缺氧誘導因子脯胺酸羥化酶

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HIF脯胺酸羥化酶（英語：HIF prolyl-hydroxylase）是一個包含在缺氧誘導因子（英語：Hypoxia-inducible factor，简称：HIF）訊息路徑中的酶，也是一系列稱為HIF脯胺酸羥化酶抑制劑 治療性藥物的目標

缺氧誘導因子(HIF)是一個在演化上被保留下來的轉錄因子[1]，它讓細胞可以針對低氧濃度環境作出生理性的反應[2]。其中一種特定作用在HIF上的脯胺酸羥化酶已經被確認存在；[3]而羥基化的HIF能讓蛋白質被作為降解的目標[3]

HIF脯胺酸羥化酶已經被各式各樣抑制劑作為目標，用來治療中風[4]，腎臟疾病[5]缺血[6]，贫血[7]，和其他重大疾病。在紅血球過多症相關以及乳癌相關的PHD2突變的案例中，臨床觀察下的脯胺酸羥化酶區域突變會影響它對HIF受質的選擇性，這點對藥物設計有重要的意義[8] 。 在人體中，HIF脯胺酸雙氧化酶有三種種型。分別是 PHD1、PHD2和PHD3。其中，PHD2因為它對氧氣緩慢的反應速度而被視為人體最重要的氧氣感應器[9]。

參考文獻[编辑]

  1. ^ Bacon, N. C.; Wappner, P; O'Rourke, J. F.; Bartlett, S. M.; Shilo, B; Pugh, C. W.; Ratcliffe, P. J. Regulation of the Drosophila bHLH-PAS protein Sima by hypoxia: Functional evidence for homology with mammalian HIF-1 alpha. Biochemical and Biophysical Research Communications. 1998, 249 (3): 811–6. PMID 9731218. doi:10.1006/bbrc.1998.9234. 
  2. ^ Smith, T. G.; Robbins, P. A.; Ratcliffe, P. J. The human side of hypoxia-inducible factor. British Journal of Haematology. 2008, 141 (3): 325–34. PMC 2408651 可免费查阅. PMID 18410568. doi:10.1111/j.1365-2141.2008.07029.x. 
  3. ^ 3.0 3.1 Bruick, R. K. A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF. Science. 2001, 294 (5545): 1337–40. PMID 11598268. doi:10.1126/science.1066373. 
  4. ^ Karuppagounder, S. S.; Ratan, R. R. Hypoxia-inducible factor prolyl hydroxylase inhibition: Robust new target or another big bust for stroke therapeutics?. Journal of Cerebral Blood Flow & Metabolism. 2012, 32 (7): 1347–1361. PMC 3390817 可免费查阅. PMID 22415525. doi:10.1038/jcbfm.2012.28. 
  5. ^ Warnecke, C.; Griethe, W.; Weidemann, A.; Jurgensen, J. S.; Willam, C.; Bachmann, S.; Ivashchenko, Y.; Wagner, I.; Frei, U. Activation of the hypoxia-inducible factor pathway and stimulation of angiogenesis by application of prolyl hydroxylase inhibitors. The FASEB Journal. 2003, 17 (9): 1186–8. PMID 12709400. doi:10.1096/fj.02-1062fje. 
  6. ^ Selvaraju, V; Parinandi, N. L.; Adluri, R. S.; Goldman, J. W.; Hussain, N; Sanchez, J. A.; Maulik, N. Molecular Mechanisms of Action and Therapeutic Uses of Pharmacological Inhibitors of HIF-Prolyl 4-Hydroxylases for Treatment of Ischemic Diseases. Antioxidants & Redox Signaling. 2013, 20 (16): 2631–2665. PMC 4026215 可免费查阅. PMID 23992027. doi:10.1089/ars.2013.5186. 
  7. ^ Muchnik, E; Kaplan, J. HIF prolyl hydroxylase inhibitors for anemia. Expert Opinion on Investigational Drugs. 2011, 20 (5): 645–56. PMID 21406036. doi:10.1517/13543784.2011.566861. 
  8. ^ Chowdhury, Rasheduzzaman; Leung, Ivanhoe K. H.; Tian, Ya-Min; Abboud, Martine I.; Ge, Wei; Domene, Carmen; Cantrelle, François-Xavier; Landrieu, Isabelle; Hardy, Adam P. Structural basis for oxygen degradation domain selectivity of the HIF prolyl hydroxylases. Nature Communications. 2016-08-26, 7: 12673. PMC 5007464 可免费查阅. PMID 27561929. doi:10.1038/ncomms12673 （英语）. 
  9. ^ Berra E, Benizri E, Ginouvès A, Volmat V, Roux D, Pouysségur J. HIF prolylhydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1α in normoxia. EMBO J. Aug 2003, 22 (16): 4082–4090. PMC 175782 可免费查阅. PMID 12912907. doi:10.1093/emboj/cdg392. 
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