On interpreting the inhibition of and catalysis by dihydrofolate reductase

Kazunari Taira, Carol A. Fierke, Jin Tann Chen, Kenneth A. Johnson, Stephen J. Benkovic

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Inhibition of dihydrofolate reductase by methotrexate requires the presence of the p-aminobenzoyl glutamate side chain to achieve an isomerization of the initial encounter complex to the final tightly bound enzyme species. Site-specific mutagenesis at Phe31 revealed that hydrophobic interactions at this residue alone may contribute ∼ 2.5 kcal mol-1 to the binding energy of the drug. This binding perturbation extends to the folate substrates but with a minimal (less than twofold) effect on the chemical step in turnover owing to a uniform effect on ground and transition states.

Original languageEnglish (US)
Pages (from-to)275-278
Number of pages4
JournalTrends in Biochemical Sciences
Volume12
Issue numberC
DOIs
StatePublished - 1987

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology

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