2-oxoglutarate-dependent hydroxylases (2-OG hydroxylases)

Tumor-associated hydroxylases are a diverse group of enzymes, primarily belonging to the 2-oxoglutarate-dependent dioxygenase (2-OGDD) family, that play critical roles in cancer biology and the tumor microenvironment. These enzymes, which include hypoxia-inducible factor prolyl hydroxylases (PHDs), Ten-Eleven Translocation (TET) DNA hydroxylases, and aspartate beta-hydroxylase (ASPH), utilize oxygen and alpha-ketoglutarate to catalyze the hydroxylation of various substrates. In many malignancies, particularly those with IDH1 or IDH2 mutations, the production of the oncometabolite 2-hydroxyglutarate (2-HG) leads to the competitive inhibition of these hydroxylases, resulting in impaired hypoxic signaling and global DNA hypermethylation. Conversely, enzymes like ASPH are frequently overexpressed on the surface of solid tumors, where they promote malignant phenotypes such as increased motility, invasion, and metastasis. Therapeutic interventions include small molecule inhibitors of specific hydroxylases, vaccines like SNS-301 targeting tumor-specific expression, and IDH inhibitors designed to restore normal hydroxylase function by reducing 2-HG levels.

Other names

2-oxoglutarate-dependent dioxygenasesAlpha-ketoglutarate-dependent dioxygenases2-OGDDsHIF hydroxylasesTumor-associated aspartyl beta-hydroxylase (ASPH)TET enzymesCollagen prolyl hydroxylases

Inhibition of 2-oxoglutarate-dependent dioxygenase activity; Restoration of 2-oxoglutarate-dependent dioxygenase activity (via IDH inhibition); Vaccine-mediated immune response against hydroxylase-expressing cells; Inhibition of steroid 17-alpha-hydroxylase activity.