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] 。
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^ 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 .
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^ 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 .
^ 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 .
^ 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 .
^ 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 .
^ 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) .
^ 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 .