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Inhibition of Folate Metabolism in Chemotherapy pp 55–74Cite as

Dihydrofolate Reductase

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 64))

Abstract

The discovery of the antibacterial activity of the sulfonamides had two important consequences. First, a new agent of unprecedented efficacy became available for the treatment of infectious diseases. Less obvious was the support it gave to the concept that biochemical differences between humans and their parasites could serve as the basis for a rational approach to the design of chemotherapeutic agents. Knowledge of the mechanism of action of the sulfonamides (Woods 1940) suggested that chemotherapeutic effort be directed toward essential enzymes and pathways present in prokaryotic parasites, but lacking in their mammalian host. That such an approach would be fruitful was not obvious. At least superficially, it appeared to run counter to the increasingly well-documented concept of “the unity of biochemistry” which emphasized the commonality of pathways employed by both prokaryotes and eukaryotes for their growth and reproduction (Florkin 1974).

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References

  • Amyes SGB, Smith JT (1974) R-factor trimethoprim resistance mechanism: an insusceptible target site. Biochem Biophys Res Commun 58: 412–418

    Article  PubMed  CAS  Google Scholar 

  • Amyes SGB, Smith JT (1976) The purification and properties of the trimethoprim resistant dihydrofolate reductase mediated by the R-factor, R 388. Eur J Biochem 61: 597–603

    Article  PubMed  CAS  Google Scholar 

  • Baccanari DP, Joyner SS (1981) Dihydrofolate reductase hysteresis and its effect on inhibitor binding analyses. Biochemistry 20: 1710–1716

    Article  PubMed  CAS  Google Scholar 

  • Baccanari D, Phillips AW, Smith S, Sinski D, Burchall J (1975) Purification and properties of Escherichia colidihydrofolate reductase. Biochemistry 14: 5267–5273

    Article  PubMed  CAS  Google Scholar 

  • Baccanari D, Averett D, Briggs C, Burchall J (1977) Escherichia coli dihydrofolate reductase: Isolation and characterization of two isozymes. Biochemistry 16:3566–3572

    Article  PubMed  CAS  Google Scholar 

  • Baccanari D, Stone D, Kuyper L (1981) Effect of a single amino acid substitution on Escherichia colidihydrofolate reductase. J Biol Chem 256: 1738–1747

    PubMed  CAS  Google Scholar 

  • Baker DJ, Beddell CR, Champness JN, Goodford PJ, Norrington FEA, Smith DR, Stammers DK (1981) The binding of trimethoprim to bacterial dihydrofolate reductase. FEBS Lett 126: 49–52

    Article  PubMed  CAS  Google Scholar 

  • Bauman H, Wilson KJ (1975) Dihydrofolate reductase from bovine liver. Eur J Biochem 60: 9–15

    Article  Google Scholar 

  • Benkovic SJ (1980) On the mechanism of action of folate-and biopterin-requiring enzymes. Annu Rev Biochem 49: 227–251

    Article  PubMed  CAS  Google Scholar 

  • Bennett CS, Rodkey JA, Sondey JM, Hirschman R (1978) Dihydrofolate reductase: the amino acid sequence of the enzyme from a methotrexate-resistant mutant of Escherichia coli. Biochemistry 17: 1328–1337

    Article  PubMed  CAS  Google Scholar 

  • Bertino JR, Booth BA, Bieber AL, Cashmore A, Sartorelli AC (1964) Studies on the inhibi- tion of dihydrofolate reductase by the folate antagonists. J Biol Chem 239: 479–485

    PubMed  CAS  Google Scholar 

  • Birdsall B, Roberts GCK, Feeney J, Burgen ASV (1977) 31PNMR studies of the binding of adenosine-2’-phosphate to Lactobacillus casei dihydrofolate reductase. FEBS Lett 80:313–316

    Article  PubMed  CAS  Google Scholar 

  • Birdsall B, Burgen ASV, de Miranda JR, Roberts GCK (1978) Cooperativity in ligand binding to dihydrofolate reductase. Biochemistry 17: 2102–2110

    Article  PubMed  CAS  Google Scholar 

  • Birdsall B, Burgen ASV, Roberts GCK (1980a) Effects of coenzyme analogues on the binding of p-aminobenzoyl-L-glutamate and 2,4-diaminopyrimidine to Lactobacillus caseidihydrofolate reductase. Biochemistry 19: 3732–3737

