrobiopterin recycling by dihydrofolate reductase in regulation of endothelial nitric-oxide synthase coupling: relative importance of the de novo biopterin synthesis versus salvage pathways | journal = The Journal of Biological Chemistry | volume = 284 | issue = 41 | pages = 28128–36 | date = October 2009 | pmid = 19666465 | pmc = 2788863 | doi = 10.1074/jbc.M109.041483 }} 13. ^1 {{cite journal | vauthors = Wan Q, Bennett BC, Wilson MA, Kovalevsky A, Langan P, Howell EE, Dealwis C | title = Toward resolving the catalytic mechanism of dihydrofolate reductase using neutron and ultrahigh-resolution X-ray crystallography | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 51 | pages = 18225–30 | date = December 2014 | pmid = 25453083 | pmc = 4280638 | doi = 10.1073/pnas.1415856111 }} 14. ^1 {{cite journal | vauthors = Liu CT, Francis K, Layfield JP, Huang X, Hammes-Schiffer S, Kohen A, Benkovic SJ | title = Escherichia coli dihydrofolate reductase catalyzed proton and hydride transfers: temporal order and the roles of Asp27 and Tyr100 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 51 | pages = 18231–6 | date = December 2014 | pmid = 25453098 | pmc = 4280594 | doi = 10.1073/pnas.1415940111 }} 15. ^1 {{cite journal | vauthors = Czekster CM, Vandemeulebroucke A, Blanchard JS | title = Kinetic and chemical mechanism of the dihydrofolate reductase from Mycobacterium tuberculosis | journal = Biochemistry | volume = 50 | issue = 3 | pages = 367–75 | date = January 2011 | pmid = 21138249 | pmc = 3074011 | doi = 10.1021/bi1016843 }} 16. ^{{cite journal | vauthors = Reyes VM, Sawaya MR, Brown KA, Kraut J | title = Isomorphous crystal structures of Escherichia coli dihydrofolate reductase complexed with folate, 5-deazafolate, and 5,10-dideazatetrahydrofolate: mechanistic implications | journal = Biochemistry | volume = 34 | issue = 8 | pages = 2710–23 | date = February 1995 | pmid = 7873554 | doi = 10.1021/bi00008a039 }} 17. ^{{cite journal | vauthors = Chen YQ, Kraut J, Blakley RL, Callender R | title = Determination by Raman spectroscopy of the pKa of N5 of dihydrofolate bound to dihydrofolate reductase: mechanistic implications | journal = Biochemistry | volume = 33 | issue = 23 | pages = 7021–6 | date = June 1994 | pmid = 8003467 | doi = 10.1021/bi00189a001 }} 18. ^{{cite journal | vauthors = Shrimpton P, Allemann RK | title = Role of water in the catalytic cycle of E. coli dihydrofolate reductase | journal = Protein Science | volume = 11 | issue = 6 | pages = 1442–51 | date = June 2002 | pmid = 12021443 | pmc = 2373639 | doi = 10.1110/ps.5060102 }} 19. ^1 2 {{cite journal | vauthors = Fierke CA, Johnson KA, Benkovic SJ | title = Construction and evaluation of the kinetic scheme associated with dihydrofolate reductase from Escherichia coli | journal = Biochemistry | volume = 26 | issue = 13 | pages = 4085–92 | date = June 1987 | pmid = 3307916 | doi = 10.1021/bi00387a052 }} 20. ^{{cite journal | vauthors = Antikainen NM, Smiley RD, Benkovic SJ, Hammes GG | title = Conformation coupled enzyme catalysis: single-molecule and transient kinetics investigation of dihydrofolate reductase | journal = Biochemistry | volume = 44 | issue = 51 | pages = 16835–43 | date = December 2005 | pmid = 16363797 | doi = 10.1021/bi051378i }} 21. ^1 2 {{cite journal | vauthors = Sawaya MR, Kraut J | title = Loop and subdomain movements in the mechanism of Escherichia coli dihydrofolate reductase: crystallographic evidence | journal = Biochemistry | volume = 36 | issue = 3 | pages = 586–603 | date = January 1997 | pmid = 9012674 | doi = 10.1021/bi962337c }} 22. ^1 2 3 {{cite journal | vauthors = Rod TH, Brooks CL | title = How dihydrofolate reductase facilitates protonation of dihydrofolate | journal = Journal of the American Chemical Society | volume = 125 | issue = 29 | pages = 8718–9 | date = July 2003 | pmid = 12862454 | doi = 10.1021/ja035272r }} 23. ^{{cite journal | vauthors = Narayana N, Matthews DA, Howell EE, Nguyen-huu X | title = A plasmid-encoded dihydrofolate reductase from trimethoprim-resistant bacteria has a novel D2-symmetric active site | journal = Nature Structural Biology | volume = 2 | issue = 11 | pages = 1018–25 | date = November 1995 | pmid = 7583655 | via = | doi=10.1038/nsb1195-1018}} 24. ^{{cite journal | vauthors = Bradrick TD, Beechem JM, Howell EE | title = Unusual binding stoichiometries and cooperativity are observed during binary and ternary complex formation in the single active pore of R67 dihydrofolate reductase, a D2 symmetric protein | journal = Biochemistry | volume = 35 | issue = 35 | pages = 11414–24 | date = September 1996 | pmid = 8784197 | doi = 10.1021/bi960205d }} 25. ^{{cite journal | vauthors = Park H, Zhuang P, Nichols R, Howell EE | title = Mechanistic studies of R67 dihydrofolate reductase. Effects of pH and an H62C mutation | journal = The Journal of Biological Chemistry | volume = 272 | issue = 4 | pages = 2252–8 | date = January 1997 | pmid = 8999931 | doi = 10.1074/jbc.272.4.2252 }} 26. ^{{cite journal | vauthors = Kamath G, Howell EE, Agarwal PK | title = The tail wagging the dog: insights into catalysis in R67 dihydrofolate reductase | journal = Biochemistry | volume = 49 | issue = 42 | pages = 9078–88 | date = October 2010 | pmid = 20795731 | doi = 10.1021/bi1007222 }} 27. ^{{cite journal | vauthors = Cowman AF, Lew AM | title = Antifolate drug selection results in duplication and rearrangement of chromosome 7 in Plasmodium chabaudi | journal = Molecular and Cellular Biology | volume = 9 | issue = 11 | pages = 5182–8 | date = November 1989 | pmid = 2601715 | pmc = 363670 | doi = 10.1128/mcb.9.11.5182 }} 28. ^{{cite journal | vauthors = Banka S, Blom HJ, Walter J, Aziz M, Urquhart J, Clouthier CM, Rice GI, de Brouwer AP, Hilton E, Vassallo G, Will A, Smith DE, Smulders YM, Wevers RA, Steinfeld R, Heales S, Crow YJ, Pelletier JN, Jones S, Newman WG | display-authors = 6 | title = Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency | journal = American Journal of Human Genetics | volume = 88 | issue = 2 | pages = 216–25 | date = February 2011 | pmid = 21310276 | pmc = 3035707 | doi = 10.1016/j.ajhg.2011.01.004 }} 29. ^{{cite book | first1 = William L | last1 = Nyhan | first2 = Georg F. | last2 = Hoffmann | first3 = Bruce A | last3 = Barshop | name-list-format = vanc |title=Atlas of Inherited Metabolic Diseases 3E|url=https://books.google.com/books?id=vCvSBQAAQBAJ&pg=PA141|date=30 December 2011|publisher=CRC Press|isbn=978-1-4441-4948-7|pages=141–}} 30. ^{{cite journal | vauthors = Li R, Sirawaraporn R, Chitnumsub P, Sirawaraporn W, Wooden J, Athappilly F, Turley S, Hol WG | title = Three-dimensional structure of M. tuberculosis dihydrofolate reductase reveals opportunities for the design of novel tuberculosis drugs | journal = Journal of Molecular Biology | volume = 295 | issue = 2 | pages = 307–23 | date = January 2000 | pmid = 10623528 | doi = 10.1006/jmbi.1999.3328 }} 31. ^{{cite journal | vauthors = Benkovic SJ, Fierke CA, Naylor AM | title = Insights into enzyme function from studies on mutants of dihydrofolate reductase | journal = Science | volume = 239 | issue = 4844 | pages = 1105–10 | date = March 1988 | pmid = 3125607 | doi = 10.1126/science.3125607 }} 32. ^{{cite journal | vauthors = Srinivasan B, Tonddast-Navaei S, Roy A, Zhou H, Skolnick J | title = Chemical space of Escherichia coli dihydrofolate reductase inhibitors: New approaches for discovering novel drugs for old bugs | journal = Medicinal Research Reviews | date = September 2018 | pmid = 30192413 | doi = 10.1002/med.21538 }} 33. ^1 2 {{cite journal | vauthors = Hawser S, Lociuro S, Islam K | title = Dihydrofolate reductase inhibitors as antibacterial agents | journal = Biochemical Pharmacology | volume = 71 | issue = 7 | pages = 941–8 | date = March 2006 | pmid = 16359642 | doi = 10.1016/j.bcp.2005.10.052 }} 34. ^{{cite journal | vauthors = Narayana N, Matthews DA, Howell EE, Nguyen-huu X | title = A plasmid-encoded dihydrofolate reductase from trimethoprim-resistant bacteria has a novel D2-symmetric active site | journal = Nature Structural Biology | volume = 2 | issue = 11 | pages = 1018–25 | date = November 1995 | pmid = 7583655 | doi = 10.1038/nsb1195-1018 }} 35. ^{{cite journal | vauthors = Huennekens FM | title = In search of dihydrofolate reductase | journal = Protein Science | volume = 5 | issue = 6 | pages = 1201–8 | date = June 1996 | pmid = 8762155 | pmc = 2143423 | doi = 10.1002/pro.5560050626 }} 36. ^{{cite journal | vauthors = Banerjee D, Mayer-Kuckuk P, Capiaux G, Budak-Alpdogan T, Gorlick R, Bertino JR | title = Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase | journal = Biochimica et Biophysica Acta | volume = 1587 | issue = 2–3 | pages = 164–73 | date = July 2002 | pmid = 12084458 | doi = 10.1016/S0925-4439(02)00079-0 }} 37. ^{{cite journal | vauthors = Bailey SW, Ayling JE | title = The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 36 | pages = 15424–9 | date = September 2009 | pmid = 19706381 | pmc = 2730961 | doi = 10.1073/pnas.0902072106 }} 38. ^{{cite journal | vauthors = Murad AM, Santiago FF, Petroianu A, Rocha PR, Rodrigues MA, Rausch M | title = Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer | journal = Cancer | volume = 72 | issue = 1 | pages = 37–41 | date = July 1993 | pmid = 8508427 | doi = 10.1002/1097-0142(19930701)72:1<37::AID-CNCR2820720109>3.0.CO;2-P }} 39. ^{{cite journal | vauthors = Srinivasan B, Skolnick J | title = Insights into the slow-onset tight-binding inhibition of Escherichia coli dihydrofolate reductase: detailed mechanistic characterization of pyrrolo [3,2-f] quinazoline-1,3-diamine and its derivatives as novel tight-binding inhibitors | journal = The FEBS Journal | volume = 282 | issue = 10 | pages = 1922–38 | date = May 2015 | pmid = 25703118 | pmc = 4445455 | doi = 10.1111/febs.13244 }} 40. ^{{cite journal | vauthors = Srinivasan B, Tonddast-Navaei S, Skolnick J | title = Ligand binding studies, preliminary structure-activity relationship and detailed mechanistic characterization of 1-phenyl-6,6-dimethyl-1,3,5-triazine-2,4-diamine derivatives as inhibitors of Escherichia coli dihydrofolate reductase | journal = European Journal of Medicinal Chemistry | volume = 103 | issue = | pages = 600–14 | date = October 2015 | pmid = 26414808 | pmc = 4610388 | doi = 10.1016/j.ejmech.2015.08.021 }} 41. ^1 {{cite journal | vauthors = Beierlein JM, Karri NG, Anderson AC | title = Targeted mutations of Bacillus anthracis dihydrofolate reductase condense complex structure−activity relationships | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 20 | pages = 7327–36 | date = October 2010 | pmid = 20882962 | pmc = 3618964 | doi = 10.1021/jm100727t }} 42. ^{{cite journal | vauthors = Mayhew M, da Silva AC, Martin J, Erdjument-Bromage H, Tempst P, Hartl FU | title = Protein folding in the central cavity of the GroEL-GroES chaperonin complex | journal = Nature | volume = 379 | issue = 6564 | pages = 420–6 | date = February 1996 | pmid = 8559246 | doi = 10.1038/379420a0 }} 43. ^{{cite journal | vauthors = Maguire M, Nield PC, Devling T, Jenkins RE, Park BK, Polański R, Vlatković N, Boyd MT | title = MDM2 regulates dihydrofolate reductase activity through monoubiquitination | journal = Cancer Research | volume = 68 | issue = 9 | pages = 3232–42 | date = May 2008 | pmid = 18451149 | pmc = 3536468 | doi = 10.1158/0008-5472.CAN-07-5271 }} Further reading{{refbegin | 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External links
3 : Protein domains|EC 1.5.1|Enzymes of known structure |
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