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丝氨酸蛋白酶抑制剂

丝氨酸蛋白酶抑制剂
Serpin (serine protease inhibitor)
一个丝氨酸蛋白酶抑制剂(白色)与它的“反应中心环”(蓝色)结合到蛋白酶(灰色)。一旦蛋白酶企图催化就将被不可逆地抑制。(PDB 1K9O)
鑑定
標誌Serpin / SERPIN
PfamPF00079旧版
InterPro英语InterProIPR000215
PROSITE英语PROSITEPDOC00256
SCOP英语Structural Classification of Proteins1hle / SUPFAM
CDD英语Conserved Domain Databasecd00172

丝氨酸蛋白酶抑制剂(英語:serpinserine protease inhibitors)是具有相似结构蛋白质蛋白质超家族,它是由于蛋白酶抑制活性被识别的,和在生命的各个被发现的第一个蛋白质超家族[1]。英文缩写丝氨酸蛋白酶抑制剂(英語:serpin)最初被创造,是因为第一个丝氨酸蛋白酶抑制剂对胰凝乳蛋白酶样丝氨酸蛋白酶(丝氨酸蛋白酶抑制剂)将要被识别的行为[2][3]。它们值得注意的是其动作的不同寻常的机制,它们不可逆地通过经历大的构象改变,扰乱其活性位点抑制它们的靶蛋白酶[4]。与此相反,通过对于结合并阻止访问蛋白酶活性位点的蛋白酶抑制剂是更常见的竞争抑制剂英语Competitive inhibition机制[5]

由丝氨酸蛋白酶抑制剂的蛋白酶抑制控制的一系列生物过程,包括凝血炎症,因此这些蛋白质是医学研究的目标 [6]。对于结构生物学蛋白质折叠研究社区,它们独特的构象变化也使它们成为研究的兴趣[4][5]。构象变化机制赋予某些优点,但是它也具有缺点:丝氨酸蛋白酶抑制剂易受到突变的影响,所述突变可导致丝氨酸蛋白酶抑制剂病例如蛋白质错误折叠(Proteopathy)和形成无活性的长链聚合物[7][8]。丝氨酸蛋白酶抑制剂聚合不仅减少活性抑制剂的量,而且导致聚合物的积聚,引起细胞死亡器官衰竭[6]

虽然大多数丝氨酸蛋白酶抑制剂控制蛋白酶解级联,但一些具有丝氨酸蛋白酶抑制剂结构的蛋白质并不是酶抑制剂,而是执行多样化的功能,例如储藏英语Storage protein(例如蛋白-卵清蛋白英语Ovalbumin),运输例如激素载体蛋白甲状腺素结合球蛋白皮质激素传递球蛋白英语Transcortin)和分子伴侣HSP47英语Heat shock protein 47[9]。术语“丝氨酸蛋白酶抑制剂”也被用于描述这些成员,尽管它们具有非抑制功能,因为它们在进化上是相关的[1]

历史

首先在1800年代末期报道了血浆中的蛋白酶抑制活性[10],但是直到1950年代,丝氨酸蛋白酶抗凝血酶和α1-抗胰蛋白酶才被分离出[11]。最初的研究集中在它们在人类疾病中的作用:α1-抗胰蛋白酶缺乏是最常见的遗传疾病之一,引起肺气肿[7][12][13],而抗凝血酶缺乏导致血栓形成[14][15]

在1980年代,才清楚这些抑制剂是包括蛋白酶抑制剂(例如α1-抗胰蛋白酶)和非抑制性成员(例如卵白蛋白英语Ovalbumin[16])的相关的蛋白超家族的一部分。其名称“丝氨酸蛋白酶抑制剂” (serpin, serine protease inhibitors)是基于超家族(丝氨酸蛋白酶抑制剂)最常见的活性而创造的[16]。大约在同一时间,第一个丝氨酸蛋白酶抑制蛋白结构被解决了(首先在放松的构象,后来在应激构象)[17][18]。结构表明抑制机制涉及异常的构象变化,并促使后续的丝氨酸蛋白酶抑制剂研究聚焦在结构[5][18]

现在已经鉴定了超过1000种丝氨酸蛋白酶抑制剂,包括36种人类蛋白质,以及所有生物界中的分子--动物植物真菌细菌古菌以及一些病毒[19][20][21]。在2000年代,一个系统命名法被引入,以便根据其进化关系对丝氨酸蛋白酶抑制剂超家族成员进行分类[1]。因此,丝氨酸蛋白酶抑制剂是蛋白酶抑制剂中最大的和最多样的超家族[22]

