Demethylase

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Demethylases are enzymes that remove methyl (CH3) groups from nucleic acids, proteins (particularly histones), and other molecules. Demethylases are important epigenetic proteins, as they are responsible for transcriptional regulation of the genome by controlling the methylation of DNA and histones, and by extension, the chromatin state at specific gene loci.

Contents

Histone lysine demethylation

Lysine demethylatiuon mechanisms of histone lysine demethylase 1A (KDM1A) and the JmjC-domain-containing histone lysine demethylases (JHDMs). Both mechanisms involve the oxidation of a methyl group (with FAD or a-ketoglutarate as cofactors) followed by the elimination of formaldehyde. The mechanism of KDM1A and KDM1B is dependent on the formation of an iminium intermediate and therefore they may only demethylate mono- and dimethylated lysine substrates. Lysine demethylation.svg
Lysine demethylatiuon mechanisms of histone lysine demethylase 1A (KDM1A) and the JmjC-domain-containing histone lysine demethylases (JHDMs). Both mechanisms involve the oxidation of a methyl group (with FAD or α-ketoglutarate as cofactors) followed by the elimination of formaldehyde. The mechanism of KDM1A and KDM1B is dependent on the formation of an iminium intermediate and therefore they may only demethylate mono- and dimethylated lysine substrates.

Histone methylation was initially considered an effectively irreversible process as the half-life of the histone methylation was approximately equal to the histone half-life. [1] Histone lysine demethylase LSD1 (later classified as KDM1A) was first identified in 2004 as a nuclear amine oxidase homolog. [2] Two main classes of histone lysine demethylases exist, defined by their mechanisms: flavin adenine dinucleotide (FAD)-dependent amine oxidases and α-ketoglutarate-dependent hydroxylases.

Histone lysine demethylases possess a variety of domains that are responsible for histone recognition, DNA binding, methylated amino acid substrate binding and catalytic activity. These include:

Histone lysine demethylases are classified according to their domains and unique substrate specificities. The lysine substrates and identified according to their position in the corresponding histone amino acid sequence and methylation state (for example, H3K9me3 refers to trimethylated histone 3 lysine 9.)

