Demethylases are enzymes that remove methyl (CH3-) groups from nucleic acids, proteins (in particular histones), and other molecules. Demethylase enzymes are important in epigenetic modification mechanisms. The demethylase proteins alter transcriptional regulation of the genome by controlling the methylation levels that occur on DNA and histones and, in turn, regulate the chromatin state at specific gene loci within organisms.
For many years histone methylation was thought to be irreversible, due to the fact that the half-life of the histone methylation was approximately equal to the half-life of histones themselves. In 2004, Shi et al. published their discovery of the histone demethylase LSD1 (later classified as KDM1A), a nuclear amine oxidase homolog. Since then many more histone demethylases have been found. Defined by their mechanisms, two main classes of histone demethylases exist: a flavin adenine dinucleotide (FAD)-dependent amine oxidase, and an Fe(II) and α-ketoglutarate-dependent hydroxylase. Both operate by hydroxylation of a methyl group, followed by dissociation of formaldehyde. Demethylation has implications for epigenetics.
- hydroxylation: R2NCH3 + [O] → R2NCH2OH
- loss of formaldehyde: R2NCH2OH → R2NH + CH2O
Histone demethylase proteins have a variety of domains that serve different functions. These functions include binding to the histone (or sometimes the DNA on the nucleosome), recognizing the correct methylated amino acid substrate and catalyzing the reaction, and binding cofactors. Cofactors include: alpha-keto glutarate (JmjC-domain containing demethylases), CoREST (LSD), FAD, Fe (II) or NOG (N-oxalylglycine). Domains include:
- SWIRM1 (Swi3, Rsc, and Moira domain): Proposed anchor site for histone molecules; found in several chromatin modifying complexes; facilitates demethylase protein and co-factor CoREST (nucleosomal substrate binding)
- Jumonji (N/C terminal domains): Binding domain of key cofactors such as alpha-keto glutarate; connected by a beta-hairpin/mixed domain
- PHD-finger: hydrophobic cage of residues that acts to bind methylated peptides; plays key role in recognition and selectivity for methylated histone residues
- Zinc-finger: DNA binding domain
- Amine oxidase domain: catalytic active site of LSD proteins; larger than related proteins to help fit size of the histone tail 
There are several families of histone demethylases, which act on different substrates and play different roles in cellular function. A code has been developed to indicate the substrate for a histone demethylase. The substrate is first specified by the histone subunit (H1, H2A, H2B, H3, H4) and then the one letter designation and number of the amino acid that is methylated. Lastly, the level of methylation is sometimes noted by the addition of "me#", with the numbers being 1, 2, and 3 for monomethylated, dimethylated, and trimethylated substrates, respectively. For example, H3K9me2 is histone H3 with a dimethylated lysine in the ninth position.
- The KDM1 family includes KDM1A and KDM1B. KDM1A (also referred to as LSD1/AOF2/BHC110) can act on mono- and dimethylated H3K4 and H3K9, and KDM1B (also referred to as LSD2/AOF1) acts only on mono- and dimethylated H3K4. These enzymes can have roles critical in embryogenesis and tissue-specific differentiation, as well as oocyte growth. KDM1A was the first demethylase to be discovered and thus it has been studied most extensively.
- Deletion of the gene for KDM1A can have effects on the growth and differentiation of embryonic stem cells and can lead to embryonic lethality in knockout mice, who do not produce the KDM1A gene product. KDM1A is also thought to play a role in cancer, as poorer outcomes can be correlated with higher expression of this gene. Therefore, the inhibition of KDM1A may be a possible treatment for cancer. KDM1A has many different binding partners, which may be necessary for its demethylation activity.
- KDM1B, however, is mostly involved in oocyte development. Deletion of this gene leads to maternal effect lethality in mice. Orthologs of KDM1 in D. melanogaster and C. elegans appear to function similarly to KDM1B rather than KDM1A.
- The KDM2 family includes KDM2A and KDM2B. KDM2A (also referred to as JHDM1A/FBXL11) can act on mono- and dimethylated H3K36 and trimethylated H3K4. KDM2B (also referred to as JHDM1B/FBXL10) acts only on mono- and dimethylated H3K36. KDM2A has roles in either promoting or inhibiting tumor function, and KDM2B has roles in oncogenesis.
