Lysine-specific demethylase

Histone methylation is a common posttranslational modification fond in histones. Histone methylations have been identified on lysine and arginine residues. In case of lysines S-adenosyl-methionine (SAM) dependent methyl transferases catalyze the transfer of one, two or three methyl groups. Lysine methylation is reversible and lysine specific demethylases have been... 

Lysine specific demethylases have been classified into seven groups named KDMl to KDM7 (KDM for Lysine DeMethylase) [90,91,95]. The KDMl group comprises the first enzyme that has been identified as a lysine specific histone demethylase (LS D1). 

LSDl, also known as BHCllO, is the first lysine specific demethylase that was discovered. It has been assigned to group I of lysine demethylases (KDMl) [90, 91]. LSDl contains an amine oxidase domain responsible of the enzymatic activity and has been isolated as a stable component from several histone modifying complexes. The enzymatic characterization of this protein revealed that FAD (flavine adenine dinucleotide) is required as a cofactor for the removal of the methyl group. Furthermore, LSDl requires a protonated nitrogen in order to initiate demethylation so that this enzyme is only able to demethylate mono- or dimethylated substrates but not trimethylated substrates [98, 99]. 

Chen, Y, Yang, Y, Wang, F., Wan, K., Yamane, K., Zhang, Y. and Lei, M. (2006) Crystal structure ofhuman histone lysine-specific demethylase 1 (LSDl). Proceedings of the National Academy of Sciences of the United States of America, 103 (38), 13956-13961. 

There are demethylases which act like amine oxidases that are dependent in their mechanism on their cosubstrate flavine adenine dinucleotide (FAD). So far, lysine-specific demethylase 1 (LSDl) is the only representative of this class [62]. LSDl, as an amine oxidase leads to oxidation of the methylated lysine residue, generating an imine intermediate, while the protein-bound cosubstrate FAD is reduced to FAD H2. In a second step, the imine intermediate is hydrolyzed to produce the demethylated histone lysine residue and formaldehyde. Importantly the reduced cosubstrate is regenerated to its oxidized form by molecular oxygen, producing hydrogen peroxide (Figure 5.7) [62, 63]. 

Stavropoulos P, Blobel G, Hoelz A. Crystal structure and mechanism of human lysine-specific demethylase-1. Nat. Struct. Mol. 111. Biol. 2006 13 626-632. 

Alkylamino- and alkylguanidinolysine analog inhibitors of lysine-specific demethylase 1... 

Parnate Inhibits lysine-specific demethylase 1 Li et al. (2009b)... 

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