imprints, activates gene expression via H3K4 methylation [14], and possesses a
demethylase-activity-independent repression function [15]. Recently, it has been
reported that LSD2 possesses unexpected E3 ubiquitin ligase activity and inhibits
lung cancer cell growth by promoting the ubiquitylation and degradation of O-linked
N-acetylglucosamine transferase [16].
3 Structural Studies and Catalytic Mechanism of LSD1/2
The X-ray crystal structure of LSD1 complexed with CoREST and a histone H3
peptide was determined by Yang et al. [17]. This crystal structure was able to shed
light on how histone H3 is recognized. The structural data revealed that histone H3
adopts three consecutive γ-turns, establishing a side chain spacing that places its N
terminus in an anionic pocket comprised of Asn, Trp, and two Asp residues. The
structural data also confirmed the positioning of the lysine methyl groups in sufficient proximity to FAD for FAD-mediated catalysis.
The crystal structures of LSD1 and the detailed analysis of the catalytic mechanism have led to a solid understanding of the catalytic mechanism for the demethylation of methylated lysine substrates by LSD1 (Fig. 1) [6, 17–19]. First, the
methylated lysine substrate is converted into an iminium cation, presumably through
a two single-electron oxidation reactions of the amine by FAD. Next, the addition of
a water molecule to the iminium cation and the subsequent deformylation afford
demethylated lysine. The FADH 2 generated in the first step is oxidized by molecular
oxygen to FAD, which is utilized again for lysine demethylation. As would be
expected from the mechanism, the demethylation by LSD1 is limited to mono- or
dimethylated lysine; LSD1 cannot demethylate trimethylated lysine. This proposed
catalytic mechanism for the demethylation of methylated lysine substrates provides a
basis for the design of selective LSD1 inhibitors.
For the structural study of LSD2, Fang et al. characterized NPAC protein (also
known as GLYR1) as an LSD2-specific cofactor that facilitates LSD2-mediated
H3K4me1 and H3K4me2 demethylation [20]. They also determined the crystal
structures of LSD2 alone and LSD2 in complex with the NPAC protein in the
absence and presence of a histone H3 peptide. The structures revealed that the
NPAC protein stabilizes the interaction between LSD2 and the histone H3 peptide,
thus enhancing the enzymatic activity of LSD2 [21].
4 Link of LSD1/2 to Diseases
Whereas LSD1 is involved in many normal biological events, such as organogenesis
[22, 23] and adipocyte differentiation [24], it is associated with several disease states
as well, including cancer, viral infection, globin disorders, metabolic syndromes, and
neurological disorders. In this section, the links of LSD1/2 to diseases are presented.
200
T. Suzuki
demethylase-activity-independent repression function [15]. Recently, it has been
reported that LSD2 possesses unexpected E3 ubiquitin ligase activity and inhibits
lung cancer cell growth by promoting the ubiquitylation and degradation of O-linked
N-acetylglucosamine transferase [16].
3 Structural Studies and Catalytic Mechanism of LSD1/2
The X-ray crystal structure of LSD1 complexed with CoREST and a histone H3
peptide was determined by Yang et al. [17]. This crystal structure was able to shed
light on how histone H3 is recognized. The structural data revealed that histone H3
adopts three consecutive γ-turns, establishing a side chain spacing that places its N
terminus in an anionic pocket comprised of Asn, Trp, and two Asp residues. The
structural data also confirmed the positioning of the lysine methyl groups in sufficient proximity to FAD for FAD-mediated catalysis.
The crystal structures of LSD1 and the detailed analysis of the catalytic mechanism have led to a solid understanding of the catalytic mechanism for the demethylation of methylated lysine substrates by LSD1 (Fig. 1) [6, 17–19]. First, the
methylated lysine substrate is converted into an iminium cation, presumably through
a two single-electron oxidation reactions of the amine by FAD. Next, the addition of
a water molecule to the iminium cation and the subsequent deformylation afford
demethylated lysine. The FADH 2 generated in the first step is oxidized by molecular
oxygen to FAD, which is utilized again for lysine demethylation. As would be
expected from the mechanism, the demethylation by LSD1 is limited to mono- or
dimethylated lysine; LSD1 cannot demethylate trimethylated lysine. This proposed
catalytic mechanism for the demethylation of methylated lysine substrates provides a
basis for the design of selective LSD1 inhibitors.
For the structural study of LSD2, Fang et al. characterized NPAC protein (also
known as GLYR1) as an LSD2-specific cofactor that facilitates LSD2-mediated
H3K4me1 and H3K4me2 demethylation [20]. They also determined the crystal
structures of LSD2 alone and LSD2 in complex with the NPAC protein in the
absence and presence of a histone H3 peptide. The structures revealed that the
NPAC protein stabilizes the interaction between LSD2 and the histone H3 peptide,
thus enhancing the enzymatic activity of LSD2 [21].
4 Link of LSD1/2 to Diseases
Whereas LSD1 is involved in many normal biological events, such as organogenesis
[22, 23] and adipocyte differentiation [24], it is associated with several disease states
as well, including cancer, viral infection, globin disorders, metabolic syndromes, and
neurological disorders. In this section, the links of LSD1/2 to diseases are presented.
200
T. Suzuki