Structure of JmJDA (coordinates from PDB file:2UXX); Some domains from above are highlighted: JmJ(N-terminus, red; C-terminus, yellow), Zinc finger domain (light purple), Beta-hairpin (light blue), and mixed domain linker (green). Jmjd2a(2UXX) with domains highlighted.png
Structure of JmJDA (coordinates from PDB file:2UXX); Some domains from above are highlighted: JmJ(N-terminus, red; C-terminus, yellow), Zinc finger domain (light purple), Beta-hairpin (light blue), and mixed domain linker (green).
Structure of KDM1A (coordinates from PDB file:2Z5U) Lysine specific demethylase 1.png
Structure of KDM1A (coordinates from PDB file:2Z5U)
KDM1
The KDM1 homologs include KDM1A and KDM1B. KDM1A demethylates H3K4me1/2 and H3K9me1/2, and KDM1B emethylates H3K4me1/2. KDM1 activity is critical to embryogenesis and tissue-specific differentiation, as well as oocyte growth. [1] Deletion of the gene for KDM1A can have effects on the growth and differentiation of embryonic stem cells and is universally lethal in knockout mice. [5] [6] KDM1A gene expression is observed to be upregulated in some cancers, [7] [8] and so KDM1A inhibition has therefore been considered a possible epigenetic treatment for cancer. [9] [10] [11] :KDM1B, however, is mostly involved in oocyte development. Deletion of this gene leads to maternal effect lethality in mice. [12] Orthologs of KDM1 in D. melanogaster and C. elegans appear to function similarly to KDM1B rather than KDM1A. [13] [14]
KDM2
The KDM2 homologs include KDM2A and KDM2B. KDM2A and KDM2B demethylate H3K4me3 and H3K36me2/3. KDM2A has roles in either promoting or inhibiting tumor function, and KDM2B has roles in oncogenesis. [1] KDM2A and KDM2B possess CXXC zinc finger domains responsible for binding to unmethylated CpG islands, and it is believed that they may bind to many gene regulatory elements in the absence of sequence-specific transcription factors. [15] :Overexpressed KDM2B has been observed in human lymphoma and adenocarcinoma, and underexpressed KDM2B has been observed in human prostate cancer and glioblastoma. KDM2B has been additionally shown to prevent senescence in some cells through ectopic expression. [16]
KDM3
The KDM3 homologs include KDM3A, KDM3B and KDM3C. KDM3A, KDM3B and KDM3C demethylate H3K9me1/2. KDM3A has roles in spermatogenesis and metabolic functions, however, the activity of KDM3B and KDM3C are not specifically known. [1] :Knockdown studies of KDM3A in mice resulted in male infertility and adult onset-obesity. Additional studies have indicated that KDM3A may play a role in regulation of androgen receptor-dependent genes as well as genes involved in pluripotency, indicating a potential role for KDM3A in tumorigenesis. [17]
KDM4
The KDM4 homologs include KDM4A, KDM4B, KDM4C, KDM4D, KDM4E and KDM4F. KDM4A, KDM4B and KDM4C demethylate H3K9me2/3, H3K9me3 and H3K36me2/3, and KDM4D, KDM4E and KDM4F demethylate H3K9me2/3. KDM4A, KDM4B, KDM4C and KDM4D have roles in tumorigenesis, however, the activity of KDM4E and KDM4F are not specifically known.. [1] KDM4B upregulation has bee observed in medulloblastoma, and KDM4C amplification has been documented in oesophageal squamous carcinoma, medulloblastoma and breast cancer. [18] [19] [20] [21] Other gene expression data has also suggested KDM4A, KDM4B, and KDM4C are overexpressed in prostate cancer. [22]
KDM5
The KDM5 homologs includes KDM5A, KDM5B, KDM5C and KDM5D. KDM5A, KDM5B, KDM5C and KDM5D demethylate H3K4me2/3. [1] The KDM5 family appears to regulate key developmental functions, including cellular differentiation, mitochondrial function and cell cycle progression. [23] [24] [25] [26] [27] [28] KDM5B and KDM5C have also shown to interaction with PcG proteins, which are involved in transcriptional repression. KDM5C mutations on the X-chromosome have also been observed in patients with X-linked intellectual disability. [29] Depletion of KDM5C homologs in D. rerio have shown brain-patterning defects and neuronal cell death. [30]
KDM6
The KDM6 family includes KDM6A, KDM6B and KDM6C. KDM6A and KDM6B demethylate H3K27me2/3, and KDM4C demethylates H3K27me3. KDM6A and KDM6B possess tumor-suppressive characteristics. KDM6A knockdowns in fibroblasts lead to an immediate increase in fibroblast population. KDM6B expressed in fibroblasts induces oncogenes of the Ras/Raf/MEK/ERK pathway. [31] Point mutations of KDM6A have been identified as one cause of Kabuki syndrome, a congenital disorder resulting in intellectual disability. [32] [33] Deletion of KDM6A in D. rerio results in decreased expression of HOX genes, which play a role in regulating body patterning during development. [34] In mammalian studies, KDM6A has been shown to regulate HOX genes as well. [35] [36] Mutation of KDM5B disrupt gonad development in C.elegans. [35] Other studies have shown that KDM6B expression is upregulated in activated macrophages and dynamically expressed during differentiation of stem cells. [37] [38]

Ester demethylation

Cartoon representation of the molecular structure of protein registered with 1A2O pdb code. 1a2o structure.png
Cartoon representation of the molecular structure of protein registered with 1A2O pdb code.

Another example of a demethylase is protein-glutamate methylesterase, also known as CheB protein (EC 3.1.1.61), which demethylates MCPs (methyl-accepting chemotaxis proteins) through hydrolysis of carboxylic ester bonds. The association of a chemotaxis receptor with an agonist leads to the phosphorylation of CheB. Phosphorylation of CheB protein enhances its catalytic MCP demethylating activity resulting in adaption of the cell to environmental stimuli. [39] MCPs respond to extracellular attractants and repellents in bacteria like E. coli in chemotaxis regulation. CheB is more specifically termed a methylesterase, as it removes methyl groups from methylglutamate residues located on the MCPs through hydrolysis, producing glutamate accompanied by the release of methanol. [40]

CheB is of particular interest to researchers as it may be a therapeutic target for mitigating the spread of bacterial infections. [41]

Chemotaxis signalling. Chemoattractants or repellents are sensed by transmembrane receptors. Note the role of CheB (B) in demethylation of MCP receptors. Chemotaxis Regulation within E. coli.png
Chemotaxis signalling. Chemoattractants or repellents are sensed by transmembrane receptors. Note the role of CheB (B) in demethylation of MCP receptors.