    Article  CAS  Google Scholar 

  • Birdsall B, Burgen ASV, Roberts GCK (1980b) Binding of coenzyme analogues to Lactobacillus caseidihydrofolate reductase: binary and ternary complexes. Biochemistry 19: 3723–3731

    Article  CAS  Google Scholar 

  • Bitar KG, Blankenship DT, Walsh KA, Dunlap RB, Reddy AV, Freisheim JH (1977) Amino acid sequence of dihydrofolate reductase from an amethopterin resistant strain of Lactobacillus casei. FEBS Lett 80: 119–122

    Article  PubMed  CAS  Google Scholar 

  • Blakley RL (1969) The biochemistry of folic acid and related pteridines. John Wiley and Sons, New York

    Google Scholar 

  • Blakley RL, Ramasastri BU, McDougall BM (1963) The biosynthesis of thymidylic acid. V. Hydrogen isotope studies with dihydrofolate reductase and thymidylate synthetase. J Biol Chem 238: 3075–3079

    PubMed  CAS  Google Scholar 

  • Blakley RL, Schrock M, Sommer K, Nixon PF (1971) Kinetic studies of the reaction mechanism of dihydrofolate reductase. Ann NY Acad Sci 186: 119–130

    Article  PubMed  CAS  Google Scholar 

  • Breeze AS, Sims P, Stacey KA (1975) Trimethoprim resistant mutants of E. coliK 12: preliminary genetic mapping. Genet Res 25: 207–214

    Article  PubMed  CAS  Google Scholar 

  • Broquist HP, Stockstad ELR, Jukes TH (1950) Some biological and chemical properties of the citrovorum factor. J Biol Chem 185: 399–409

    PubMed  CAS  Google Scholar 

  • Burchall JJ (1968) Protection of microbial dihydrofolate reductase against inactivation by pronase. Mol Pharmacol 4: 238–248

    PubMed  CAS  Google Scholar 

  • Burchall JJ (1970) Purification and properties of dihydrofolate reductase from Escherichia coli. In: Iwai K, Akino M, Goto M, Iwanami Y (eds) Chemistry and biology of pteridines. Int Acad Printing Co, Tokyo, Japan, pp 351–355

    Google Scholar 

  • Burchall JJ (1979) The development of the diaminopyrimidines. J Antimicrob Chemother [Suppl B] 5: 3–14

    CAS  Google Scholar 

  • Burchall JJ, Hitchings GH (1965) Inhibitor binding analysis of dihydrofolate reductases from various species. Mol Pharmacol 1: 126–136

    PubMed  CAS  Google Scholar 

  • Cayley PJ, Albrand JP, Feeney J, Roberts GCK, Piper EA, Burgen ASV (1979) Nuclear magnetic resonance studies of the binding of trimethoprim to dihydrofolate reductase. Biochemistry 18: 3886–3894

    Article  PubMed  CAS  Google Scholar 

  • Chang ACY, Nunberg JH, Kaufman RJ, Erlich HA, Schimke RT, Cohen SN (1978) Phenotypic expression in E. coliof a DNA sequence coding for mouse dihydrofolate reductase. Nature 275: 617–624

    Article  PubMed  CAS  Google Scholar 

  • Charlton PA, Young DW, Birdsall B, Feeney J, Roberts GCK (1979) Stereochemistry of reduction of folic acid using dihydrofolate reductase. J Chem Soc Chem Commun 20: 922–924

    Article  Google Scholar 

  • Coward JK, Parameswaran KN, Cashmore AR, Bertino JR (1974) 7,8-dihydropteroyloligo-y-L-glutamates: synthesis and kinetic studies with purified dihydrofolate reductase from mammalian sources. Biochemistry 13:3899–3903

    Article  PubMed  CAS  Google Scholar 

  • Dannenberg PV, Dannenberg KD, Cleland WW (1978) The interaction of liver alcohol dehydrogenase with phenyl adenine dinucleotide, a novel analog of pyridine nucleotide coenzymes. J Biol Chem 253: 5886–5887

    Google Scholar 

  • Dunn SMJ, King RW (1980) Kinetics of ternary complex formation between dihydrofolate reductase coenzyme and inhibitors. Biochemistry 19: 766–773

    Article  PubMed  CAS  Google Scholar 

  • Feeney J, Roberts GCK, Kapstein R, Birdsall B, Gronenborn A, Burgen ASV (1980) PhotoCIDNP studies of the influence of ligand binding on the surface accessibility of aromatic residues in dihydrofolate reductase. Biochemistry 19: 2466–2472

