Thrombin-Like Enzymes in Snake Venoms

  • Stephen P. MackessyEmail author


Snake venoms, particularly from vipers, are rich sources of serine proteinases, some of which contain thrombin-like activity. Following human envenomations, these toxins often produce rapid coagulopathies via the depletion of circulating fibrinogen, typically via specific proteolysis of the Aα and Bβ subunits. Hypofibrinogenemia following bites may be prolonged, contributing to hemorrhagic effects of the venom and occasionally leading to life-threatening conditions such as disseminated intravascular coagulation. However, they have also been used as therapeutic drugs for treating a diversity of human disorders, including strokes, deep vein thromboses and cerebral and myocardial infarctions. Many snake venom thrombin-like enzymes (SV-TLEs) have been sequenced, and important structural elements (six disulfides, the catalytic triad) are highly conserved. SV-TLEs are commonly glycosylated, and this modification may confer a high level of stability; unlike trypsin, they are exceptionally stable in aqueous solution. Structurally, they are closely related to other serine proteinases such as trypsin and chymotrypsin, but as a result of gene duplication, accelerated point mutations and ASSET, venom TLEs have evolved a diversity of activities. The relationship between structure and function of the different venom serine proteinases is still unclear, and future studies of substrate specificity of this diverse family of toxins will help resolve this uncertainty.


Serine Proteinase Snake Venom Venom Component Snake Venom Toxin Colubrid Snake 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Alape-Girón, A., Sanz, L., Escolano, J., Flores-Díaz, M., Madrigal, M., Sasa, M., Calvete, J.J., 2008. Snake venomics of the lancehead pitviper Bothrops asper: geographic, individual, and ontogenetic variations. J. Proteome Res. 7, 3556–3571.PubMedCrossRefGoogle Scholar
  2. Alexander, G., Grothusen, J., Zepeda, H., Schwartzman, R.J., 1988. Gyroxin, a toxin from the venom of Crotalus durissus terrificus, is a thrombin-like enzyme. Toxicon 26, 953–960.PubMedCrossRefGoogle Scholar
  3. Allegra, A., Coppolino, G., Bolignano, D., Giacobbe, M.S., Alonci, A., D’Angelo, A., Bellomo, G., Teti, D., Loddo, S., Musolino, C., Buemi, M., 2009. Endothelial progenitor cells: pathogenetic role and therapeutic perspectives. J. Nephrol. 22, 463–475.PubMedGoogle Scholar
  4. Alves da Silva, J.A., Muramoto, E., Ribela, M.T.C., Rogero, J.R., Camillo, M.A.P., 2006. Biodistribution of gyroxin using 125I as radiotracer. J. Radioanalyt. Nucl. Chem. 269, 579–583.CrossRefGoogle Scholar
  5. Amiconi, G., Amoresano, A., Boumis, G., Brancaccio, A., De Cristofaro, R., De Pascalis, A., Di Girolamo, S., Maras, B., Scaloni, A., 2000. A novel venombin B from Agkistrodon contortrix contortrix: evidence for recognition properties in the surface around the primary specificity pocket different from thrombin. Biochemistry 39, 10294–10308.PubMedCrossRefGoogle Scholar
  6. Asahara, T., Masuda, H., Takahashi, T., Kalka, C., Pastore, C., Silver, M., Kearne, M., Magner, M., Isner, J.M., 1999. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ. Res. 85, 221–228.PubMedCrossRefGoogle Scholar
