Dihydrofolate reductase as a therapeutic target

FASEB J. 1990 May;4(8):2441-52. doi: 10.1096/fasebj.4.8.2185970.


The folate antagonists are an important class of therapeutic compounds, as evidenced by their use as antiinfective, antineoplastic, and antiinflammatory drugs. Thus far, all of the clinically useful drugs of this class have been inhibitors of dihydrofolate reductase (DHFR), a key enzyme in the synthesis of thymidylate, and therefore, of DNA. The basis of the antiinfective selectivity of these compounds is clear; the antifolates trimethoprim and pyrimethamine are potent inhibitors of bacterial and protozoal DHFRs, respectively, but are only weak inhibitors of mammalian DHFRs. These species-selective agents apparently exploit the differences in the active site regions of the parasite and host enzymes. Methotrexate is the DHFR inhibitor used most often in a clinical setting as an anticancer drug and as an antiinflammatory and immunosuppressive agent. Considerable progress has been made recently in understanding the biochemical basis for the selectivity of this drug and the biochemical mechanism (or mechanisms) responsible for the development of resistance to treatment with the drug. This understanding has led to a new generation of DHFR inhibitors that are now in clinical trials.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Amino Acids
  • Animals
  • Drug Resistance / genetics
  • Folic Acid Antagonists*
  • Humans
  • Kinetics
  • Methotrexate / therapeutic use
  • Models, Molecular
  • Molecular Structure
  • Protein Conformation
  • Species Specificity
  • Tetrahydrofolate Dehydrogenase / genetics
  • Tetrahydrofolate Dehydrogenase / metabolism


  • Amino Acids
  • Folic Acid Antagonists
  • Tetrahydrofolate Dehydrogenase
  • Methotrexate