Ascorbate-dependent metalloenzymes and redox systems

Ascorbate-dependent metalloenzymes and redox systems comprise a diverse group of enzymes that require ascorbic acid (Vitamin C) as a crucial reducing cofactor to maintain their metal centers in an active state. These enzymes primarily include copper-containing monooxygenases, such as dopamine beta-hydroxylase, and iron-containing 2-oxoglutarate-dependent dioxygenases, such as prolyl hydroxylases and TET DNA demethylases (PMID: 31443510, 34681640). They play essential roles in physiological processes including collagen triple-helix stabilization, neurotransmitter synthesis, and the epigenetic regulation of gene expression through DNA and histone demethylation (PMID: 23868258, 11375444). In clinical contexts, these systems are targeted by ascorbic acid supplementation to treat deficiency (scurvy) or by specific inhibitors like Roxadustat and Daprodustat, which target HIF-prolyl hydroxylases to treat anemia associated with chronic kidney disease (PMID: 28438194). Dysregulation of these enzymes is also implicated in cancer progression, where altered activity of TET enzymes or JmjC demethylases can lead to aberrant gene expression patterns (PMID: 25817211).

Other names

Vitamin C-dependent enzymesAscorbate-dependent monooxygenasesAscorbate-dependent dioxygenases2-oxoglutarate-dependent dioxygenasesFe(II)/2-oxoglutarate-dependent hydroxylases

Ascorbic acid acts as a specific electron donor to maintain prosthetic metal ions, typically iron (Fe2+) or copper (Cu+), in their reduced and catalytically active states. In the case of 2-oxoglutarate-dependent dioxygenases, ascorbate prevents the irreversible oxidation of the iron center that occurs during uncoupled catalytic cycles, thereby ensuring the continued hydroxylation of substrates such as proline residues in collagen or methyl groups on DNA and histones (PMID: 31443510, 11375444).