See also

Related Research Articles

<span class="mw-page-title-main">Histone</span> Family proteins package and order the DNA into structural units called nucleosomes.

In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wrapped into 30-nanometer fibers that form tightly packed chromatin. Histones prevent DNA from becoming tangled and protect it from DNA damage. In addition, histones play important roles in gene regulation and DNA replication. Without histones, unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA if completely stretched out; however, when wound about histones, this length is reduced to about 90 micrometers (0.09 mm) of 30 nm diameter chromatin fibers.

<span class="mw-page-title-main">Histone methyltransferase</span> Histone-modifying enzymes

Histone methyltransferases (HMT) are histone-modifying enzymes, that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues of histone proteins. The attachment of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3 and H4. Two major types of histone methyltranferases exist, lysine-specific and arginine-specific. In both types of histone methyltransferases, S-Adenosyl methionine (SAM) serves as a cofactor and methyl donor group.
The genomic DNA of eukaryotes associates with histones to form chromatin. The level of chromatin compaction depends heavily on histone methylation and other post-translational modifications of histones. Histone methylation is a principal epigenetic modification of chromatin that determines gene expression, genomic stability, stem cell maturation, cell lineage development, genetic imprinting, DNA methylation, and cell mitosis.

Histone methylation is a process by which methyl groups are transferred to amino acids of histone proteins that make up nucleosomes, which the DNA double helix wraps around to form chromosomes. Methylation of histones can either increase or decrease transcription of genes, depending on which amino acids in the histones are methylated, and how many methyl groups are attached. Methylation events that weaken chemical attractions between histone tails and DNA increase transcription because they enable the DNA to uncoil from nucleosomes so that transcription factor proteins and RNA polymerase can access the DNA. This process is critical for the regulation of gene expression that allows different cells to express different genes.

The histone code is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications to histone proteins, primarily on their unstructured ends. Together with similar modifications such as DNA methylation it is part of the epigenetic code. Histones associate with DNA to form nucleosomes, which themselves bundle to form chromatin fibers, which in turn make up the more familiar chromosome. Histones are globular proteins with a flexible N-terminus that protrudes from the nucleosome. Many of the histone tail modifications correlate very well to chromatin structure and both histone modification state and chromatin structure correlate well to gene expression levels. The critical concept of the histone code hypothesis is that the histone modifications serve to recruit other proteins by specific recognition of the modified histone via protein domains specialized for such purposes, rather than through simply stabilizing or destabilizing the interaction between histone and the underlying DNA. These recruited proteins then act to alter chromatin structure actively or to promote transcription. For details of gene expression regulation by histone modifications see table below.

<span class="mw-page-title-main">PHD finger</span>

The PHD finger was discovered in 1993 as a Cys4-His-Cys3 motif in the plant homeodomain proteins HAT3.1 in Arabidopsis and maize ZmHox1a. The PHD zinc finger motif resembles the metal binding RING domain (Cys3-His-Cys4) and FYVE domain. It occurs as a single finger, but often in clusters of two or three, and it also occurs together with other domains, such as the chromodomain and the bromodomain.

<span class="mw-page-title-main">KDM1A</span> Protein-coding gene in the species Homo sapiens

Lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a protein that in humans is encoded by the KDM1A gene. LSD1 is a flavin-dependent monoamine oxidase, which can demethylate mono- and di-methylated lysines, specifically histone 3, lysine 4 (H3K4). Other reported methylated lysine substrates such as histone H3K9 and TP53 have not been biochemically validated. This enzyme plays a critical role in oocyte growth, embryogenesis, hematopoiesis and tissue-specific differentiation. LSD1 was the first histone demethylase to be discovered though more than 30 have since been described.

