Lysine histone 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... 

Whetstine JR, Nottke A, Lan F, Huarte M, Smolikov S, Chen Z, Spooner E, Li E, Zhang G, Colaiacovo M et al (2006) Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125 467 81... 

Another speculation has been put forth. Because the turnover of methyl groups such as the modification on lysine residues is low, ubiquitination of histone N-termini might serve as a signal for proteolysis of methylated histones such that dynamic regulation of the chromatin is possible. Since no histone demethylases have been identified, ubiquitin-mediated proteolysis might be a way to reverse the effects of histone methylation. ... 

Reversible histone methylation is a highly specific process that is catalyzed by the action of histone methyltransferases (HMTs) and histone demethylases on lysine and arginine residues. Like DNMTs, HMTs employ a SAM cofactor. Lysine can be... 

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]. 

Figure 13.2 (a) Sequential methylation and demethylation of lysines catalyzed by histone methyl transferases (HMTs) and histone demethylases (HDMs), respectively, (b) Sequential methylation and demethylation of arginines catalyzed by HMTs and HDMs, respectively, leading to symmetric and asymmetric dimethylarginines. 

Kahl, P., Gullotti, L., Heukamp, L.C., Wolf, S., Friedrichs, N., Vorreuther, R., Solleder, G., Bastian, P.J., Ellinger, J., Metzger, E., Schule, R. and Buettner, R. (2006) Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence. Cancer Research, 66, 11341-11347. 

De Santa, F., Totaro, M.G., Prosperini, E., Notarbartolo, S., Testa, G. and Natoli, G. (2007) The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell, 130, 1083-1094. 

Histone modifications, such as phosphorylation, acetylation, and methylation, regulate gene expression. " Histone lysine methylation was considered a static modification, until relatively recently, when histone demethylases were discovered." One such enzyme is ESDI, which belongs to the amine oxidase superfamily. ESDI catalyzes the demethylation of mono- and disubstituted Eys 4 of histone H3" in a reductive halfreaction very similar to those catalyzed by DAAO and MAO by oxidizing the amino group of the methylated lysine to the corresponding imino product, which hydrolyzes nonenzymatically to formaldehyde (Equation (2)). 

Figure 5.13 Histone demethylases. Structures and mechanisms are illustrated for the two subclasses of histone lysine demethylases. (a) Views from an X-ray crystal structure of LSDl (PDB ID 2V1D) in complex with cofactor FAD and a peptide substrate analogue, where methionine replaces methylated lysine, and outline mechanism of the LSDl-catalysed demethylation reaction, (b) Views from an X-ray crystal structure of JMJD2A (PDB ID 20Q6) in complex with co-factor analogue N-oxa-lylglycine and histone substrate trimethylated at H3K9 (note that Ni(II) replaces Fe(II) for crystallography), and outline mechanism of JmjC-domain catalysed lysine demethylation. (c) Representative inhibitors of LSDl and JmjC-domain demethylases.

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