alphaketoglutaratedependent

Alphaketoglutaratedependent refers to alpha-ketoglutarate-dependent dioxygenases, a widespread family of non-heme iron(II)-dependent enzymes that use molecular oxygen and the co-substrate alpha-ketoglutarate (2-oxoglutarate) to introduce oxygen into diverse substrates. In the canonical reaction, alpha-ketoglutarate is decarboxylated to succinate and CO2 while the substrate is hydroxylated or otherwise oxidized. The reaction requires a ferrous iron (Fe2+) at the active site and is often assisted by ascorbate to maintain iron in the +2 state.

Most alphaketoglutaratedependent enzymes operate via an Fe(II)/2-oxoglutarate-dependent mechanism that generates a high-valent Fe(IV)=O intermediate capable of abstracting a hydrogen atom from the substrate and inserting an -OH group at the site of abstraction. Variants catalyze other oxidation patterns, including halogenation in some bacterial enzymes.

Biological roles span metabolism, epigenetics and structural biology. Prolyl-4-hydroxylases and prolyl hydroxylases regulate collagen synthesis and hypoxia signaling; factor inhibiting HIF (FIH) hydroxylates asparagine residues affecting HIF activity. Histone demethylases of the JmjC family and TET family DNA demethylases are alpha-ketoglutarate-dependent, linking metabolism to gene regulation. The AlkB family repairs alkylated DNA, and FTO is a broader demethylase. Collagen biosynthesis also relies on lysyl and prolyl hydroxylases that modify collagen residues.

Because many members require 2-oxoglutarate and Fe2+, their activity can be influenced by cellular metabolite levels and iron availability, making them relevant in contexts such as cancer and fibrosis. They are widespread across bacteria, plants and animals, reflecting essential roles in development, adaptation and epigenetic regulation.