HIF Prolyl-4-Hydroxylases
(Reference Number: UTSD:0871)

This technology features a family of HIF (hypoxia-inducible factor) prolyl hydroxylase (HPH) enzymes and the assays for such enzymatic activities.  Almost all mammalian cells express components of a hypoxia response pathway.  HIF lies at the heart of this pathway.  It is a heterodimer composed of HIF-1alpha and HIF-1beta.  Under normoxic condition, HIF-1alpha is constitutively expressed and rapidly targeted for proteasome-mediated degradation through a protein ubiquitin ligase complex containing the product of the von Hippel Lindau tumor suppressor protein (pVHL).  Only under normoxic condition, pVHL recognized the oxygen degradation domain (ODD) of HIF-1alpha through a conserved proline residue that is hydroxylated exclusively.  When cells are exposed to hypoxic enviroment, this degradation pathway is blocked, thereby allowing HIF-1alpha to accumulate and migrate to the nucleus, where it activates hypoxia-responsive genes.  The novel HPH enzymes plays a critical role modulating this HIF-1alpha hydroxylation and degradation process.  Overexpression of HPH attentuates the inappropriate accumulation of HIF-1 caused by forced expression of the HIF-1alpha subunit.  Suppression of HPH under normoxic condition results in elevated expression of hypoxia-inducible gene.  These results indicate that human HPH enzymes may be attractive targets for drug discovery.  Selective antagonists or agonists of the HPH enzymes could potentially be unique therapetuics chemicals for a variety of conditions, including but not limited to edema, inflammation, angiogenesis, etc.