Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor

M Ivan, T Haberberger, DC Gervasi… - Proceedings of the …, 2002 - National Acad Sciences
M Ivan, T Haberberger, DC Gervasi, KS Michelson, V Günzler, K Kondo, H Yang, I Sorokina…
Proceedings of the National Academy of Sciences, 2002National Acad Sciences
The product of the von Hippel–Lindau gene, pVHL, targets the α subunits of the
heterodimeric transcription factor hypoxia-inducible factor (HIF) for polyubiquitination in the
presence of oxygen. The binding of pVHL to HIF is governed by the enzymatic hydroxylation
of conserved prolyl residues within peptidic motifs present in the HIFα family members. By
using a biochemical purification strategy, we have identified a human homolog of
Caenorhabditis elegans Egl9 as a HIF prolyl hydroxylase. In addition, we studied the activity …
The product of the von Hippel–Lindau gene, pVHL, targets the α subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF) for polyubiquitination in the presence of oxygen. The binding of pVHL to HIF is governed by the enzymatic hydroxylation of conserved prolyl residues within peptidic motifs present in the HIFα family members. By using a biochemical purification strategy, we have identified a human homolog of Caenorhabditis elegans Egl9 as a HIF prolyl hydroxylase. In addition, we studied the activity of a structurally diverse collection of low molecular weight inhibitors of procollagen prolyl 4-hydroxylase as potential inhibitors of the HIF hydroxylase. A model compound of this series stabilized HIF in a variety of cells, leading to the increased production of its downstream target, vascular endothelial growth factor.
National Acad Sciences