  7. Assakura, M.T., Reichl, A.P., Mandelbaum, F.R., 1994. Isolation and characterization of five fibrin(ogen)olytic enzymes from the venom of Philodryas olfersii (green snake). Toxicon 32, 819–831.PubMedCrossRefGoogle Scholar
  8. Au, L.C., Lin, S.B., Chou, J.S., Teh, G.W., Chang, K.J., Shih, C.M., 1993. Molecular cloning and sequence analysis of the cDNA for ancrod, a thrombin-like enzyme from the venom of Calloselasma rhodostoma. Biochem. J. 294, 387–390.PubMedGoogle Scholar
  9. Bandow, J.E., 2010. Comparison of protein enrichment strategies for proteome analysis of plasma. Proteomics 2010 Feb 1. [Epub ahead of print].Google Scholar
  10. Barbosa, M.D.S., Stipp, A.C., Passanezi, E. Greghi, S.L.A., 2008. Fibrin adhesive derived from snake venom in periodontal surgery. Histological analysis. J. Appl. Oral Sci. 16, 310–315.PubMedCrossRefGoogle Scholar
  11. Bell, G.I., Quinto, C., Quiroga, M., Valenzuela, P., Craik, C.S., Rutter, W.J., 1984. Isolation and sequence of a rat chymotrypsin B gene. J. Biol. Chem. 259, 14265–14270.PubMedGoogle Scholar
  12. Botos, I., Wlodawer, A., 2007. The expanding diversity of serine hydrolases. Curr. Opin. Struct. Biol. 17, 683–690.PubMedCrossRefGoogle Scholar
  13. Boyer, L.V., Seifert, S.A., Clark, R.F., McNally, J.T., Williams, S.R., Nordt, S.P., Walter, F.G., Dart, R.C., 1999. Recurrent and persistent coagulopathy following pit viper envenomation. Arch Intern Med. 159, 706–710.PubMedCrossRefGoogle Scholar
  14. Braud, S., Bon, C., Wisner, A., 2000. Snake venom proteins acting on hemostasis. Biochemie 82, 851–859.CrossRefGoogle Scholar
  15. Burkhart, W., Smith, G.F., Su, J.L., Parikh, I., LeVine, H., 3rd., 1992. Amino acid sequence determination of ancrod, the thrombin-like alpha-fibrinogenase from the venom of Agkistrodon rhodostoma. FEBS Lett. 297, 297–301.PubMedCrossRefGoogle Scholar
  16. Calvete, J.J., Fasoli, E., Sanz, L., Boschetti, E., Righetti, P.G., 2009. Exploring the venom proteome of the western diamondback rattlesnake, Crotalus atrox, via snake venomics and combinatorial peptide ligand library approaches. J. Proteome Res. 8, 3055–67.PubMedCrossRefGoogle Scholar
  17. Castro, H.C., Silva, D.M., Craik, C., Zingali, R.B., 2001. Structural features of a snake venom thrombin-like enzyme: thrombin and trypsin on a single catalytic platform? Biochim. Biophys. Acta 1547, 183–195.CrossRefGoogle Scholar
  18. Castro, H.C., Zingali, R.B., Albuquerque, M.G., Pujol-Luz, M., Rodrigues, C.R., 2004. Snake venom thrombin-like enzymes: from reptilase to now. Cell. Mol. Life Sci. 61, 843–856.PubMedCrossRefGoogle Scholar
  19. Ching, A.T.C., Rocha, M.M.T., Paes Leme, A.F., Pimenta, D.C., Furtado, M.F.D., Serrano, S.M.T., Ho, P.L., Junqueira-de-Azevedo, I.L.M., 2006. Some aspects of the venom proteome of the Colubridae snake Philodryas olfersii revealed from a Duvernoy’s (venom) gland transcriptome. FEBS Lett. 580, 4417–4422.PubMedCrossRefGoogle Scholar
  20. Cole, C.W., 1998. Controlling acute elevation of plasma fibrinogen with ancrod. Cerebrovasc. Dis. 1, 29–34.CrossRefGoogle Scholar
  21. Craik, C.S., Choo, Q.L., Swift, G.H., Quinto, C., MacDonald, R.J., Rutter, W.J., 1984. Structure of two related rat pancreatic trypsin genes. J. Biol. Chem. 259, 14255–14264.PubMedGoogle Scholar
