Fe2ketoglutarate

Fe2ketoglutarate, also known as ferrous α-ketoglutarate or Fe(II)-α-ketoglutarate, refers to the coordination complex between Fe2+ and α-ketoglutarate (αKG) that acts as a cofactor in a family of enzymes called α-ketoglutarate-dependent dioxygenases. In biological systems, this complex is typically an integral part of the active site rather than a isolated standalone compound.

In non-heme iron enzymes, Fe2+ is usually coordinated by a 2-His-1-carboxylate facial triad, with αKG binding to the metal center in a bidentate fashion. The enzyme binds molecular oxygen, triggering oxidative decarboxylation of αKG to succinate and CO2 and generating a highly reactive Fe(IV)=O species. This ferryl intermediate can hydroxylate substrates or perform other oxidation reactions. After the reaction, Fe(II) is regenerated to continue turnover, typically with the help of reductants present in the cellular environment.

Biological roles of Fe2ketoglutarate–dependent systems are diverse. They include collagen and hypoxia-inducible factor (HIF) regulation (via prolyl and asparagine hydroxylases), DNA and histone demethylation (via TET and Jumonji family enzymes), and various metabolic and biosynthetic hydroxylation steps. These enzymes participate in processes such as collagen maturation, gene expression control, and cellular response to oxygen availability.

Chemically, Fe2ketoglutarate is studied primarily within enzyme active sites or as model complexes. Its activity depends on maintaining the Fe2+ oxidation state and the availability of αKG and molecular oxygen. Dysregulation of αKG-dependent pathways has been implicated in disease contexts and is of interest in drug development and biocatalysis.