Emerging novel functions of the oxygen-sensing prolyl hydroxylase domain enzymes

Brian W. Wong, Anna Kuchnio, Ulrike Bruning, Peter Carmeliet

Research output: Contribution to journalReview articlepeer-review

104 Scopus citations

Abstract

Oxygen-sensing prolyl hydroxylase domain enzymes (PHDs) target hypoxia-inducible factor (HIF)-α 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 α-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.

Original languageEnglish
Pages (from-to)3-11
Number of pages9
JournalTrends in biochemical sciences
Volume38
Issue number1
DOIs
StatePublished - Jan 2013

Keywords

  • Glycolysis
  • Hypoxia inducible factor
  • Metabolism
  • Oxygen sensing
  • Prolyl hydroxylase domain enzymes

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