Iron(II) and 2-oxoglutarate-dependent dioxygenase superfamily (2OGDDs)

The Iron(II) and 2-oxoglutarate (2OG)-dependent dioxygenase superfamily, often grouped to include various 'other' enzymes beyond the well-characterized HIF hydroxylases, represents a vast array of oxidoreductases essential for diverse metabolic and regulatory pathways. These enzymes utilize Fe(II) as a cofactor and 2-oxoglutarate as a co-substrate to catalyze reactions such as hydroxylation, demethylation, and oxidative ring closure (Hausinger, 2004; Martinez & Hausinger, 2015). Key members within this 'other' category include the AlkB homologues involved in DNA repair, the FTO protein which regulates RNA methylation and energy homeostasis, and enzymes like phytanoyl-CoA hydroxylase required for fatty acid metabolism (Islam et al., 2018). Dysregulation of these enzymes is linked to a variety of conditions, including obesity (FTO), Refsum disease (PHYH), and various cancers where DNA repair or epigenetic mechanisms are compromised (Rose et al., 2011). While many members are being explored as therapeutic targets, the primary challenge in drug development is achieving selectivity due to the highly conserved 2-oxoglutarate binding pocket shared across the entire superfamily (Maxwell & Eckardt, 2016). Consequently, inhibitors must be carefully designed to avoid broad-spectrum inhibition that could lead to significant toxicity or unintended metabolic consequences.

Other names

2-oxoglutarate-dependent oxygenasesAlpha-ketoglutarate-dependent hydroxylasesFe(II)/2OG dioxygenases2OG-dependent dioxygenases

Inhibition of enzymatic activity through competitive binding at the 2-oxoglutarate co-substrate site or by chelating the catalytic iron (FeII) atom, thereby blocking the oxidative decarboxylation required for substrate transformation (Martinez & Hausinger, 2015).