  22. Dekhil, H., Wisner, A., Marrakchi, N., El Ayeb, M., Bon, C., Karoui, H., 2003. Molecular cloning and expression of a functional snake venom serine proteinase, with platelet aggregating activity, from the Cerastes cerastes viper. Biochemistry 42, 10609–10618.PubMedCrossRefGoogle Scholar
  23. Deshimaru, M., Ogawa, T., Nakashima, K., Nobuhisa, I., Chijiwa, T., Shimohigashi, Y., Fukumaki, Y., Niwa, M., Yamashina, I., Hattori, S., Ohno, M., 1996. Accelerated evolution of crotalinae snake venom gland serine proteases. FEBS Lett. 397, 83–88.PubMedCrossRefGoogle Scholar
  24. Di Cera, E., 2008. Thrombin. Mol. Aspects Med. 29, 203–254.PubMedCrossRefGoogle Scholar
  25. Doley, R., Mackessy, S.P., Kini, R.M., 2009. Role of accelerated segment switch in exons to alter targeting (ASSET) in the molecular evolution of snake venom proteins. BMC Evol. Biol. 9, 146.PubMedCrossRefGoogle Scholar
  26. Doley, R., Pahari, S., Mackessy, S.P., Kini, R.M., 2008. Accelerated exchange of exon segments in Viperid three-finger toxin genes (Sistrurus catenatus edwardsii; Desert Massasauga). BMC Evol. Biol. 8, 196.PubMedCrossRefGoogle Scholar
  27. Escalante, T., Shannon, J., Moura-da-Silva, A.M., Gutiérrez, J.M., Fox, J.W., 2006. Novel insights into capillary vessel basement membrane damage by snake venom hemorrhagic metalloproteinases: a biochemical and immunohistochemical study. Arch. Biochem. Biophys. 455, 144–153.PubMedCrossRefGoogle Scholar
  28. Farid, T.M., Tu, A.T., el-Asmar, M.F., 1989. Characterization of cerastobin, a thrombin-like enzyme from the venom of Cerastes vipera (Sahara sand viper). Biochemistry 28, 371–377.PubMedCrossRefGoogle Scholar
  29. Farid, T.M., Tu, A.T., el-Asmar, M.F., 1990. Effect of cerastobin, a thrombinlike enzyme from Cerastes vipera (Egyptian sand snake) venom, on human platelets. Haemostasis 20, 296–304.PubMedGoogle Scholar
  30. Ferreira, S.H., 1965. A bradykinin-potentiating factor (bpf) present in the venom of Bothrops jararaca. Br. J. Pharmacol. Chemother. 24, 163–169.PubMedCrossRefGoogle Scholar
  31. Fox, J.W., Serrano, S.M.T., 2007. Approaching the golden age of natural product pharmaceuticals from venom libraries: an overview of toxins and toxin-derivatives currently involved in therapeutic or diagnostic applications. Curr. Pharm. Des. 13, 2927–2934.PubMedCrossRefGoogle Scholar
  32. Fox, J.W., Serrano, S.M.T., 2008. Insights into and speculations about snake venom metalloproteinases (SVMP) synthesis, folding and disulfide bond formation and their contribution to venom complexity. FEBS J. 275, 3016–3030.PubMedCrossRefGoogle Scholar
  33. Fox, J.W., Serrano, S.M.T., 2009. Snake venom metalloproteinases, in: Mackessy, S.P. (Ed.), Handbook of Venoms and Toxins of Reptiles. CRC Press/Taylor & Francis Group, Boca Raton, FL, pp. 95–113.Google Scholar
  34. Fry, B.G., 2005. From genome to “venome”: molecular origin and evolution of the snake venom proteome inferred from the phylogenetic analysis of toxin sequences and related body proteins. Genome Res. 15, 403–420.PubMedCrossRefGoogle Scholar
  35. Fry, B.G., Vidal, N., Norman, J.A., Vonk, F.J., Scheib, H., Ramjan, S.F., Kuruppu, S., Fung, K., Hedges, S.B., Richardson, M.K., Hodgson, W.C., Ignjatovic, V., Summerhayes, R., Kochva, E., 2006. Early evolution of the venom system in lizards and snakes. Nature 439, 584–588.PubMedCrossRefGoogle Scholar
