ketoglutaratedependent

Ketoglutarate-dependent enzymes, also known as α-ketoglutarate–dependent enzymes, form a large family of non-heme iron(II)–dependent dioxygenases that use α-ketoglutarate (α-KG) and molecular oxygen to catalyze oxidation reactions. They act on a diverse set of substrates and participate in processes such as protein modification, DNA repair, and epigenetic regulation, as well as collagen biosynthesis and metabolism.

The common mechanism involves an Fe(II) center coordinated by a facial triad of ligands. α-KG binds as a co-substrate and is decarboxylated to succinate and CO2, with the activated oxygen inserted into the substrate. Depending on the enzyme, the reaction results in hydroxylation, demethylation, desaturation, or ring opening. Some reactions require ascorbate to maintain iron in the active, reduced state.

Key members and roles include:

- Prolyl hydroxylases that regulate hypoxia-inducible factor (HIF) stability, linking oxygen sensing to gene expression.

- Factor inhibiting HIF (FIH), which hydroxylates HIF on an asparagine residue, modulating transcriptional activity.

- JmjC-domain histone demethylases and TET family DNA dioxygenases, which modify chromatin and DNA methylation status, impacting epigenetic regulation.

- Collagen prolyl and lysyl hydroxylases, essential for collagen stability and extracellular matrix formation.

- AlkB family enzymes involved in repair of methylated DNA or RNA bases.

Clinical relevance includes alterations in α-KG–dependent enzymes in cancer and metabolism. Oncometabolites such as 2-hydroxyglutarate can inhibit these enzymes, affecting epigenetic regulation and cell fate. Because of their broad roles, these enzymes are active areas of research for cancer therapy, hypoxia signaling, and epigenetic modulation.

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