蜱源Kunitz型丝氨酸蛋白酶抑制分子的结构与功能研究进展

doi:10.12140/j.issn.1000-7423.2023.05.015

中国寄生虫学与寄生虫病杂志 ›› 2023, Vol. 41 ›› Issue (5): 625-630.doi: 10.12140/j.issn.1000-7423.2023.05.015

蜱源Kunitz型丝氨酸蛋白酶抑制分子的结构与功能研究进展

刘岳青¹^,²(), 马林源², 陈开廷², 高金亮², 王鹏¹^,^*()

1 内蒙古科技大学包头医学院第一附属医院医学检验科，包头 014010
2 鄂尔多斯市中心医院分子医学实验室，内蒙古鄂尔多斯 017000

收稿日期:2023-06-02 修回日期:2023-09-12 出版日期:2023-10-30 发布日期:2023-11-06
通讯作者: *王鹏（1978-），男，硕士，主任技师，从事临床检验技术的开发与应用研究。E-mail：wp1003847851@163.com
作者简介:刘岳青（1998-），男，硕士，初级检验师，从事蜱源抗凝蛋白研究。E-mail：15044857509@163.com
基金资助:
内蒙古自治区自然科学基金(2021MS08063);内蒙古医科大学“科技百万工程”项目(YKD2020KJBW(LH)052);内蒙古自治区科技创新引导项目

Research progress on the structure and function of tick-derived serine protease inhibitor containing Kunitz domains

LIU Yueqing¹^,²(), MA Linyuan², CHEN Kaiting², GAO Jinliang², WANG Peng¹^,^*()

1 Department of Clinical Laboratory, the First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou 014010, China
2 Laboratory of Molecular Medicine, Ordos Central Hospital, Ordos 017000, Inner Mongolia, China

Received:2023-06-02 Revised:2023-09-12 Online:2023-10-30 Published:2023-11-06
Contact: *E-mail: wp1003847851@163.com
Supported by:
Natural Science Foundation of Inner Mongolia Autonomous Region(2021MS08063);Inner Mongolia Medical University “Science and Technology Million Project”(YKD2020KJBW(LH)052);Inner Mongolia Autonomous Region Science and Technology Innovation Guidance Project

摘要/Abstract

摘要：

蜱是一类体外吸血寄生虫，在吸血过程中蜱会向宿主体内释放多种抗凝血物质以保证血液的供应。其中含Kunitz结构域的丝氨酸蛋白酶抑制剂在抗凝血作用中占主要地位。不同的Kunitz型丝氨酸蛋白酶抑制剂具有相似的保守序列，但总体结构不同，在凝血级联中通过抑制丝氨酸蛋白酶类的凝血因子而阻断下游凝血因子的活化，以达到抑制凝血的效果。蜱源Kunitz型丝氨酸蛋白酶抑制剂在凝血系统中的靶点繁多且抑制机制各异。本文对该类蛋白酶抑制剂的抗凝靶点及作用机制进行归纳，有助于抗凝和抗血栓药物的研发，同时进一步解释蜱与宿主间的相互作用以及蜱源抗凝药物的药理作用，为预防蜱对宿主的侵害提供参考资料。

关键词: 蜱, Kunitz型丝氨酸蛋白酶抑制剂, 抗凝血

Abstract:

Ticks are blood-sucking ectoparasites. During their blood-sucking process, ticks release variou anticoagulant substances to the hosts to facilitate blood meal. Serine protease inhibitors containing Kunitz domains play an important role in anticoagulation. Different Kunitz serine protease inhibitors have similar conserved sequences but with different overall structures. In the coagulation cascade, inhibition of one or more serine proteases can block the activation of downstream coagulation factors, which could achieve the effect of inhibiting coagulation. Targets for different tick-derived Kunitz serine protease inhibitors in the blood clotting system are varied, and so do their inhibitory mechanisms. To summarize, the anticoagulant targets and anticoagulation mechanisms of those protease inhibitors could contribute to the research and development of anticoagulant and antithrombotic drugs. They could further explain the interaction between ticks and their hosts and the pharmacological action of tick-derived anticoagulant drugs. This can also prevent the invasion of ticks to their hosts.

