Regulation of the 2-oxoglutarate-dependent dioxygenases and implications for cancer

Abstract

There is growing interest in the family of 2-OG (2-oxoglutarate)-dependent dioxygenase enzymes that catalyse the hydroxylation of a wide range of organic targets. Members of this family that regulate the cell's hypoxic response and epigenetic processes, particularly the demethylation of histones and DNA, have been identified in mammalian cells. The dependence of these enzymes on molecular oxygen and 2-OG as obligatory substrates, together with their need for iron and ascorbate as cofactors, has implications for their role as metabolic sensors. The oxygen-sensing property is utilized by the hydroxylases that regulate hypoxia-inducible factor and this has been well characterized, particularly with respect to tumour biology. However, the potential for metabolic sensing more generally is also of interest, and future research will expand our understanding of the effect of mitochondrial viability and nutrient (iron and ascorbate) supply on 2-OG-dependent dioxygenase activity.