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

• DOI: 10.1073/pnas.192342099
• Publication Date: 2002-10-15T16:43:03Z
• Authors: Mircea Ivan; Thomas Haberberger; David C. Gervasi; Kristen S. Michelson; Volkmar Günzler; Keiichi Kondo; Haifeng Yang; Irina Sorokina; Ronald C. Conaway; Joan W. Conaway; William G. Kaelin
• Keywords: Hydroxylation; Hypoxia-Inducible Factors; Hypoxia-Inducible Factor 1

The product of the von Hippel-Lindau gene, pVHL, targets alpha subunits heterodimeric transcription factor hypoxia-inducible (HIF) for polyubiquitination in presence oxygen. binding pVHL to HIF is governed by enzymatic hydroxylation conserved prolyl residues within peptidic motifs present HIFalpha family members. By using a biochemical purification strategy, we have identified human homolog Caenorhabditis elegans Egl9 as hydroxylase. In addition, studied activity structurally diverse collection low molecular weight inhibitors procollagen 4-hydroxylase potential A model compound this series stabilized variety cells, leading increased production its downstream target, vascular endothelial growth factor.