Key words: Tick, Kunitz type serine protease inhibitor, Anticoagulant

中图分类号:

384.41

刘岳青, 马林源, 陈开廷, 高金亮, 王鹏. 蜱源Kunitz型丝氨酸蛋白酶抑制分子的结构与功能研究进展[J]. 中国寄生虫学与寄生虫病杂志, 2023, 41(5): 625-630.

LIU Yueqing, MA Linyuan, CHEN Kaiting, GAO Jinliang, WANG Peng. Research progress on the structure and function of tick-derived serine protease inhibitor containing Kunitz domains[J]. Chinese Journal of Parasitology and Parasitic Diseases, 2023, 41(5): 625-630.

图/表 1

参考文献 49

[1]	Gui Z, Wu L, Cai H, et al. Genetic diversity analysis of Dermacentor nuttalli within Inner Mongolia, China[J]. Parasit Vectors, 2021, 14(1): 131. doi: 10.1186/s13071-021-04625-5
[2]	Nava S, Guglielmone AA, Mangold AJ. An overview of systematics and evolution of ticks[J]. Front Biosci (Landmark Ed), 2009, 14(8): 2857-2877. doi: 10.2741/3418 pmid: 19273240
[3]	Martins LA, Kotál J, Bensaoud C, et al. Small protease inhibitors in tick saliva and salivary glands and their role in tick-host-pathogen interactions[J]. Biochim Biophys Acta Proteins Proteom, 2020, 1868(2): 140336. doi: 10.1016/j.bbapap.2019.140336
[4]	Perner J, Kropáčková S, Kopáček P, et al. Sialome diversity of ticks revealed by RNAseq of single tick salivary glands[J]. PLoS Negl Trop Dis, 2018, 12(4): e0006410. doi: 10.1371/journal.pntd.0006410
[5]	Sojka D, Franta Z, Horn M, et al. New insights into the machinery of blood digestion by ticks[J]. Trends Parasitol, 2013, 29(6): 276-285. doi: 10.1016/j.pt.2013.04.002 pmid: 23664173
[6]	Francischetti IM, Mans BJ, Meng ZJ, et al. An insight into the sialome of the soft tick, Ornithodorus parkeri[J]. Insect Biochem Mol Biol, 2008, 38(1): 1-21. doi: 10.1016/j.ibmb.2007.09.009
[7]	Bomediano Camillo LM, Ferreira GC, Duran AFA, et al. Structural modelling and thermostability of a serine protease inhibitor belonging to the Kunitz-BPTI family from the Rhipicephalus microplus tick[J]. Biochimie, 2021, 181: 226-233. doi: 10.1016/j.biochi.2020.12.014 pmid: 33359560
[8]	Paesen GC, Siebold C, Dallas ML, et al. An ion-channel modulator from the saliva of the brown ear tick has a highly modified Kunitz/BPTI structure[J]. J Mol Biol, 2009, 389(4): 734-747. doi: 10.1016/j.jmb.2009.04.045 pmid: 19394347
[9]	Blisnick AA, Foulon T, Bonnet SI. Serine protease inhibitors in ticks: an overview of their role in tick biology and tick-borne pathogen transmission[J]. Front Cell Infect Microbiol, 2017, 7: 199. doi: 10.3389/fcimb.2017.00199
[10]	Drewes CC, Dias RY, Branco VG, et al. Post-transcriptional control of amblyomin-X on secretion of vascular endothelial growth factor and expression of adhesion molecules in endothelial cells[J]. Toxicon, 2015, 101:1-10. doi: 10.1016/j.toxicon.2015.04.002 pmid: 25912945
