Lysine-specific demethylase 1 (LSD-1): Difference between revisions
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== Introduction == | == Introduction == | ||
[[Image:Histonemm.png |250px|right|thumb| Figure 1: The crystal structure of a histone core octamer (each subunit in a different color) bound to DNA. PDB:5y0c]] | [[Image:Histonemm.png |250px|right|thumb| Figure 1: The crystal structure of a histone core octamer (each subunit in a different color) bound to DNA. PDB:5y0c]] | ||
<scene name='83/834203/Overall_lsd-1/1'>LSD-1</scene>, '''human lysine-specific demethylase 1,''' is an enzyme that affects the ability of DNA to associate with [https://proteopedia.org/wiki/index.php/Nucleosome histone proteins]. Histone proteins contain residues that give them an overall positive charge and allow them to act as spools upon which negatively charged DNA can wrap around for storage in the nucleus of a cell (Figure 1). When DNA is tightly condensed it forms into [https://proteopedia.org/wiki/index.php/Nucleosome_structure nucleosomes] which consist of eight histone core proteins (2 H2A, 2 H2B, 2 H3, 2 H4) with DNA tightly coiled around them. This tightly coiled DNA is known as [https://en.wikipedia.org/wiki/Heterochromatin heterochromatin], which is inaccessible to [https://en.wikipedia.org/wiki/Transcription_factor transcription factors] and [https://en.wikipedia.org/wiki/RNA_polymerase RNA polymerase]. This can be reversed by [https://en.wikipedia.org/wiki/Post-translational_modification modifications] to the histone protein structure that cause the DNA to relax and form [https://en.wikipedia.org/wiki/Euchromatin euchromatin], which allows for gene expression. One key histone modification is the [https://en.wikipedia.org/wiki/Methyltransferase methylation] and subsequent [https://en.wikipedia.org/wiki/Demethylase demethylation] of lysine residues. Before 2004, it was believed that methylation of histone tails was stable and irreversible. In 2004, it was discovered that histone tails can also be demethylated by demethylase enzymes such as LSD-1.<ref name="Shi">doi: 10.1016/j.cell.2004.12.012</ref> | <scene name='83/834203/Overall_lsd-1/1'>LSD-1</scene>, '''human lysine-specific demethylase 1,''' is an enzyme that affects the ability of DNA to associate with [https://proteopedia.org/wiki/index.php/Nucleosome histone proteins]. Histone proteins contain residues that give them an overall positive charge and allow them to act as spools upon which negatively charged DNA can wrap around for storage in the nucleus of a cell (Figure 1). When DNA is tightly condensed it forms into [https://proteopedia.org/wiki/index.php/Nucleosome_structure nucleosomes] which consist of eight histone core proteins (2 H2A, 2 H2B, 2 H3, 2 H4) with DNA tightly coiled around them. This tightly coiled DNA is known as [https://en.wikipedia.org/wiki/Heterochromatin heterochromatin], which is inaccessible to [https://en.wikipedia.org/wiki/Transcription_factor transcription factors] and [https://en.wikipedia.org/wiki/RNA_polymerase RNA polymerase]. This can be reversed by [https://en.wikipedia.org/wiki/Post-translational_modification post-translational modifications] to the histone protein structure that cause the DNA to relax and form [https://en.wikipedia.org/wiki/Euchromatin euchromatin], which allows for gene expression. One key histone modification is the [https://en.wikipedia.org/wiki/Methyltransferase methylation] and subsequent [https://en.wikipedia.org/wiki/Demethylase demethylation] of lysine residues. Before 2004, it was believed that methylation of histone tails was stable and irreversible. In 2004, it was discovered that histone tails can also be demethylated by demethylase enzymes such as LSD-1.<ref name="Shi">doi: 10.1016/j.cell.2004.12.012</ref> | ||
There are two main classes of demethylases, and they are categorized by their cofactors and reaction mechanisms. The KDM1 family of demethylases employs a flavin adenine dinucleotide [https://en.wikipedia.org/wiki/Flavin_adenine_dinucleotide (FAD)] cofactor to catalyze the demethylation reaction. The other class of demethylases consists of five families (KDM2-6) and use an Fe<sup>2+</sup> ion cofactor and [https://en.wikipedia.org/wiki/Alpha-Ketoglutaric_acid α-ketoglutarate] as a cosubstrate to catalyze the reaction. Although the cofactors used are different, both classes operate by hydroxylating the target methyl group. LSD-1 is in the KDM1 family of histone demethylases that uses FAD as a cofactor. LSD-1 specifically demethylates mono- or di-methylated lysine substrates at Lys4 or Lys9 in the tail of histone H3.<ref name="Forneris">PMID: 15811342</ref> Demethylation of these lysine residues is commonly associated with transcriptional activation, but it also has the ability to silence genes depending on the residue being demethylated, the cofactors present, and the environment in which the demethylation occurs. | There are two main classes of demethylases, and they are categorized by their cofactors and reaction mechanisms. The KDM1 family of demethylases employs a flavin adenine dinucleotide [https://en.wikipedia.org/wiki/Flavin_adenine_dinucleotide (FAD)] cofactor to catalyze the demethylation reaction. The other class of demethylases consists of five families (KDM2-6) and use an Fe<sup>2+</sup> ion cofactor and [https://en.wikipedia.org/wiki/Alpha-Ketoglutaric_acid α-ketoglutarate] as a cosubstrate to catalyze the reaction. Although the cofactors used are different, both classes operate by hydroxylating the target methyl group. LSD-1 is in the KDM1 family of histone demethylases that uses FAD as a cofactor. LSD-1 specifically demethylates mono- or di-methylated lysine substrates at Lys4 or Lys9 in the tail of histone H3.<ref name="Forneris">PMID: 15811342</ref> Demethylation of these lysine residues is commonly associated with transcriptional activation, but it also has the ability to silence genes depending on the residue being demethylated, the cofactors present, and the environment in which the demethylation occurs. | ||