ironIIketoglutarate

Iron(II) ketoglutarate, commonly described as Fe(II)–α-ketoglutarate, refers to the coordination complex formed between ferrous iron and the substrate α-ketoglutarate (2-oxoglutarate). In biochemistry, this complex functions as a cosubstrate or cofactor for a large family of non-heme iron(II)-dependent dioxygenases. These enzymes use Fe2+ and α-ketoglutarate to activate molecular oxygen for oxidative transformations, linking cellular metabolism to diverse biochemical processes.

In the enzyme active site, iron(II) is typically coordinated by a facial triad of ligands, often two histidines and one aspartate or glutamate. α-Ketoglutarate binds to Fe2+ as a bidentate ligand, forming a Fe2+–α-ketoglutarate complex that can recruit O2. Upon oxygen activation, α-ketoglutarate is oxidatively decarboxylated to succinate and CO2, generating a highly reactive iron-oxo (Fe(IV)=O) intermediate that hydroxylates or otherwise oxidizes the substrate. The catalytic cycle is completed when Fe(III) is reduced back to Fe(II), frequently with the help of cellular reducing agents such as ascorbate.

Significance and context: these cofactors are central to numerous physiological processes, including collagen biosynthesis, hypoxia signaling, and epigenetic regulation via histone and DNA demethylases. α-Ketoglutarate itself is a key metabolite of the tricarboxylic acid cycle, and its availability modulates the activity of these enzymes. Inhibitors or metabolic disturbances that affect Fe2+ or α-ketoglutarate levels can influence the function of this enzyme class.