    Article  PubMed  CAS  Google Scholar 

  • Ferone R, Roland S (1980) Dihydrofolate reductase: thymidylate synthetase, a functional polypeptide from Crithidia fasciculata. Proc Natl Acad Sci USA 77: 5802–5806

    Article  PubMed  CAS  Google Scholar 

  • Ferone R, Burchall J, Hitchings G (1969) Plasmodium berghei dihydrofolate reductases. Isolation, properties and inhibition by antifolates. Mol Pharmacol 5:49–59

    PubMed  CAS  Google Scholar 

  • Fleming MP, Datta N, Gruneberg RN (1972) Trimethoprim resistance determined by R-factors. Br Med J 1: 726–728

    Article  PubMed  CAS  Google Scholar 

  • Fling M, Elwell LP, Inamine JH (1978) Cloning and amplification of DNA sequence encoding a trimethoprim-resistant dihydrofolate reductase gene. In: Boyer HW, Nicosia S (eds) Genetic engineering. Elsevier/North Holland, Amsterdam, pp 173–180

    Google Scholar 

  • Florkin M (1974) Concepts of molecular biosemiotics and of molecular evolution. In: Florkin M, Stotz EH (eds) Comprehensive biochemistry, vol 29 A. Elsevier, Amsterdam, pp 1–124

    Google Scholar 

  • Fontecilla-Camps JC, Bugg CE, Temple C, Rose JD, Montgomery JA, Kisliuk RL (1979) X-ray crystallographic studies of the structure of 5,10-methylenetetrahydrofolic acid. In: Kisliuk RL, Brown GM (eds) Chemistry and biology of pteridines. Elsevier/North Holland, New York, pp 235–240

    Google Scholar 

  • Franklin AL, Stockstad ELR, Belt M, Jukes TH (1947) Biochemical experiments with a synthetic preparation having an action antagonistic to that of pteroylglutamic acid. J Biol Chem 169: 427–435

    PubMed  CAS  Google Scholar 

  • Freisheim JH, Ericsson CH, Bitar KG, Dunlap RB, Reddy AV (1977) An active center tryptophan residue in dihydrofolate reductase: chemical modification, sequence surrounding the critical residue, and structure homology consideration. Arch Biochem Biophys 180: 310–317

    Article  PubMed  CAS  Google Scholar 

  • Freisheim JH, Bitar KG, Reddy AV, Blankenship DT (1978) Dihydrofolate reductase from amethopterin-resistant Lactobacillus casei. J Biol Chem 253: 6437–6444

    PubMed  CAS  Google Scholar 

  • Freisheim JH, Kumar AA, Blankenship DT, Kaufman BT (1979) Structure-function relationships of dihydrofolate reductase: sequence homology considerations and active center residues. In: Kisliuk RL, Brown GM (eds) Chemistry and biology of pteridines. Elsevier/North Holland, New York, pp 419–424

    Google Scholar 

  • Gleisner JM, Peterson DL, Blakley RL (1974) Amino acid sequence of dihydrofolate reductase from a methotrexate-resistant mutant of Streptococcus faeciumand identification of methionine residue at the inhibitor binding site. Proc Natl Acad Sci USA 71: 3001–3005

    Article  PubMed  CAS  Google Scholar 

  • Gready JE (1980) Dihydrofolate reductase: binding of substrates and inhibitors and catalytic mechanism. Adv Pharmacol Chemother 17: 37–102

    Article  PubMed  CAS  Google Scholar 

  • Gutteridge WE, Jaffe JJ, McCormack JJ (1969) The gel-filtration behaviour of dihydrofolate reductases from culture forms of trypanosomatids. Biochim Biophys Acta 191: 753–755

    PubMed  CAS  Google Scholar 

  • Hakala MT, Suolinna EM (1966) Specific protection of folate reductase against chemical and proteolytic inactivation. Mol Pharmacol 2: 465–480

    PubMed  CAS  Google Scholar 

  • Hayman R, McGready R, Van der Weyden MB (1980) A rapid radiometric assay for dihydrofolate reductase. Anal Biochem 87: 460–465

    Article  Google Scholar 

  • Hillcoat BL, Swett V, Bertino JR (1967) Increase of dihydrofolate reductase activity in cultured mammalian cells after exposure to methotrexate. Proc Natl Acad Sci USA 58: 1632–1637