- In many eukaryotes, the KDM2A protein contains a CXXC zinc finger domain capable of binding unmethylated CpG islands. It is currently thought that KDM2A proteins may bind to many gene regulatory elements without the aid of sequence specific transcription factors. Although the role of KDM2 in eukaryotic developmental differentiation is still largely a mystery, both KDM2A and KDM2B have been shown to play roles in tumor growth and suppression. KDM2B has been shown to be over-expressed in human lymphomas and adenocarcinomas; prostate cancers and glioblastomas, however, show reduced expression of both KDM2A and KDM2B. Additionally, KDM2B has been shown to prevent senescence in some cells through ectopic expression further indicating its potential as an oncogene.
- The KDM3 family includes KDM3A, KDM3B and JMJD1C. KDM3A (also referred to as JHDM2A/JMJD1A/TSGA) can act on mono- and dimethylated H3K9. The substrates for KDM3B (also referred to as JHDM2B/JMJD1B) and JMJD1C (also referred to as JHDM2C/TRIP8) are not known. The KDM3A has roles in spermatogenesis and metabolic functions; the roles are of KDM3B and JMJD1C are unknown.
- Knockdown studies of KDM3A in mice, where the mouse produces reduced levels of KDM3A, 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.
- The KDM4 family includes KDM4A, KDM4B, KDM4C, and KDM4D. These are also referred to as JMDM3A/JMJD2A, JMDM3B/JMJD2B, JMDM3C/JMJD2C, and JMDM3D/JMJD2D, respectively. These enzymes can act on di- and trimethylated H3K9, H3K36, H1K26. KDM4B and KDM4C have roles in tumorigenesis, and the role of KDM4D is unknown.
- The KDM4 family of proteins have been linked to malignant transformation. Specifically, KDM4C amplification has been documented in oesophageal squamous carcinomas, medulloblastomas and breast cancers; amplification of KDM4B has also been found in medulloblastomas. Other gene expression data has also suggested KDM4A, KDM4B, and KDM4C are over-expressed in prostate cancer.
- The KDM5 family includes KDM5A, KDM5B, KDM5C, and KDM5D. These are also referred to as JARID1A/RBP2, JARID1B/PLU-1, JARID1C/SMCX, and JARID1D/SMCY, respectively. These enzymes can act on di- and trimethylated H3K4.
- KDM5 protein family appear to play key developmental functions. The deletion of the JmjC domain of retinoblastoma binding protein related 2 (RBR-2) in C. elegans express defects in vulva formation. Mutations to the JmjC domain in Drosophila causes either lethal effects on larval or many developmental defects in those that survive.
- KDM5A in cell culture systems have also shown links to regulation of differentiation, mitochondrial function, cell cycle progression. KDM5B and KDM5C have also shown to interaction with PcG proteins, which are involved in transcriptional repression. KDM5C mutations (found on the X-chromosome) have also been found in patients with X-linked mental retardation. Depletion of KDM5C homologs in D. rerio have shown brain-patterning defects and neuronal cell death.
- The KDM6 family includes KDM6A, KDM6B, and UTY. KDM6A (also referred to as UTX) and KDM6B (also referred to as JMJD3) act on di- and trimethylated H3K27 and have roles in development; the substrate and role of UTY is unknown. On the whole, both 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 pathway. Deletions and point mutations of KDM6A have been identified as one cause of Kabuki Syndrome, a congenital disorder resulting in intellectual disability.
- Other possible roles have been suggested for KDM6B. Specifically in one study, mutating homologs of KDM6B disrupted gonadal development in C.elegans. Other studies have shown that KDM6B expression is up-regulated in activated macrophages and dynamically expressed during differentiation of stem cells.
- On the other hand, depletion of homologs of KDM6A in D. rerio have shown decreased expression of HOX genes, which play a role in regulating body patterning during development. In mammalian studies, KDM6A has been shown to regulate HOX genes as well.
Another example of a demethylase is protein-glutamate methylesterase, also known as CheB protein (EC 18.104.22.168), 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. 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.
CheB is of particular interest to researchers as it may be a therapeutic target for mitigating the spread of bacterial infections.
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