Nytko, K J; Spielmann, P; Camenisch, G; Wenger, R H; Stiehl, D P (2007). Regulated Function of the Prolyl-4-Hydroxylase Domain (PHD) Oxygen Sensor Proteins. Antioxidants & Redox Signaling, 9(9):1329-1338.
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ABSTRACT Cellular oxygen is sensed by prolyl-4-hydroxylase domain (PHD) proteins that hydroxylate hypoxia-inducible factor (HIF) α subunits. Under normoxic conditions, hydroxylated HIFα is bound by the von Hippel-Lindau (pVHL) tumor suppressor, leading to ubiquitinylation and proteasomal degradation. Under hypoxic conditions hydroxylation becomes reduced, leading to HIFα stabilization. We recently showed that changes in PHD abundance and activity can regulate HIFα 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, we applied a cell-free in vitro microtiter plate-based peptide hydroxylation assay to investigate the influence of ferrous iron, Krebs cycle intermediates, transition metals, 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.
|Item Type:||Journal Article, refereed|
|Communities & Collections:||04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
|Dewey Decimal Classification:||570 Life sciences; biology|
|Uncontrolled Keywords:||PHD, Prolyl-4-Hydroxylase ascorbate, HIF, hypoxia, oxygen sensing|
|Deposited On:||11 Feb 2008 12:21|
|Last Modified:||05 Apr 2016 12:18|
|Publisher:||Mary Ann Liebert|
|Funders:||Forschungskredit of the University of Zürich, Olga Mayenfisch-Stiftung, Sassella-Stifung, Krebsliga des Kantons Zürich, 6th Framework Programme of the European Commission/SBF (EUROXY LSHC-CT-2003-502932/SBF Nr. 03.0647-2), Swiss National Science Fou|
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