Biology:HIF prolyl-hydroxylase
HIF prolyl-hydroxylase is an enzyme involved in the HIF (Hypoxia-inducible factor) signalling pathways, and is the target for a set of therapeutic drugs called HIF prolyl-hydroxylase inhibitors. Hypoxia-inducible factor (HIF) is an evolutionarily conserved transcription factor[1] that allows the cell to respond physiologically to low concentrations of oxygen.[2] A class of prolyl hydroxylases which act specifically on HIF has been identified;[3] hydroxylation of HIF allows the protein to be targeted for degradation.[3] HIF prolyl-hydroxylase has been targeted by a variety of inhibitors that aim to treat stroke,[4] kidney disease,[5] ischemia,[6] anemia,[7] and other important diseases. Clinically observed prolyl hydroxylase domain mutations, as in the case of erythrocytosis- and breast cancer-associated PHD2 mutations, affect its selectivity for its HIF substrate, which has important implication for drug design.[8]
In humans, there are three isoforms of hypoxia-inducible factor-proline dioxygenase. These are PHD1, PHD2 and PHD3. PHD2, in particular, was identified as the most important human oxygen sensors due to its slow reaction with oxygen.[9]
References
- ↑ Bacon, N. C.; Wappner, P; O'Rourke, J. F.; Bartlett, S. M.; Shilo, B; Pugh, C. W.; Ratcliffe, P. J. (1998). "Regulation of the Drosophila bHLH-PAS protein Sima by hypoxia: Functional evidence for homology with mammalian HIF-1 alpha". Biochemical and Biophysical Research Communications 249 (3): 811–6. doi:10.1006/bbrc.1998.9234. PMID 9731218.
- ↑ Smith, T. G.; Robbins, P. A.; Ratcliffe, P. J. (2008). "The human side of hypoxia-inducible factor". British Journal of Haematology 141 (3): 325–34. doi:10.1111/j.1365-2141.2008.07029.x. PMID 18410568.
- ↑ 3.0 3.1 Bruick, R. K. (2001). "A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF". Science 294 (5545): 1337–40. doi:10.1126/science.1066373. PMID 11598268.
- ↑ Karuppagounder, S. S.; Ratan, R. R. (2012). "Hypoxia-inducible factor prolyl hydroxylase inhibition: Robust new target or another big bust for stroke therapeutics?". Journal of Cerebral Blood Flow & Metabolism 32 (7): 1347–1361. doi:10.1038/jcbfm.2012.28. PMID 22415525.
- ↑ Warnecke, C.; Griethe, W.; Weidemann, A.; Jurgensen, J. S.; Willam, C.; Bachmann, S.; Ivashchenko, Y.; Wagner, I. et al. (2003). "Activation of the hypoxia-inducible factor pathway and stimulation of angiogenesis by application of prolyl hydroxylase inhibitors". The FASEB Journal 17 (9): 1186–8. doi:10.1096/fj.02-1062fje. PMID 12709400.
- ↑ Selvaraju, V; Parinandi, N. L.; Adluri, R. S.; Goldman, J. W.; Hussain, N; Sanchez, J. A.; Maulik, N (2013). "Molecular Mechanisms of Action and Therapeutic Uses of Pharmacological Inhibitors of HIF-Prolyl 4-Hydroxylases for Treatment of Ischemic Diseases". Antioxidants & Redox Signaling 20 (16): 2631–2665. doi:10.1089/ars.2013.5186. PMID 23992027.
- ↑ Muchnik, E; Kaplan, J (2011). "HIF prolyl hydroxylase inhibitors for anemia". Expert Opinion on Investigational Drugs 20 (5): 645–56. doi:10.1517/13543784.2011.566861. PMID 21406036.
- ↑ Chowdhury, Rasheduzzaman; Leung, Ivanhoe K. H.; Tian, Ya-Min; Abboud, Martine I.; Ge, Wei; Domene, Carmen; Cantrelle, François-Xavier; Landrieu, Isabelle et al. (2016-08-26). "Structural basis for oxygen degradation domain selectivity of the HIF prolyl hydroxylases" (in en). Nature Communications 7: 12673. doi:10.1038/ncomms12673. PMID 27561929.
- ↑ "HIF prolylhydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1α in normoxia". EMBO J 22 (16): 4082–4090. Aug 2003. doi:10.1093/emboj/cdg392. PMID 12912907.
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