A domino effect in antifolate drug action in Escherichia coli

Yun Kyung Kwon, Wenyun Lu, Eugene Melamud, Nurussaba Khanam, Andrew Bognar, Joshua D. Rabinowitz

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

Mass spectrometry technologies for measurement of cellular metabolism are opening new avenues to explore drug activity. Trimethoprim is an antibiotic that inhibits bacterial dihydrofolate reductase (DHFR). Kinetic flux profiling with 15N-labeled ammonia in Escherichia coli reveals that trimethoprim leads to blockade not only of DHFR but also of another critical enzyme of folate metabolism: folylpoly-γ-glutamate synthetase (FP-γ-GS). Inhibition of FP-γ-GS is not directly due to trimethoprim. Instead, it arises from accumulation of DHFR's substrate dihydrofolate, which we show is a potent FP-γ-GS inhibitor. Thus, owing to the inherent connectivity of the metabolic network, falling DHFR activity leads to falling FP-γ-GS activity in a domino-like cascade. This cascade results in complex folate dynamics, and its incorporation in a computational model of folate metabolism recapitulates the dynamics observed experimentally. These results highlight the potential for quantitative analysis of cellular metabolism to reveal mechanisms of drug action.

Original languageEnglish (US)
Pages (from-to)602-608
Number of pages7
JournalNature Chemical Biology
Volume4
Issue number10
DOIs
StatePublished - Oct 2008

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'A domino effect in antifolate drug action in Escherichia coli'. Together they form a unique fingerprint.

  • Cite this