[11]	Laskowski M Jr, Kato I. Protein inhibitors of proteinases[J]. Annu Rev Biochem, 1980, 49: 593-626. pmid: 6996568
[12]	Ranasinghe S, McManus DP. Structure and function of invertebrate kunitz serine protease inhibitors[J]. Dev Comp Immunol, 2013, 39(3): 219-227. doi: 10.1016/j.dci.2012.10.005 pmid: 23186642
[13]	Huang ZF, Wun TC, Jr Broze GJ. Kinetics of factor Xa inhibition by tissue factor pathway inhibitor[J]. J Biol Chem, 1993, 268(36): 26950-26955. pmid: 8262929
[14]	Francischetti IMB, Mather TN, Ribeiro JMC. Penthalaris, a novel recombinant five-Kunitz tissue factor pathway inhibitor (TFPI) from the salivary gland of the tick vector of Lyme disease, Ixodes scapularis[J]. Thromb Haemost, 2004, 91(5): 886-898. doi: 10.1160/TH03-11-0715
[15]	Lai R, Takeuchi H, Jonczy J, et al. A thrombin inhibitor from the ixodid tick, Amblyomma hebraeum[J]. Gene, 2004, 342(2): 243-249. doi: 10.1016/j.gene.2004.07.012
[16]	Louw E, van der Merwe NA, Neitz AWH, et al. Evolution of the tissue factor pathway inhibitor-like Kunitz domain-containing protein family in Rhipicephalus microplus[J]. Int J Parasitol, 2013, 43(1): 81-94. doi: 10.1016/j.ijpara.2012.11.006
[17]	Francischetti IMB, Sa-Nunes A, Mans BJ, et al. The role of saliva in tick feeding[J]. Front Biosci (Landmark Ed), 2009, 14(6): 2051-2088. doi: 10.2741/3363 pmid: 19273185
[18]	Monteiro RQ. Targeting exosites on blood coagulation proteases[J]. An Acad Bras Cienc, 2005, 77(2): 275-280. pmid: 15895163
[19]	Ganesh V, Lee AY, Clardy J, et al. Comparison of the structures of the cyclotheonamide A complexes of human alpha-thrombin and bovine beta-trypsin[J]. Protein Sci, 1996, 5(5): 825-835. pmid: 8732754
[20]	Bode W, Mayr I, Baumann U, et al. The refined 1.9 A crystal structure of human alpha-thrombin: interaction with D-Phe-Pro-Arg chloromethylketone and significance of the Tyr-Pro-Pro-Trp insertion segment[J]. EMBO J, 1989, 8(11): 3467-3475. doi: 10.1002/j.1460-2075.1989.tb08511.x pmid: 2583108
[21]	Hortin GL, Trimpe BL. Allosteric changes in thrombin’s activity produced by peptides corresponding to segments of natural inhibitors and substrates[J]. J Biol Chem, 1991, 266(11): 6866-6871. pmid: 1849894
[22]	van de Locht A, Stubbs MT, Bode W, et al. The ornithodorin-thrombin crystal structure, a key to the TAP enigma?[J]. EMBO J, 1996, 15(22): 6011-6017. pmid: 8947023
[23]	Nienaber J, Gaspar AR, Neitz AW. Savignin, a potent thrombin inhibitor isolated from the salivary glands of the tick Ornithodoros savignyi (Acari ∶ Argasidae)[J]. Exp Parasitol, 1999, 93(2): 82-91. doi: 10.1006/expr.1999.4448 pmid: 10502470
[24]	Mans BJ, Andersen JF, Schwan TG, et al. Characterization of anti-hemostatic factors in the argasid, Argas monolakensis: implications for the evolution of blood-feeding in the soft tick family[J]. Insect Biochem Mol Biol, 2008, 38(1): 22-41. doi: 10.1016/j.ibmb.2007.09.002
