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

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

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)13459-13464
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number21
DOIs
StatePublished - Oct 15 2002

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Ivan, M., Haberberger, T., Gervasi, D. C., Michelson, K. S., Günzler, V., Kondo, K., Yang, H., Sorokina, I., Conaway, R. C., Conaway, J. W., & Kaelin, W. G. (2002). Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proceedings of the National Academy of Sciences of the United States of America, 99(21), 13459-13464. https://doi.org/10.1073/pnas.192342099