<span class="mw-page-title-main">Histone-modifying enzymes</span> Type of enzymes

Histone-modifying enzymes are enzymes involved in the modification of histone substrates after protein translation and affect cellular processes including gene expression. To safely store the eukaryotic genome, DNA is wrapped around four core histone proteins, which then join to form nucleosomes. These nucleosomes further fold together into highly condensed chromatin, which renders the organism's genetic material far less accessible to the factors required for gene transcription, DNA replication, recombination and repair. Subsequently, eukaryotic organisms have developed intricate mechanisms to overcome this repressive barrier imposed by the chromatin through histone modification, a type of post-translational modification which typically involves covalently attaching certain groups to histone residues. Once added to the histone, these groups elicit either a loose and open histone conformation, euchromatin, or a tight and closed histone conformation, heterochromatin. Euchromatin marks active transcription and gene expression, as the light packing of histones in this way allows entry for proteins involved in the transcription process. As such, the tightly packed heterochromatin marks the absence of current gene expression.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">SETDB1</span> Enzyme-coding gene in humans

Histone-lysine N-methyltransferase SETDB1 is an enzyme that in humans is encoded by the SETDB1 gene. SETDB1 is also known as KMT1E or H3K9 methyltransferase ESET.

<span class="mw-page-title-main">KDM5A</span> Protein-coding gene in the species Homo sapiens

Lysine-specific demethylase 5A is an enzyme that in humans is encoded by the KDM5A gene.

<span class="mw-page-title-main">KDM4A</span> Lysine-specific demethylase 4A is an enzyme that in humans is encoded by the Kdm4a gene

Lysine-specific demethylase 4A is an enzyme that in humans is encoded by the KDM4A gene.

<span class="mw-page-title-main">KDM5C</span> Protein-coding gene in the species Homo sapiens

Lysine-specific demethylase 5C is an enzyme that in humans is encoded by the KDM5C gene. KDM5C belongs to the alpha-ketoglutarate-dependent hydroxylase superfamily.

<span class="mw-page-title-main">KMT2D</span> Protein-coding gene in humans

Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and sometimes MLL2 in humans and Mll4 in mice, is a major mammalian histone H3 lysine 4 (H3K4) mono-methyltransferase. It is part of a family of six Set1-like H3K4 methyltransferases that also contains KMT2A, KMT2B, KMT2C, KMT2F, and KMT2G.

<span class="mw-page-title-main">KDM4C</span> Protein-coding gene in the species Homo sapiens

Lysine-specific demethylase 4C is an enzyme that in humans is encoded by the KDM4C gene.

miR-137

In molecular biology, miR-137 is a short non-coding RNA molecule that functions to regulate the expression levels of other genes by various mechanisms. miR-137 is located on human chromosome 1p22 and has been implicated to act as a tumor suppressor in several cancer types including colorectal cancer, squamous cell carcinoma and melanoma via cell cycle control.

<span class="mw-page-title-main">KDM1B</span> Protein-coding gene in the species Homo sapiens

Lysine (K)-specific demethylase 1B is a protein that in humans is encoded by the KDM1B gene.

<span class="mw-page-title-main">Rob Klose</span> Canadian geneticist

Rob Klose is a Canadian researcher and Professor of Genetics at the Department of Biochemistry, University of Oxford. His research investigates how chromatin-based and epigenetic mechanisms contribute to the ways in which gene expression is regulated.

<span class="mw-page-title-main">Yi Zhang (biochemist)</span> Chinese-American biochemist

Yi Zhang is a Chinese-American biochemist who specializes in the fields of epigenetics, chromatin, and developmental reprogramming. He is a Fred Rosen Professor of Pediatrics and professor of genetics at Harvard Medical School, a senior investigator of Program in Cellular and Molecular Medicine at Boston Children's Hospital, and an investigator of the Howard Hughes Medical Institute. He is also an associate member of the Harvard Stem Cell Institute, as well as the Broad Institute of MIT and Harvard. He is best known for his discovery of several classes of epigenetic enzymes and the identification of epigenetic barriers of SCNT cloning.

H3K4me1 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the mono-methylation at the 4th lysine residue of the histone H3 protein and often associated with gene enhancers.

<span class="mw-page-title-main">Bomedemstat</span> Chemical compound

Bomedmestat is an investigational drug under development by Imago BioSciences for the treatment of myeloproliferative neoplasms including essential thrombocythemia, polycythemia vera and myelofibrosis.

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