[25]	Soares TS, Watanabe RMO, Tanaka-Azevedo AM, et al. Expression and functional characterization of boophilin, a thrombin inhibitor from Rhipicephalus (Boophilus) microplus midgut[J]. Vet Parasitol, 2012, 187(3/4): 521-528. doi: 10.1016/j.vetpar.2012.01.027
[26]	Assumpção TC, Ma DY, Mizurini DM, et al. In vitro mode of action and anti-thrombotic activity of boophilin, a multifunctional kunitz protease inhibitor from the midgut of a tick vector of babesiosis, Rhipicephalus microplus[J]. PLoS Negl Trop Dis, 2016, 10(1): e0004298. doi: 10.1371/journal.pntd.0004298
[27]	Liu L, Tang H, Feng LL, et al. Hemalin from Haemaphysalis flava ticks: cloning, expression and antithrombogenicity[J]. Med Vet Entomol, 2021, 35(1): 42-50. doi: 10.1111/mve.v35.1
[28]	Liao M, Zhou JL, Gong HY, et al. Hemalin, a thrombin inhibitor isolated from a midgut cDNA library from the hard tick Haemaphysalis longicornis[J]. J Insect Physiol, 2009, 55(2): 164-173. doi: 10.1016/j.jinsphys.2008.11.004 pmid: 19061894
[29]	Costa GCA, Ribeiro ICT, Melo-Junior O, et al. Amblyomma sculptum salivary protease inhibitors as potential anti-tick vaccines[J]. Front Immunol, 2020, 11: 611104. doi: 10.3389/fimmu.2020.611104
[30]	Esteves E, Maruyama SR, Kawahara R, et al. Analysis of the salivary gland transcriptome of unfed and partially fed Amblyomma sculptum ticks and descriptive proteome of the saliva[J]. Front Cell Infect Microbiol, 2017, 7: 476. doi: 10.3389/fcimb.2017.00476
[31]	Lim-Wilby MS, Hallenga K, de Maeyer M, et al. NMR structure determination of tick anticoagulant peptide (TAP)[J]. Protein Sci, 1995, 4(2): 178-186. pmid: 7538849
[32]	Jordan SP, Waxman L, Smith DE, et al. Tick anticoagulant peptide: kinetic analysis of the recombinant inhibitor with blood coagulation factor Ⅹa[J]. Biochemistry, 1990, 29(50): 11095-11100. doi: 10.1021/bi00502a012 pmid: 2271697
[33]	Waxman L, Smith DE, Arcuri KE, et al. Tick anticoagulant peptide (TAP) is a novel inhibitor of blood coagulation factor Xa[J]. Science, 1990, 248(4955): 593-596. doi: 10.1126/science.2333510 pmid: 2333510
[34]	Monteiro RQ, Rezaie AR, Bae JS, et al. Ixolaris binding to factor X reveals a precursor state of factor Ⅹa heparin-binding exosite[J]. Protein Sci, 2008, 17(1): 146-153. doi: 10.1110/ps.073016308 pmid: 18042685
[35]	Gao X, Shi L, Zhou YZ, et al. Characterization of the anticoagulant protein Rhipilin-1 from the Rhipicephalus haemaphysaloides tick[J]. J Insect Physiol, 2011, 57(2): 339-343. doi: 10.1016/j.jinsphys.2010.12.001
[36]	Ribeiro JM, Anderson JM, Manoukis NC, et al. A further insight into the sialome of the tropical bont tick, Amblyomma variegatum[J]. BMC Genomics, 2011, 12: 136. doi: 10.1186/1471-2164-12-136 pmid: 21362191