    Article  PubMed  CAS  Google Scholar 

  • Hitchings GH, Roth B (1980) Dihydrofolate reductase as targets for selective inhibitors. In: Sandler M (ed) Enzyme inhibitors as drugs. Macmillan, London Basingstoke, pp 263–280

    Google Scholar 

  • Hitchings GH, Smith SL (1980) Dihydrofolate reductases as targets for inhibitors. In: Weber G (ed) Adv Enzyme Regul, pp 349–370

    Google Scholar 

  • Hitchings GH, Elion GB, Vanderwerff H, Falco EA (1948) Pyrimidine derivatives as antagonists of pteroylglutamic acid. J Biol Chem 174: 765–766

    PubMed  CAS  Google Scholar 

  • Hitchings GH, Burchall JJ, Ferone R (1968) The comparative enzymology of dihydrofolate reductase and the design of chemotherapeutic agents. In: Welch AD (ed) Proc 3rd Int Pharmacol Meeting. The control of growth processes by chemical agents, vol 5. Perga-mon, New York, pp 3–18

    Google Scholar 

  • Huennekens FM, Vitols KS, Whiteley JM, Neef VG (1976) Dihydrofolate reductase. Methods Cancer Res 13: 199–225

    CAS  Google Scholar 

  • Hyde EI, Birdsall B, Roberts GCK, Feeney J, Burgen ASV (1980) Proton nuclear magnetic resonance saturation transfer studies of coenzyme binding to Lactobacillus caseidihydrofolate reductase. Biochemistry 19: 3738–3746

    Article  PubMed  CAS  Google Scholar 

  • Lai PH, Pan YC, Gleisner JM, Peterson DL, Blakeley RL (1979) Primary sequence of bovine liver dihydrofolate reductase. In: Kisliuk RL, Brown GM (eds) Chemistry and biology of pteridines. Elsevier/North Holland, New York, pp 437–440

    Google Scholar 

  • Lindquist CA, Cadman EC, Bertino JR (1977) A fluorometric assay for dihydrofolate reductase. Anal Biochem 83: 20–25

    Article  PubMed  CAS  Google Scholar 

  • Matthews DA, Alden RA, Bolin JT, Freer ST, Hamlin R, Xuong N, Kraut J, Poe M, Williams M, Hoogsteen K (1977) Dihydrofolate reductase: X-ray structure of the binary complex with methotrexate. Science 197: 452–455

    Article  PubMed  CAS  Google Scholar 

  • Matthews DA (1979) Interpretation of nuclear magnetic resonance spectra for Lactobacillus caseidihydrofolate reductase based on the x-ray structure of the enzyme-methotrexateNADPH complex. Biochemistry 18: 1602–1610

    Article  PubMed  CAS  Google Scholar 

  • Matthews DA, Alden RA, Bolin JT, Filman DJ, Freer ST, Hamlin R, Hol WGJ, Kisliuk RL, Pastore EJ, Plante LT, Xuong N, Kraut J (1978) Dihydrofolate reductase from Lactobacillus caseix-ray structure of the enzyme-methotrexate-NADPH complex. J Biol Chem 253: 6946–6954

    PubMed  CAS  Google Scholar 

  • Matthews DA, Alden RA, Freer ST, Xuong N, Kraut J (1979) Dihydrofolate reductase from Lactobacilluscasei/Stereochemistry of NADPH binding. J Biol Chem 254: 4144–4151

    PubMed  CAS  Google Scholar 

  • McCuen RW, Sirotnak FM (1974) Hyperproduction of dihydrofolate reductase in Diplococcus pneumoniaby mutation in the structure gene. Biochim Biophys Acta 338: 540–544

    Article  CAS  Google Scholar 

  • McCullough JL, Nixon PF, Bertino JR (1971) Kinetic investigations of the reaction mechanisms of dihydrofolate reductase from L 1210 cells. Ann NY Acad Sci 186: 131–142

    Article  PubMed  CAS  Google Scholar 

  • Mosher RA, DiKenzo AB, Mathews CK (1977) Bacteriophage T4 virion dihydrofolate reductase; approaches to quantitation and assessment of function. J Virol 23: 645–658

    PubMed  CAS  Google Scholar 

  • Nichol CA, Welch AD (1950) Synthesis of citrovorum factor from folic acid by liver slices; augmentation by ascorbic acid. Proc Soc Exp Biol Med 74: 52–55

