A Mechanism-Based Inactivator for Histone Demethylase LSD1

摘要

Histone modification has emerged as a major mechanism of regulation in gene expression,replication,and repair.Such histone modifications are thought to affect histone interactions with DNA and other proteins.Among the post-translational histone modifications,methylation of lysine residues has emerged as critical in blocking histone acetylation and mediating protein-protein interactions that can activate or repress transcription.Lysine methylation was viewed as a permanent histone mark until recently when the first histone lysine demethylase,LSD1 (also called BHC110),was discovered.LSD 1 belongs to the amine oxidase family which are flavin-dependent enzymes that utilize O_2 and generate H_2O_2 and formaldehyde as byproducts (Scheme 1).LSD1 has been shown to be specific for Lys-4 of histone H3 and can oxidatively demethylate the dimethyl or monomethyl Lys-containing substrates.