  36. Gao, R., Zhang, Y., Meng, Q.-X., Lee, W.-H., Li, D.-S., Xiong, Y.-L., Wang, W.-Y., 1998. Characterization of three fibrinogenolytic enzymes from Chinese green tree viper (Trimeresurus stejnegeri) venom. Toxicon 36, 457–467.PubMedCrossRefGoogle Scholar
  37. Guo, Y.W., Chang, T.Y., Lin, K.T., Liu, H.W., Shih, K.C., Cheng, S.H., 2001. Cloning and functional expression of the mucrosobin protein, a beta-fibrinogenase of Trimeresurus mucrosquamatus (Taiwan Habu). Protein Exp. Purif. 23, 483–490.CrossRefGoogle Scholar
  38. Gutiérrez, J.M., Rucavado, A., Escalante, T. 2009. Snake venom metalloproteinases. Biological roles and participation in the pathology of envenomation, in: Mackessy, S.P. (Ed.), Handbook of Venoms and Toxins of Reptiles. CRC Press/Taylor & Francis Group, Boca Raton, FL, pp. 115–138.Google Scholar
  39. Hahn, B.S., Yang, K.Y., Park, E.M., Chang, I.M., Kim, Y.S., 1996. Purification and molecular cloning of calobin, a thrombin-like enzyme from Agkistrodon caliginosus (Korean viper). J. Biochem. (Tokyo) 119, 835–843.CrossRefGoogle Scholar
  40. Hahn, B.S., Baek, K., Kim, W.S., Lee, C.S., Chang, I.L., Kim, Y.S., 1998. Molecular cloning of capillary permeability-increasing enzyme-2 from Agkistrodon caliginosus (Korean viper). Toxicon 36, 1887–1893.PubMedCrossRefGoogle Scholar
  41. Hartley, B.S., Kilby, B.A., 1954. The reaction of p-nitrophenyl esters with chymotrypsin and insulin. Biochem. J. 56, 288–297.PubMedGoogle Scholar
  42. Henschen-Edman, A.H., Theodor, I., Edwards, B.F., Pirkle, H., 1999. Crotalase, a fibrinogen-clotting snake venom enzyme: primary structure and evidence for a fibrinogen recognition exosite different from thrombin. Thromb. Haemost. 81, 81–86.PubMedGoogle Scholar
  43. Hiestand, P.C., Hiestand, R.R. 1979. Dispholidus typus (Boomslang) snake venom: purification and properties of the coagulant principle. Toxicon 17, 489–498.PubMedCrossRefGoogle Scholar
  44. Huisman, T.H., 1993. The structure and function of normal and abnormal haemoglobins. Baillieres Clin. Haematol. 6, 1–30.PubMedCrossRefGoogle Scholar
  45. Isbister, GK, Duffull, SB, Brown, SG, ASP Investigators. 2009. Failure of antivenom to improve recovery in Australian snakebite coagulopathy. QJM 102, 563–568.PubMedCrossRefGoogle Scholar
  46. Itoh, N., Tanaka, N., Mihashi, S., Yamashina, I., 1987. Molecular cloning and sequence analysis of cDNA for batroxobin, a thrombin-like snake venom enzyme. J. Biol. Chem. 262, 3132–3135.PubMedGoogle Scholar
  47. Itoh, N., Tanaka, N., Funakoshi, I., Kawasaki, T., Mihashi, S., Yamashina, I., 1988. Organization of the gene for batroxobin, a thrombin-like snake venom enzyme. Homology with the trypsin/kallikrein gene family. J. Biol. Chem. 263, 7628–7631.PubMedGoogle Scholar
  48. Jin, Y., Lee, W.H., Zhang, Y., 2007. Molecular cloning of serine proteases from elapid snake venoms. Toxicon 49, 1200–1207.PubMedCrossRefGoogle Scholar
  49. Juárez, P., Sanz, L., Calvete, J.J., 2004. Snake venomics: characterization of protein families in Sistrurus barbouri venom by cysteine mapping, N-terminal sequencing, and tandem mass spectrometry analysis. Proteomics 4, 327–338.PubMedCrossRefGoogle Scholar
