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LSD1 and the chemistry of histone demethylation - PubMed

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LSD1 and the chemistry of histone demethylation

Jeffrey C Culhane et al. Curr Opin Chem Biol. 2007 Oct.

Abstract

The recent discovery that histone demethylation can be catalyzed by the flavin-dependent amine oxidase LSD1 has ushered in a new chapter in the chromatin-remodeling community. Herein, we discuss the rapid progress of the histone demethylase field including the recent identification of the non-heme iron-dependent histone demethylases (JmjC family), the basis for LSD1 substrate site specificity and the newly emerging potential for inhibition of these enzymes in structural and functional analysis.

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Figures

Figure 1
Figure 1. Catalytic mechanisms of demethylase enzymes

(a) The FAD dependent demethylation of Lys-4 of histone H3 proceeds through the hydrolysis of an iminium ion following a two electron oxidation of the amine by the flavin. R = ribosyl adenine dinucleotide (b) The iron(II) dependent demethylation of trimethyl-lysine substrates proceeds through an iron(II), α-ketoglutarate, and O2 derived hydroxyl radical oxidation of the methyl C-H bond.

Figure 2
Figure 2. Mechanism-based inactivation of LSD1

(a) The proposed mechanism of inactivation of LSD1 by an N-methylpropargylamine containing H3 peptide proceeds through conjugate addition of the flavin N5 to the gamma carbon of the electrophile following a two electron oxidation to the iminium ion. (b) Reduction of the trimethine linkage of the FADinactivator conjugate with NaBH4 was necessary for crystallographic studies. (c) The proposed catalytic mechanism of inactivation of LSD1 by tranylcypromine proceeds through radical recombination and subsequent dehydration following a one electron oxidation and ring opening on the amine. R = ribosyl adenine dinucleotide in a-c

Figure 3
Figure 3. LSD1 substrate specificity revealed by an LSD1-inactivator crystal structure

(a) Active site view of the key interactions between Asp-556 and Ala-1, the N-terminus of the H3 peptide, and both Trp-552 and Asp-556 with Arg-2 of the H3 peptide. (b) Active site view of the configuration of the three consecutive gamma turns that the H3 peptide backbone adopts between Arg-2 and Lys-4, Thr-3 and Gln-5, and Lys-4 and Thr-6. (c) Rendering of a H3 peptide containing three consecutive gamma turns to illustrate the pseudo 7-membered rings inferred by the i, i+2 backbone hydrogen bonding.

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