A mechanism-based inactivator for histone demethylase LSD1

J Am Chem Soc. 2006 Apr 12;128(14):4536-7. doi: 10.1021/ja0602748.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Enzyme Activation
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Flavin-Adenine Dinucleotide / analogs & derivatives
  • Flavin-Adenine Dinucleotide / chemistry
  • Flavin-Adenine Dinucleotide / metabolism
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / chemistry*
  • Histone Deacetylases / metabolism
  • Kinetics
  • Lysine / analogs & derivatives*
  • Lysine / chemistry
  • Lysine / pharmacology
  • Molecular Sequence Data
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization


  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Flavin-Adenine Dinucleotide
  • 1,5-dihydro-FAD
  • Histone Deacetylases
  • Lysine