[37]	Valenzuela JG, Francischetti IMB, Pham VM, et al. Exploring the sialome of the tick Ixodes scapularis[J]. J Exp Biol, 2002, 205(Pt 18): 2843-2864. doi: 10.1242/jeb.205.18.2843
[38]	Cao J, Shi L, Zhou YZ, et al. Characterization of a new Kunitz-type serine protease inhibitor from the hard tick Rhipicephalus hemaphysaloides[J]. Arch Insect Biochem Physiol, 2013, 84(2): 104-113. doi: 10.1002/arch.v84.2
[39]	Maria DA, de Souza JG, Morais KLP, et al. A novel proteasome inhibitor acting in mitochondrial dysfunction, ER stress and ROS production[J]. Invest New Drugs, 2013, 31(3): 493-505. doi: 10.1007/s10637-012-9871-1
[40]	Tankersley DL, Finlayson JS. Kinetics of activation and autoactivation of human factor Ⅻ[J]. Biochemistry, 1984, 23(2): 273-279. pmid: 6607744
[41]	Kaplan AP, Joseph K, Silverberg M. Pathways for bradykinin formation and inflammatory disease[J]. J Allergy Clin Immunol, 2002, 109(2): 195-209. doi: 10.1067/mai.2002.121316
[42]	Pireaux V, Tassignon J, Demoulin S, et al. Anticoagulation with an inhibitor of factors Ⅺa and Ⅻa during cardiopulmonary bypass[J]. J Am Coll Cardiol, 2019, 74(17): 2178-2189. doi: 10.1016/j.jacc.2019.08.1028
[43]	Kalinin DV. Factor Ⅻ(a) inhibitors: a review of the patent literature[J]. Expert Opin Ther Pat, 2021, 31(12): 1155-1176. doi: 10.1080/13543776.2021.1945580
[44]	Demoulin S, Godfroid E, Hermans C. Dual inhibition of factor Ⅻa and factor Ⅺa as a therapeutic approach for safe thromboprotection[J]. J Thromb Haemost, 2021, 19(2): 323-329. doi: 10.1111/jth.15130
[45]	Decrem Y, Rath G, Blasioli V, et al. Ir-CPI, a coagulation contact phase inhibitor from the tick Ixodes ricinus, inhibits thrombus formation without impairing hemostasis[J]. J Exp Med, 2009, 206(11): 2381-2395. doi: 10.1084/jem.20091007
[46]	Chen Z, Yang XJ, Bu FJ, et al. Ticks (Acari ∶ Ixodoidea ∶ Argasidae, Ixodidae) of China[J]. Exp Appl Acarol, 2010, 51(4): 393-404. doi: 10.1007/s10493-010-9335-2 pmid: 20101443
[47]	Zhang HS, Qiao RQ, Gong HY, et al. Identification and anticoagulant activity of a novel Kunitz-type protein HA11 from the salivary gland of the tick Hyalomma asiaticum[J]. Exp Appl Acarol, 2017, 71(1): 71-85. doi: 10.1007/s10493-017-0106-1
[48]	Ferreira GC, Bomediano Camillo LdM, Sasaki SD. Structural and functional properties of rBmTI-A: a Kunitz-BPTI serine protease inhibitor with therapeutical potential[J]. Biochimie, 2023, 204: 1-7. doi: 10.1016/j.biochi.2022.08.004
[49]	Sasaki SD, Tanaka AS. rBmTI-6, a Kunitz-BPTI domain protease inhibitor from the tick Boophilus microplus, its cloning, expression and biochemical characterization[J]. Vet Parasitol, 2008, 155(1/2): 133-141. doi: 10.1016/j.vetpar.2008.03.031

