Fe22oxoglutaratedependent

Fe2+/2-oxoglutarate-dependent dioxygenases, also known as Fe(II)/2-oxoglutarate-dependent dioxygenases or 2-OG oxygenases, are a large family of non-heme iron enzymes that catalyze diverse oxidative reactions using ferrous iron and 2-oxoglutarate (2-OG) as cosubstrates. They typically hydroxylate substrates but can also perform other oxidative transformations, incorporating one atom of molecular oxygen into the substrate while converting 2-OG to succinate and CO2.

Mechanism and active site: The active site binds Fe2+ through a conserved facial triad formed by two histidines and one aspartate or glutamate. Substrate and 2-OG coordinate to the iron, facilitating O2 binding and activation. Decarboxylation of 2-OG drives formation of a high-valent iron-oxo intermediate (often described as FeIV=O) that abstracts hydrogen from the substrate and delivers the oxidative modification. This mechanism underpins the broad substrate scope and reaction diversity seen in the family.

Scope and roles: 2-OG–dependent dioxygenases participate in many biological processes. They include collagen prolyl and lysyl hydroxylases essential for collagen maturation, hypoxia-inducible factor prolyl hydrolases that regulate cellular oxygen sensing, AlkB family enzymes that reverse methylation on DNA and RNA, and JmjC-domain histone demethylases involved in epigenetic regulation. They are present in bacteria, archaea, and eukaryotes and contribute to metabolism, repair, and regulation.

Structure and regulation: Most members share a double-stranded beta-helix (DSBH) fold with the conserved metal-binding motif and rely on Fe2+ and 2-OG. Ascorbate can support Fe2+ recycling in some enzymes, and activity is sensitive to redox conditions and metal availability.

Clinical and research relevance: Because of roles in collagen biosynthesis, gene regulation, and DNA/RNA repair, dysregulation or inhibition of these enzymes is linked to fibrosis, cancer, anemia, and developmental disorders. They are active targets in biochemical and therapeutic research.