- Advanced search
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
The hypoxia inducible factor (HIF) is a transcriptional complex that is involved in oxygen homeostasis . At normal oxygen levels, the alpha subunit of HIF (HIF-1α) is targeted for degradation by prolyl hydroxylation by the PHD proteins 1-3 (HIF-PHs) whch are 2-oxoglutarate (2OG) oxygenases responsible for the post-translational modification of a specific proline in each of the oxygen-dependent degradation (ODD) domains of HIF-1α. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex . 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 . Small molecule HIF-PH inhibitors are in clinical trial as novel therapies for the amelioration of anemia associated with chronic kidney disease .
1. Bouchie A. (2013) First-in-class anemia drug takes aim at Amgen's dominion. Nat. Biotechnol., 31 (11): 948-9. [PMID:24213751]
2. Chowdhury R, Candela-Lena JI, Chan MC, Greenald DJ, Yeoh KK, Tian YM, McDonough MA, Tumber A, Rose NR, Conejo-Garcia A et al.. (2013) Selective small molecule probes for the hypoxia inducible factor (HIF) prolyl hydroxylases. ACS Chem. Biol., 8 (7): 1488-96. [PMID:23683440]
3. Forristal CE, Levesque JP. (2014) Targeting the hypoxia-sensing pathway in clinical hematology. Stem Cells Transl Med, 3 (2): 135-40. [PMID:24371328]
4. 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]
5. 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]
6. Vachal P, Miao S, Pierce JM, Guiadeen D, Colandrea VJ, Wyvratt MJ, Salowe SP, Sonatore LM, Milligan JA, Hajdu R et al.. (2012) 1,3,8-Triazaspiro[4.5]decane-2,4-diones as efficacious pan-inhibitors of hypoxia-inducible factor prolyl hydroxylase 1-3 (HIF PHD1-3) for the treatment of anemia. J. Med. Chem., 55 (7): 2945-59. [PMID:22364528]
Database page citation:
126.96.36.199 2-oxoglutarate oxygenases. Accessed on 29/03/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=900.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Southan C, Davies JA and CGTP Collaborators (2015) The Concise Guide to PHARMACOLOGY 2015/16: Enzymes. Br J Pharmacol. 172: 6024-6109.