蜱源Kunitz型丝氨酸蛋白酶抑制分子的结构与功能研究进展

Research progress on the structure and function of tick-derived serine protease inhibitor containing Kunitz domains

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 1

参考文献 49

相关文章 15

编辑推荐

Metrics

本文评价

[1]	纪鹏慧, 蒋甜甜, 贺志权, 王丹, 岳思宁, 李素华, 杨成运, 王昊, 张红卫, 周瑞敏. 河南省信阳地区家畜寄生蜱感染巴贝虫的分子流行病学调查[J]. 中国寄生虫学与寄生虫病杂志, 2023, 41(5): 567-572.
[2]	费思伟, 赵翰卿, 尹静娴, 孙芷珊, 郭晓奎, KASSEGNE Kokouvi, 周晓农. 基于文献计量分析的蜱及蜱传疾病研究领域发展趋势[J]. 中国寄生虫学与寄生虫病杂志, 2023, 41(5): 609-618.
[3]	刘雅芳, 陈彬, 芦新焱, 李光华, 杜春红, 姜丹丹, 杨兴. 云南微小扇头蜱线粒体基因组全序列测定与分析[J]. 中国寄生虫学与寄生虫病杂志, 2022, 40(5): 677-681.
[4]	宋瑞其, 翟雪洁, 李才善, 葛婷, 甘露, 张梦圆, 樊新丽, 李永畅, 张杨, 巴音查汗. 亚洲璃眼蜱和小亚璃眼蜱新疆地理株各发育阶段生物学特性的比较分析[J]. 中国寄生虫学与寄生虫病杂志, 2022, 40(3): 369-378.
[5]	张霞, 颜凤, 牟小会, 林紫敏, 聂映, 程金芝, 商正玲, 吴家红. 埃及伊蚊黄蛋白c基因的克隆、表达及其体外抗凝血作用[J]. 中国寄生虫学与寄生虫病杂志, 2022, 40(2): 153-158.
[6]	旷策嫣, 周金林. 蜱的化学感觉系统与驱避剂的研究进展[J]. 中国寄生虫学与寄生虫病杂志, 2022, 40(1): 104-108.
[7]	何文文, 伍军, 呼尔查, 阿力木江, 史倩云, 诺明达来, 甘露, 郝蕴伟, 巴音查汗. 基于最大熵模型的新疆银盾革蜱和边缘革蜱生境适应性评价[J]. 中国寄生虫学与寄生虫病杂志, 2022, 40(1): 68-75.
[8]	周淑姮, 曾志伟, 刘维俊, 王加熊, 徐国英, 肖方震. 闽东地区野生动物寄生蜱感染梨形虫状况的调查及基因型分析[J]. 中国寄生虫学与寄生虫病杂志, 2022, 40(1): 76-83.
[9]	吕立红, 张金成, 胡永红. 蜱类保护性抗原研究进展[J]. 中国寄生虫学与寄生虫病杂志, 2021, 39(4): 542-547.
[10]	乌兰图雅, 殷旭红, 崔云虹, 刘丹, 王亭富, 苗雨润, 阿木日汗, 曹民治, 赵志伟, 邢方超, 鲁建英, 高娃. 内蒙古中西部草原蜱媒病原体多样性及基因型分析[J]. 中国寄生虫学与寄生虫病杂志, 2021, 39(1): 27-35.
[11]	裴庭苇, 于志军, 刘敬泽. 蜱类miRNA研究进展[J]. 中国寄生虫学与寄生虫病杂志, 2020, 38(6): 771-776.
[12]	姚清媚, 周素芳, 张仪, 夏尚, 薛靖波. 我国蜱媒传染病与气象因素的相关性及其防治措施的研究进展[J]. 中国寄生虫学与寄生虫病杂志, 2020, 38(1): 123-127.
[13]	陈泽1*, 温廷桓2. 世界蜱类名录2. 硬蜱亚科（螨亚纲∶蜱目∶硬蜱科[J]. 中国寄生虫学与寄生虫病杂志, 2017, 35(4): 12-371-381.
[14]	宫庆龙，王春凤，杨桂连*. 血吸虫成虫抗宿主凝血机制研究进展[J]. 中国寄生虫学与寄生虫病杂志, 2016, 34(2): 14-157-160.
[15]	温廷桓1*，陈泽2. 世界蜱类名录1. 软蜱科与纳蜱科（螨亚纲∶蜱目）[J]. 中国寄生虫学与寄生虫病杂志, 2016, 34(1): 10-58-74.