Prolyl hydroxylases: Introduction

Hypoxia inducible factor (HIF) is a transcriptional complex that is involved in oxygen homeostasis [4]. At normal oxygen levels, the alpha subunit of HIF (HIF-1α) is targeted for degradation by prolyl hydroxylation by the prolyl hydrolxyases (PHD) proteins 1-3 (HIF-PHs) whch are 2-oxoglutarate oxygenases responsible for the post-translational modification of a specific proline in each of the oxygen-dependent degradation domains of HIF-1α. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex [3]. Under hypoxic conditions, the hydroxylation reaction is blunted which results in decreased HIF degradation. The surviving HIFs are then available to translocate to the nucleus where they heterodimerize with HIF-1β, effecting increased expression of hypoxia-inducible genes.
HIF-PH enzymes are being investigated as pharmacological targets as their inhibition mimics the hypoxic state and switches on transcription of genes associated with processes such as erythropoiesis and vasculogenesis [2]. Small molecule HIF-PH inhibitors are in clinical trial as novel therapies for the amelioration of anemia associated with chronic kidney disease [1].

References

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1. Bouchie A. (2013) First-in-class anemia drug takes aim at Amgen's dominion. Nat Biotechnol, 31 (11): 948-9. [PMID:24213751]

2. Forristal CE, Levesque JP. (2014) Targeting the hypoxia-sensing pathway in clinical hematology. Stem Cells Transl Med, 3 (2): 135-40. [PMID:24371328]

3. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ et al.. (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science, 292 (5516): 468-72. [PMID:11292861]

4. Semenza GL. (2001) HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell, 107 (1): 1-3. [PMID:11595178]

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Prolyl hydroxylases, introduction. Last modified on 28/11/2018. Accessed on 28/11/2022. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetomalariapharmacology.org/GRAC/FamilyIntroductionForward?familyId=900.