A mechanism-based inactivator for histone demethylase LSD1

Jeffrey C. Culhane, Lawrence M. Szewczuk, Xin Liu, Guoping Da, Ronen Marmorstein, Philip A. Cole

Research output: Contribution to journalArticle

116 Scopus citations

Abstract

Histone demethylase LSD1 is a flavin-dependent amine oxidase that catalyzes the oxidative removal of one or two methyl groups from the methyl-lysine-4 side chain of histone H3. We have designed and synthesized two peptide-based inhibitor analogues that block LSD1. One of these inhibitors, compound 1, contains a propargylamine functionality and shows time-dependent inactivation of LSD1. Peptide substrate, diMeK4H3-21, protected LSD1 against inactivation by 1 in a concentration-dependent fashion. Mass spectrometric analysis showed that 1 forms a covalent interaction with FAD. Compound 1 did not detectably inhibit monoamine oxidase B in the concentration range studied. Compound 1 is thus a selective, mechanism-based inactivator of LSD1 and is likely to serve as a useful tool in the study of histone modifications and chromatin remodeling.

Original languageEnglish (US)
Pages (from-to)4536-4537
Number of pages2
JournalJournal of the American Chemical Society
Volume128
Issue number14
DOIs
StatePublished - Apr 12 2006

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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    Culhane, J. C., Szewczuk, L. M., Liu, X., Da, G., Marmorstein, R., & Cole, P. A. (2006). A mechanism-based inactivator for histone demethylase LSD1. Journal of the American Chemical Society, 128(14), 4536-4537. https://doi.org/10.1021/ja0602748