Ascorbate-dependent hydroxylases and related enzymes

Ascorbate-dependent hydroxylases and related enzymes are a diverse group of oxidoreductases that require L-ascorbate (Vitamin C) as a critical cofactor or co-antioxidant to maintain their catalytic metal centers in a reduced state (IUPHAR/BPS Guide to Pharmacology, 2023). This family includes the prolyl hydroxylase domain (PHD) enzymes, which serve as essential oxygen sensors by regulating the stability of hypoxia-inducible factor (HIF) (Maxwell & Eckardt, 2016). Other key members include lysyl and prolyl hydroxylases involved in collagen biosynthesis, and dopamine beta-hydroxylase, which is essential for the production of norepinephrine (UniProt, 2024). Pharmacological targeting of these enzymes has led to the development of HIF-PHD inhibitors, such as roxadustat and daprodustat, which are used to treat anemia in patients with chronic kidney disease by stimulating endogenous erythropoietin production (Haase, 2013). Additionally, inhibitors of dopamine beta-hydroxylase are explored for cardiovascular and neurological conditions. Beyond these roles, the family encompasses enzymes involved in peptide hormone maturation and epigenetic modifications via histone demethylation. Consequently, these enzymes are pivotal in maintaining physiological homeostasis and represent significant targets in oncology, hematology, and metabolic medicine.

Other names

Vitamin C-dependent hydroxylases2-oxoglutarate-dependent dioxygenasesFe(II)/2-oxoglutarate-dependent hydroxylasesAscorbate-dependent monooxygenases

The primary therapeutic mechanism involves the reversible inhibition of prolyl hydroxylase domain (PHD) enzymes, which prevents the hydroxylation and subsequent proteasomal degradation of hypoxia-inducible factor (HIF) alpha subunits (Maxwell & Eckardt, 2016). This stabilization allows HIF to translocate to the nucleus and activate the transcription of erythropoietin and other genes involved in iron metabolism and red blood cell production. Other members, like dopamine beta-hydroxylase, are targeted to inhibit the conversion of dopamine to norepinephrine, thereby modulating the sympathetic nervous system (UniProt, 2024).