Modeling dioxygenase enzyme kinetics in familial paraganglioma

Justin P. Peters, Yeng F. Her, L. James Maher

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Hypoxia inducible factors (HIFs) play vital roles in cellular maintenance of oxygen homeostasis. These transcription factors are responsible for the expression of genes involved in angiogenesis, metabolism, and cell proliferation. Here, we generate a detailed mathematical model for the enzyme kinetics of α-ketoglutaratedependent HIF prolyl 4-hydroxylase domain (PHD) dioxygenases to simulate our in vitro data showing synergistic PHD inhibition by succinate and hypoxia in experimental models of succinate dehydrogenase loss, which phenocopy familial paraganglioma. Our mathematical model confirms the inhibitory synergy of succinate and hypoxia under physiologically-relevant conditions. In agreement with our experimental data, the model predicts that HIF1α is not stabilized under atmospheric oxygen concentrations, as observed. Further, the model confirms that addition of α-ketoglutarate can reverse PHD inhibition by succinate and hypoxia in SDH-deficient cells.

Original languageEnglish (US)
Pages (from-to)1281-1289
Number of pages9
JournalBiology Open
Volume4
Issue number10
DOIs
StatePublished - 2015

Keywords

  • HIF
  • Hypoxia
  • Mathematical model
  • PHD
  • Paraganglioma

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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