title: Emerging novel functions of the oxygen-sensing prolyl hydroxylase domain enzymes.
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.
authors.affiliation: Laboratory of Angiogenesis & Neurovascular Link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven, Belgium.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Wong
authors.forename: Anna
authors.initials: A
authors.lastname: Kuchnio
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bruning
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000818:Animals; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011393:Procollagen-Proline Dioxygenase; D010100:Oxygen