Triptolide Directly Inhibits dCTP Pyrophosphatase

Timothy W. Corson, Hüseyin Cavga, Nicholas Aberle, Craig M. Crews

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Triptolide is a potent natural product, with documented antiproliferative, immunosuppressive, anti-inflammatory, antifertility, and antipolycystic kidney disease effects. Despite a wealth of knowledge about the biology of this compound, direct intracellular target proteins have remained elusive. We synthesized a biotinylated photoaffinity derivative of triptolide, and used it to identify dCTP pyrophosphatase 1 (DCTPP1) as a triptolide-interacting protein. Free triptolide interacts directly with recombinant DCTPP1, and inhibits the enzymatic activity of this protein. Triptolide is thus the first dCTP pyrophosphatase inhibitor identified, and DCTPP1 is a biophysically validated target of triptolide. Nucleotide denied by triptolide: Using a photoaffinity pull-down approach, we found that the natural product triptolide binds to and inhibits the function of dCTP pyrophosphatase (DCTPP1; see scheme). Triptolide will be a useful tool for probing the function of this newly characterized metabolic enzyme.

Original languageEnglish (US)
Pages (from-to)1767-1773
Number of pages7
JournalChemBioChem
Volume12
Issue number11
DOIs
StatePublished - Jul 25 2011

Keywords

  • DCTPP1
  • Natural products
  • Nucleotides
  • Photoaffinity labeling
  • Triptolide

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology

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