Regulated function of the prolyl-4-hydroxylase domain (PHD) oxygen sensor proteins.

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Nytko KJ, Spielmann P, Camenisch G, Wenger RH, Stiehl DP

Regulated function of the prolyl-4-hydroxylase domain (PHD) oxygen sensor proteins.

Antioxid Redox Signal. 2007 Sep;9(9):1329-38.

PubMed ID

17627474 [ View in PubMed

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Abstract

Cellular oxygen is sensed by prolyl-4-hydroxylase domain (PHD) proteins that hydroxylate hypoxia-inducible factor (HIF) alpha subunits. Under normoxic conditions, hydroxylated HIFalpha is bound by the von Hippel-Lindau (pVHL) tumor suppressor, leading to ubiquitinylation and proteasomal degradation. Under hypoxic conditions, hydroxylation becomes reduced, leading to HIFalpha stabilization. The authors recently showed that changes in PHD abundance and activity can regulate HIFalpha stability under normoxic as well as under hypoxic conditions. Thus, the PHD oxygen sensors themselves represent effectors of cellular signalling pathways as well as potential drug targets. Here, a cell-free in vitro microtiter plate-based peptide hydroxylation assay was used to investigate the influence of ferrous iron, Krebs cycle intermediates, transition metals, and vitamin C and other antioxidants on the activity of purified PHD1 to 3. PHD activity depends not only on oxygen availability but is also regulated by iron, vitamin C, and Krebs cycle intermediates, suggesting a physiological relevance of their cellular concentrations. Copper but not iron, cobalt, or nickel salts catalyzed vitamin C oxidation. While vitamin C is essential for PHD activity in vitro, N-acetyl-L-cysteine had no effect, and gallic acid or n-propyl gallate efficiently inhibited the activity of all three PHDs, demonstrating different functions of these antioxidants.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Ascorbic acid	Egl nine homolog 2	Protein	Humans	Unknown	Cofactor	Details