期刊
TRENDS IN BIOCHEMICAL SCIENCES
卷 38, 期 1, 页码 3-11出版社
ELSEVIER SCIENCE LONDON
DOI: 10.1016/j.tibs.2012.10.004
关键词
prolyl hydroxylase domain enzymes; hypoxia inducible factor; oxygen sensing; metabolism; glycolysis
资金
- Fonds Wetenschappelijk Onderzoek Vlaanderen (FWO) [G.0652.08, G.0692.09, G.0532.10, G.0817.11, 1.5.202.10.N.00]
- Marie Curie International Incoming Fellowship
- Federal Government Belgium grant [IUAP06/30]
- Flemish Government, a Concerted Research Activities Belgium grant [GOA2006/11]
- Foundation Leducq Transatlantic Network (ARTEMIS)
- ERC [EU-ERC269073]
Oxygen-sensing prolyl hydroxylase domain enzymes (PHDs) target hypoxia-inducible factor (HIF)-alpha subunits for proteasomal degradation in normoxia through hydroxylation. Recently, novel mechanisms of PHD activation and function have been unveiled. Interestingly, PHD3 can unexpectedly amplify HIF signaling through hydroxylation of the glycolytic enzyme pyruvate kinase (PK) muscle isoform 2 (PKM2). Recent studies have also yielded insight into HIF-independent PHD functions, including the control of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking in synaptic transmission and the activation of transient receptor potential cation channel member A1 (TRPA1) ion channels by oxygen levels in sensory nerves. Finally, PHD activation has been shown to involve the iron chaperoning function of poly(rC) binding protein (PCBP)1 and the (R)-enantiomer of 2-hydroxyglutarate (2-HG). The intersection of these regulatory pathways and interactions highlight the complexity of PHD regulation and function.
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