缺氧诱导因子脯胺酸羟化酶

HIF脯胺酸羟化酶(英语:HIF prolyl-hydroxylase)是一个包含在缺氧诱导因子(英语:Hypoxia-inducible factor,简称:HIF)讯息路径中的酶,也是一系列称为HIF脯胺酸羟化酶抑制剂 治疗性药物的目标

Hypoxia-inducible factor-proline dioxygenase
识别码
EC编号 1.14.11.29
数据库
IntEnz IntEnz浏览
BRENDA英语BRENDA BRENDA入口
ExPASy英语ExPASy NiceZyme浏览
KEGG KEGG入口
MetaCyc英语MetaCyc 代谢路径
PRIAM英语PRIAM_enzyme-specific_profiles 概述
PDB RCSB PDB PDBj PDBe PDBsum

缺氧诱导因子(HIF)是一个在演化上被保留下来的转录因子[1],它让细胞可以针对低氧浓度环境作出生理性的反应[2]。其中一种特定作用在HIF上的脯胺酸羟化酶已经被确认存在;[3]而羟基化的HIF能让蛋白质被作为降解的目标[3]

HIF脯胺酸羟化酶已经被各式各样抑制剂作为目标,用来治疗中风[4],肾脏疾病[5]缺血[6]贫血[7],和其他重大疾病。在红血球过多症相关以及乳癌相关的PHD2突变的案例中,临床观察下的脯胺酸羟化酶区域突变会影响它对HIF受质的选择性,这点对药物设计有重要的意义[8] 。 在人体中,HIF脯胺酸双氧化酶有三种种型。分别是 PHD1、PHD2和PHD3。其中,PHD2因为它对氧气缓慢的反应速度而被视为人体最重要的氧气感应器[9]

参考文献

  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 . 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 . 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 . 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 . 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 . PMID 12912907. doi:10.1093/emboj/cdg392.