    PubMed  CAS  Google Scholar 

  • Nunberg JH, Kaufman RJ, Chang ACY, Cohen SN, Schimke RT (1980) Structure and genomic organization of the mouse dihydrofolate reductase gene. Cell 19: 355–364

    Article  PubMed  CAS  Google Scholar 

  • Osborn MJ, Huennekens FM (1958) Inhibition of dihydrofolate reductase by aminopterin and amethopterin. Proc Soc Exp Biol Med 97: 429

    PubMed  CAS  Google Scholar 

  • Pastore EJ, Friedkin M (1962) The enzymatic synthesis of thymidylate. II. Transfer of tritium from tetrahydrofolate to the methyl group of thymidylate. J Biol Chem 237: 3802–3810

    PubMed  CAS  Google Scholar 

  • Pastore EJ, Kisliuk RL, Plante LT, Wright JM, Kaplan NO (1974) Conformational changes induced in dihydrofolate reductase by folates, pyridine nucleotides coenzymes and methotrexate. Prox Natl Acad Sci USA 71: 3849–3853

    Article  CAS  Google Scholar 

  • Pattishall KH, Burchall JJ, Harvey RJ (1976) Interconvertible forms of Escherichia colidihydrofolate reductase with different affinities for analogs of dihydrofolate. J Biol Chem 251: 7011–7020

    PubMed  CAS  Google Scholar 

  • Pattishall KH, Acar J, Burchall JJ, Goldstein FW, Harvey RJ (1977) Two distinct types of TMP-resistant dihydrofolate reductases specified by R-plasmids of different compatibility groups. J Biol Chem 252: 2319–2323

    PubMed  CAS  Google Scholar 

  • Perkins JP, Bertino JR (1966) Dihydrofolate reductase from L 1210 murine lymphoma. Fluorometric measurements of the interactions of the enzyme with coenzymes, substrates and inhibitors. Biochemistry 5: 1005–1012

    Article  PubMed  CAS  Google Scholar 

  • Poe M (1977) Acidic dissociation constants of folic acid, dihydrofolic acid and methotrexate. J Biol Chem 252: 3724–3728

    PubMed  CAS  Google Scholar 

  • Poe M (1980) Stereochemistry of reduction of folic acid by chicken liver dihydrofolate reductase. Fed Proc 39: 1856

    Google Scholar 

  • Poe M, Greenfield NJ, Williams MN (1974) Dihydrofolate reductase from a methotrexateresistant Escherichia coli. J Biol Chem 249: 2710–2716

    PubMed  CAS  Google Scholar 

  • Rodkey JA, Bennett CD (1976) Micro-Edman degradation: the use of high pressure liquid chromatography and gas chromatography in the amino terminal sequence determination of 8 nanomoles of dihydrofolate reductase from a mouse sarcoma. Biochem Biophys Res Commun 72: 1407–1413

    Article  PubMed  CAS  Google Scholar 

  • Rossman MG, Liljos A, Bränden GI, Banoszak LJ (1975) Evolutionary and structural relationships among dehydrogenases. In: Boyer PD (ed) The enzymes, 3rd edn, vol 11. Academic Press, New York, pp 61–102

    Google Scholar 

  • Rothenberg SP, Perivair-Igbal M, DaCosta M (1980) An amplified radioenzymatic assay using [3H]dihydrofolate. Anal Biochem 103: 152–156

    Article  PubMed  CAS  Google Scholar 

  • Schimke RT, Kaufman RJ, Alt FW, Kellems RF (1978) Gene amplification and drug resistance in cultured murine cells. Science 202: 1051–1055

    Article  PubMed  CAS  Google Scholar 

  • Seeger DR, Smith JM, Hultquist ME (1947) Antagonists for pteroylglutamic acid. J Am Chem Soc 69: 2567

    Article  PubMed  CAS  Google Scholar 

  • Sheldon R (1977) Altered dihydrofolate reductase in folregulatory mutants of Escherichia coliK 12. Molec Gen Genet 151: 215–219

    Article  PubMed  CAS  Google Scholar 

  • Sköld O, Widh A (1974) A new dihydrofolate reductase with low trimethoprim sensitivity induced by an R-factor mediating high resistance to trimethoprim. J Biol Chem 249: 4324–4325

    PubMed  Google Scholar 

  • Smith DR, Calvo JM (1979) Regulation of dihydrofolate reductase in Escherichia coli. Molec Gen Genet 175: 31–38