参考资料

  1. ^ 1.0 1.1 1.2 Silverman GA, Bird PI, Carrell RW, Church FC, Coughlin PB, Gettins PG, Irving JA, Lomas DA, Luke CJ, Moyer RW, Pemberton PA, Remold-O'Donnell E, Salvesen GS, Travis J, Whisstock JC. The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature. The Journal of Biological Chemistry. September 2001, 276 (36): 33293–6. PMID 11435447. doi:10.1074/jbc.R100016200. 
  2. ^ Silverman GA, Whisstock JC, Bottomley SP, Huntington JA, Kaiserman D, Luke CJ, Pak SC, Reichhart JM, Bird PI. Serpins flex their muscle: I. Putting the clamps on proteolysis in diverse biological systems. The Journal of Biological Chemistry. August 2010, 285 (32): 24299–305. PMC 2915665可免费查阅. PMID 20498369. doi:10.1074/jbc.R110.112771. 
  3. ^ Whisstock JC, Silverman GA, Bird PI, Bottomley SP, Kaiserman D, Luke CJ, Pak SC, Reichhart JM, Huntington JA. Serpins flex their muscle: II. Structural insights into target peptidase recognition, polymerization, and transport functions. The Journal of Biological Chemistry. August 2010, 285 (32): 24307–12. PMC 2915666可免费查阅. PMID 20498368. doi:10.1074/jbc.R110.141408. 
  4. ^ 4.0 4.1 Gettins PG. Serpin structure, mechanism, and function. Chemical Reviews. December 2002, 102 (12): 4751–804. PMID 12475206. doi:10.1021/cr010170. 
  5. ^ 5.0 5.1 5.2 Whisstock JC, Bottomley SP. Molecular gymnastics: serpin structure, folding and misfolding. Current Opinion in Structural Biology. December 2006, 16 (6): 761–8. PMID 17079131. doi:10.1016/j.sbi.2006.10.005. 
  6. ^ 6.0 6.1 Stein PE, Carrell RW. What do dysfunctional serpins tell us about molecular mobility and disease?. Nature Structural Biology. February 1995, 2 (2): 96–113. PMID 7749926. doi:10.1038/nsb0295-96. 
  7. ^ 7.0 7.1 Janciauskiene SM, Bals R, Koczulla R, Vogelmeier C, Köhnlein T, Welte T. The discovery of α1-antitrypsin and its role in health and disease. Respiratory Medicine. August 2011, 105 (8): 1129–39. PMID 21367592. doi:10.1016/j.rmed.2011.02.002. 
  8. ^ Carrell RW, Lomas DA. Conformational disease. Lancet. July 1997, 350 (9071): 134–8. PMID 9228977. doi:10.1016/S0140-6736(97)02073-4. 
  9. ^ Law RH, Zhang Q, McGowan S, Buckle AM, Silverman GA, Wong W, Rosado CJ, Langendorf CG, Pike RN, Bird PI, Whisstock JC. An overview of the serpin superfamily. Genome Biology. 2006, 7 (5): 216. PMC 1779521可免费查阅. PMID 16737556. doi:10.1186/gb-2006-7-5-216. 
  10. ^ Fermi C, Personsi L. Untersuchungen uber die enzyme, Vergleichende Studie [Studies on the enzyme, Comparative study]. Z Hyg Infektionskr. 1984, (18): 83–89 (德语). 
  11. ^ Schultz H, Guilder I, Heide K, Schoenenberger M, Schwick G. Zur Kenntnis der alpha-globulin des menschlichen normal serums [For knowledge of the alpha - globulin of human normal serums]. Naturforsch. 1955, (10): 463 (德语). 
  12. ^ Laurell CB, Eriksson S. The electrophoretic α1-globulin pattern of serum in α1-antitrypsin deficiency. 1963. Copd. 2013,. 10 Suppl 1: 3–8. PMID 23527532. doi:10.3109/15412555.2013.771956. 
  13. ^ de Serres FJ. Worldwide Racial and Ethnic Distribution of α-Antitrypsin Deficiency. CHEST Journal. 1 November 2002, 122 (5): 1818–1829. doi:10.1378/chest.122.5.1818. 
  14. ^ Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thrombosis Et Diathesis Haemorrhagica. June 1965, 13: 516–30. PMID 14347873. 
  15. ^ Patnaik MM, Moll S. Inherited antithrombin deficiency: a review. Haemophilia. November 2008, 14 (6): 1229–39. PMID 19141163. doi:10.1111/j.1365-2516.2008.01830.x. 
  16. ^ 16.0 16.1 Hunt LT, Dayhoff MO. A surprising new protein superfamily containing ovalbumin, antithrombin-III, and alpha 1-proteinase inhibitor. Biochemical and Biophysical Research Communications. July 1980, 95 (2): 864–71. PMID 6968211. doi:10.1016/0006-291X(80)90867-0. 
  17. ^ Loebermann H, Tokuoka R, Deisenhofer J, Huber R. Human alpha 1-proteinase inhibitor. Crystal structure analysis of two crystal modifications, molecular model and preliminary analysis of the implications for function. Journal of Molecular Biology. August 1984, 177 (3): 531–57. PMID 6332197. doi:10.1016/0022-2836(84)90298-5. 
  18. ^ 18.0 18.1 Stein PE, Leslie AG, Finch JT, Turnell WG, McLaughlin PJ, Carrell RW. Crystal structure of ovalbumin as a model for the reactive centre of serpins. Nature. September 1990, 347 (6288): 99–102. PMID 2395463. doi:10.1038/347099a0. 
  19. ^ 引用错误:没有为名为Irving_2000的参考文献提供内容
  20. ^ 引用错误:没有为名为Irving_2002的参考文献提供内容
  21. ^ Steenbakkers PJ, Irving JA, Harhangi HR, Swinkels WJ, Akhmanova A, Dijkerman R, Jetten MS, van der Drift C, Whisstock JC, Op den Camp HJ. A serpin in the cellulosome of the anaerobic fungus Piromyces sp. strain E2. Mycological Research. August 2008, 112 (Pt 8): 999–1006. PMID 18539447. doi:10.1016/j.mycres.2008.01.021. 
  22. ^ Rawlings ND, Tolle DP, Barrett AJ. Evolutionary families of peptidase inhibitors. The Biochemical Journal. March 2004, 378 (Pt 3): 705–16. PMC 1224039可免费查阅. PMID 14705960. doi:10.1042/BJ20031825. 

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