Ten-eleven translocation family DNA dioxygenase (TET)

The Ten-eleven translocation (TET) family of DNA dioxygenases, comprising TET1, TET2, and TET3, are critical enzymes responsible for active DNA demethylation in mammals (UniProt, 2023). They function by converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and further oxidation products, which are eventually replaced by unmethylated cytosine through the base excision repair pathway (PubMed: 21490601). This process is essential for regulating gene expression, maintaining stem cell pluripotency, and guiding proper embryonic development (NIH, 2024). Mutations in TET genes, particularly TET2, are frequently observed in hematological malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), where loss of function leads to DNA hypermethylation and impaired hematopoietic differentiation (Nature Reviews Cancer, 2017). Therapeutic strategies involve restoring TET activity using co-factors like Vitamin C or inhibiting the production of oncometabolites like 2-hydroxyglutarate that suppress TET function (Cell, 2016). Conversely, small molecule inhibitors like Bobcat313 are being explored for research and potential therapeutic use where TET activity modulation is required (ACS Chemical Biology, 2019). Given their broad role in the epigenome, targeting TET enzymes requires careful consideration of off-target effects on global gene expression patterns.

Other names

TET proteinsMethylcytosine dioxygenaseTen-eleven translocation proteinsTET1TET2TET35mC hydroxylase

Drugs targeting TET enzymes primarily act by either enhancing their catalytic activity through cofactors like Vitamin C or inhibiting their function using small molecules that compete with the alpha-ketoglutarate substrate. Additionally, indirect modulation occurs through the inhibition of mutant IDH enzymes to reduce levels of the competitive inhibitor 2-hydroxyglutarate.