    Article  PubMed  CAS  Google Scholar 

  • Smith DR, Calvo JM (1980) Nucleotide sequence of the E. coligene coding for dihydrofolate reductase. Nucleic Acids Res 8: 2255–2273

    Article  PubMed  CAS  Google Scholar 

  • Smith SL, Burchall JJ (1980) Studies of E. coliR plasmid dihydrofolate reductase. Fed Proc 39: 1771

    Google Scholar 

  • Smith SL, Patrick P, Stone D, Phillips AW, Burchall JJ (1979a) Porcine liver dihydrofolate reductase: purification, properties, and amino acid sequence. J Biol Chem 254: 11475–11484

    CAS  Google Scholar 

  • Smith SL, Stone D, Novak P, Baccanari D, Burchall J (1979b) R-plasmid dihydrofolate reductase with subunit structure. J Biol Chem 254: 6222–6225

    CAS  Google Scholar 

  • Stone D, Phillips AW (1977) The amino acid sequence of dihydrofolate reductase from L 1210 cells. FEBS Lett 74: 85–87

    Article  PubMed  CAS  Google Scholar 

  • Stone D, Smith SL (1979) The amino acid sequence of a trimethoprim-resistant dihydrofo- late reductase specified in E. coliby R-plasmid R 67. J Biol Chem 254: 10857–10861

    PubMed  CAS  Google Scholar 

  • Stone D, Phillips AW, Burchall JJ (1977) The amino acid sequence of dihydrofolate reductase of a trimethoprim-resistant strain of Escherichia coli. Eur J Biochem 72: 613–624

    Article  PubMed  CAS  Google Scholar 

  • Stone D, Paterson SJ, Raper JH, Phillips AW (1979) The amino acid sequence of dihydrofolate reductase from the mouse lymphoma L 1210. J Biol Chem 254: 480–488

    PubMed  CAS  Google Scholar 

  • Wang CC, Stotish RL, Poe M (1975) Dihydrofolate reductase from Eimeria tenella: ration- alization of chemotherapeutic efficacy of pyrimethamine. J Protozool 22: 564–568

    PubMed  CAS  Google Scholar 

  • Williams JW, Duggleby RG, Cutler R, Morrison JR (1980) The inhibition of dihydrofolate reductase by folate analogs: structural requirements for slow-and tight-binding inhibition. Biochem Pharmacol 29: 589–595

    Article  PubMed  CAS  Google Scholar 

  • Williams MN, Poe M, Greenfield NJ, Hirschfield JM, Hoogsteen W (1973a) Methotrexate binding to dihydrofolate reductase from a methotrexate resistant strain of Escherichia coli. J Biol Chem 248: 6375–6379

    CAS  Google Scholar 

  • Williams MN, Greenfield NJ, Hoogsteen K (1973b) Evidence for two reduced triphosphopyridine nucleotide binding sites on dihydrofolate reductase from a methotrexate-resistant strain of Escherichia coli. JBC 248: 6380–6386

    CAS  Google Scholar 

  • Williams TJ, Kee TK, Dunlap RB (1977) Dihydrofolate reductase from amethopterinresistant Lactobacillus easel. Arch Biochem Biophys 181: 569–579

    Article  PubMed  CAS  Google Scholar 

  • Woods DD (1940) The relation of p-aminobenzoic acid to the mechanism of action of sulphonilamide. Br J Exp Pathol 21: 74–90

    CAS  Google Scholar 

  • Wooley DW (1952) A study of antimetabolites. Wiley, New York

    Google Scholar 

  • Zolg JW, Hänggi UJ (1981) Characterization of a R-plasmid associated, trimethoprim-resistant dihydrofolate reductase and determination of the nucleotide sequence of the reductase gene. Nucleic Acids Res 9: 697–709

    Article  PubMed  CAS  Google Scholar 

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  1. J. J. Burchall
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  1. The Wellcome Research Laboratories, Burroughs Wellcome Co., 3030 Cornwallis Road, Research Triangle Park, 27709, NC, USA

    George H. Hitchings

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Burchall, J.J. (1983). Dihydrofolate Reductase. In: Hitchings, G.H. (eds) Inhibition of Folate Metabolism in Chemotherapy. Handbook of Experimental Pharmacology, vol 64. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-81890-5_4

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  • DOI: https://doi.org/10.1007/978-3-642-81890-5_4

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