title: A mechanism-based inactivator for histone demethylase LSD1.
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.
authors.affiliation: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Culhane
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Szewczuk
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Guoping
authors.initials: G
authors.lastname: Da
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
mesh_terms: D000595:Amino Acid Sequence; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005182:Flavin-Adenine Dinucleotide / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008239:Lysine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008969:Molecular Sequence Data; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D005182:Flavin-Adenine Dinucleotide; C058805:1,5-dihydro-FAD; D006655:Histone Deacetylases; D008239:Lysine