Ten-eleven translocation family dioxygenases (TET)

The Ten-eleven translocation (TET) family of dioxygenases, comprising TET1, TET2, and TET3, are critical epigenetic regulators that catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and subsequent oxidative products. This enzymatic pathway is the primary mechanism for active DNA demethylation in mammals, playing a vital role in embryonic development, stem cell pluripotency, and hematopoiesis (PMID: 19372391, 21151104). Dysregulation or loss-of-function mutations in TET proteins, particularly TET2, are strongly associated with hematological malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), where they lead to DNA hypermethylation and blocked cellular differentiation (PMID: 20463238). In the context of drug development, TET enzymes are targeted either through restoration of activity using cofactors like Vitamin C or through the development of small-molecule inhibitors to study their role in various cancers and inflammatory diseases (PMID: 28823558, 31241916). These enzymes require Fe(II) and alpha-ketoglutarate as essential cofactors for their catalytic function, making them sensitive to metabolic changes. Consequently, metabolic alterations that affect these cofactors, such as IDH1/2 mutations producing the oncometabolite 2-hydroxyglutarate, directly impact TET activity and contribute to oncogenesis (PMID: 20164920). Understanding the balance of TET activity is essential for developing epigenetic therapies that can reprogram the methylome of diseased cells.

Other names

TET proteinsMethylcytosine dioxygenasesTen-eleven translocation proteinsTET1/2/35-methylcytosine dioxygenases

Cofactor-mediated activation of enzymatic activity to promote DNA demethylation or competitive inhibition of the alpha-ketoglutarate binding site to modulate epigenetic states.