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 journalArticle

15 Citations (Scopus)

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

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Mutagenesis
Tetrahydrofolate Dehydrogenase
Isomerization
Site-Directed Mutagenesis
Binding energy
Catalysis
Hydrophobic and Hydrophilic Interactions
Folic Acid
Methotrexate
Glutamic Acid
Substrates
Enzymes
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology

Cite this

Taira, K., Fierke, C. A., Chen, J. T., Johnson, K. A., & Benkovic, S. J. (1987). On interpreting the inhibition of and catalysis by dihydrofolate reductase. Trends in Biochemical Sciences, 12(C), 275-278. https://doi.org/10.1016/0968-0004(87)90134-4
Taira, Kazunari ; Fierke, Carol A. ; Chen, Jin Tann ; Johnson, Kenneth A. ; Benkovic, Stephen J. / On interpreting the inhibition of and catalysis by dihydrofolate reductase. In: Trends in Biochemical Sciences. 1987 ; Vol. 12, No. C. pp. 275-278.
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Taira, K, Fierke, CA, Chen, JT, Johnson, KA & Benkovic, SJ 1987, 'On interpreting the inhibition of and catalysis by dihydrofolate reductase', Trends in Biochemical Sciences, vol. 12, no. C, pp. 275-278. https://doi.org/10.1016/0968-0004(87)90134-4

On interpreting the inhibition of and catalysis by dihydrofolate reductase. / Taira, Kazunari; Fierke, Carol A.; Chen, Jin Tann; Johnson, Kenneth A.; Benkovic, Stephen J.

In: Trends in Biochemical Sciences, Vol. 12, No. C, 1987, p. 275-278.

Research output: Contribution to journalArticle

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AU - Benkovic, Stephen J.

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