Editing Α-Ketoglutaric acid (section)

====Fe2+/α-ketoglutarate-dependent dioxygenase enzymes and TET enzymes====
α-Ketoglutarate is a cofactor that activates [[Demethylase#histone-lysine demethylase|histone-lysine demethylase]] [[protein superfamily]]. This superfamily consists of two groups, the FAD-dependent amine oxidases which do not require α-ketoglutarate for activation and the Fe2+/α-ketoglutarate-dependent dioxygenases (Fe2+ is the [[ferrous]] form of iron, i.e., Fe<sup>2+</sup>). The latter group of more than 30 enzymes is classified into 7 subfamilies termed histone lysine demethylases, i.e., HDM2 to HDM7, with each subfamily having multiple members. These HDMs are characterized by containing a Jumonji C (JmjC) [[protein domain]]. They function as [[dioxygenase]]s or [[hydroxylase]]s to remove [[methyl]] groups from the [[lysine]] residues on the [[histone]]s enveloping DNA and thereby alter the expression of diverse genes.<ref name="pmid26816087">{{cite journal | vauthors = Park SY, Park JW, Chun YS | title = Jumonji histone demethylases as emerging therapeutic targets | journal = Pharmacological Research | volume = 105 | issue = | pages = 146–51 | date = March 2016 | pmid = 26816087 | doi = 10.1016/j.phrs.2016.01.026 | url = }}</ref><ref name="pmid34944554">{{cite journal | vauthors = Staehle HF, Pahl HL, Jutzi JS | title = The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies | journal = Biomolecules | volume = 11 | issue = 12 | date = December 2021 | page = 1911 | pmid = 34944554 | pmc = 8699298 | doi = 10.3390/biom11121911 | doi-access = free | url = }}</ref> These altered gene expressions lead to a wide range of changes in the functions of various cell types and thereby caused the development and/or progression of various cancers, pathological inflammations, and other disorders (see [[Alpha-ketoglutarate-dependent hydroxylases#Biological function|α-Ketoglutarate-dependent demethylase biological functions]]).<ref name="pmid36050314"/><ref name="pmid37694689">{{cite journal | vauthors = Maity J, Majumder S, Pal R, Saha B, Mukhopadhyay PK | title = Ascorbic acid modulates immune responses through Jumonji-C domain containing histone demethylases and Ten eleven translocation methylcytosine dioxygenase | journal = BioEssays | volume = 45 | issue = 11 | pages = e2300035 | date = November 2023 | pmid = 37694689 | doi = 10.1002/bies.202300035 | url = }}</ref> The [[TET enzymes]] (i.e., ten-eleven translocation (TET) methylcytosine dioxygenase family of enzymes) consists of three members, TET-1, TET-2, and TET-3. Like the Fe2+/α-ketoglutarate-dependent dioxygenases, all three TET enzymes require Fe<sup>2+</sup> and α-ketoglutarate as cofactors to become activated. Unlike the dioxygenases, however, they remove methyl groups from the 5-methylcytosines of [[DNA]] sites that regulate the expression of nearby genes. These demethylations have a variety of effects including, similar to the Fe2+/α-ketoglutarate-dependent dioxygenases, alteration of the development and/or progression of various cancers, immune responses, and other disorders (see [[TET enzymes#TET functions|functions of TET enzymes]]).<ref name="pmid35705880">{{cite journal | vauthors = Joshi K, Liu S, Breslin SJ, Zhang J | title = Mechanisms that regulate the activities of TET proteins | journal = Cellular and Molecular Life Sciences  | volume = 79 | issue = 7 | pages = 363 | date = June 2022 | pmid = 35705880 | pmc = 9756640 | doi = 10.1007/s00018-022-04396-x | url = }}</ref><ref name="pmid38360546">{{cite journal | vauthors = López-Moyado IF, Ko M, Hogan PG, Rao A | title = TET Enzymes in the Immune System: From DNA Demethylation to Immunotherapy, Inflammation, and Cancer | journal = Annual Review of Immunology | volume = 42| issue = | pages = | date = February 2024 | pmid = 38360546 | doi = 10.1146/annurev-immunol-080223-044610 | url = }}</ref>

=====β-Ketoglutaric acid and TET-2=====
β-Ketoglutaric acid has been detected in the saliva of individuals chewing [[betel quid chewing|betel quid]], a complex mixture derived from [[betel nut]]s mixed with various other materials. Chronic chewing betel quid is associated with the development of certain cancers, particularly those in the [[oral cavity]]. The study showed that β-ketoglutaric acid bound to the cancer-promoting protein [[TET-2]] thereby inhibiting α-ketoglutarate's binding to this protein. Since α-ketoglutarate's binding of TET-2 is thought to be required for it to activate TET-2, the study suggested that β-ketoglutaric acid may not fulfill the requirements for TET-2 to be activatable and therefore may prove able to block α-ketoglutarate's cancer-promoting as well as inflammation-promoting and other actions that involve its activation of TET-2.<ref name="pmid37830116">{{cite journal | vauthors = Bhatkar D, Ananda N, Lokhande KB, Khunteta K, Jain P, Hebale A, Sarode SC, Sharma NK | title = Organic Acids Derived from Saliva-amalgamated Betel Quid Filtrate Are Predicted as a Ten-eleven Translocation-2 Inhibitor | journal = Journal of Cancer Prevention | volume = 28 | issue = 3 | pages = 115–130 | date = September 2023 | pmid = 37830116 | pmc = 10564634 | doi = 10.15430/JCP.2023.28.3.115 | url = }}</ref>