  50. Kini, R.M., 2005. Serine proteases affecting blood coagulation and fibrinolysis from snake venoms. Pathophysiol. Haemost. Thromb. 34, 200–204.PubMedCrossRefGoogle Scholar
  51. Kini, R.M., Chan, Y.M., 1999. Accelerated evolution and molecular surface of venom phospholipase A2 enzymes. J. Mol. Evol. 48, 125–132.PubMedCrossRefGoogle Scholar
  52. Kirby, E.P., Niewiarowski, S., Stocker, K., Kettner, C., Shaw, E., Brudzynski, T.M., 1979. Thrombocytin, a serine protease from Bothrops atrox venom 1. Purification and characterization of the enzyme. Biochemistry 18, 3564–3570.PubMedCrossRefGoogle Scholar
  53. Komori, Y., Nikai, T., Ohara, A., Yagihashi, S., Sugihara, H., 1993. Effect of bilineobin, a thrombin-like proteinase from the venom of common cantil (Agkistrodon bilineatus). Toxicon 31, 257–270.PubMedCrossRefGoogle Scholar
  54. Kordis, D., Gubensek, F., 2000. Adaptive evolution of animal toxin multigene families. Gene 261, 43–52.PubMedCrossRefGoogle Scholar
  55. Lee, J.W., Park, W., 2000. cDNA cloning of brevinase, a heterogeneous two-chain fibrinolytic enzyme from Agkistrodon blomhoffii brevicaudus snake venom, by serial hybridization polymerase chain reaction. Arch. Biochem. Biophys. 377, 234–240.PubMedCrossRefGoogle Scholar
  56. Lee, J.W., Seu, J.H., Rhee, I.K., Jin, I., Kawamura, Y., Park, W., 1999. Purification and characterization of brevinase, a heterogeneous two-chain fibrinolytic enzyme from the venom of Korean snake, Agkistrodon blomhoffii brevicaudus. Biochem. Biophys. Res. Commun. 260, 665–670.PubMedCrossRefGoogle Scholar
  57. Levy, D.E., del Zoppo, G.J., Demaerschalk, B.M., Demchuk, A.M., Diener, H.C., Howard, G., Kaste, M., Pancioli, A.M., Ringelstein, E.B., Spatareanu, C., Wasiewski, W.W., 2009. Ancrod in acute ischemic stroke: results of 500 subjects beginning treatment within 6 hours of stroke onset in the ancrod stroke program. Stroke 40, 3796–3803.PubMedCrossRefGoogle Scholar
  58. Mackessy, S.P., 1993a. Fibrinogenolytic proteases from the venoms of juvenile and adult northern Pacific rattlesnake (Crotalus viridis oreganus). Comp. Biochem. Physiol. 106B, 181–189.Google Scholar
  59. Mackessy, S.P., 1993b. Kallikrein-like and thrombin-like proteases from the venom of juvenile northern Pacific rattlesnakes (Crotalus viridis oreganus). J. Nat. Toxins 2, 223–239.Google Scholar
  60. Mackessy, S.P., 1996. Characterization of the major metalloprotease isolated from the venom of Crotalus viridis oreganus. Toxicon 34, 1277–1285.PubMedCrossRefGoogle Scholar
  61. Mackessy, S.P. 2002. Biochemistry and pharmacology of colubrid snake venoms. J. Toxicol.-Toxin Rev. 21, 43–83.CrossRefGoogle Scholar
  62. Mackessy, S.P., 2009. The field of reptile toxinology: snakes, lizards and their venoms, in: Mackessy, S.P. (Ed.), Handbook of Venoms and Toxins of Reptiles. CRC Press/Taylor & Francis Group, Boca Raton, FL, pp. 3–23.CrossRefGoogle Scholar
  63. MacSweeney, A., Birrane, G., Walsh, M.A., O`Connell, T., Malthouse, J.P., Higgins, T.M. 2000. Crystal structure of delta-chymotrypsin bound to a peptidyl chloromethyl ketone inhibitor. Acta Crystallogr., Sect. D 56, 280–286.CrossRefGoogle Scholar
  64. Magalhães, A., Da Fonseca, B.C., Diniz, C.R., Gilroy, J., Richardson, M., 1993. The complete amino acid sequence of a thrombin-like enzyme/gyroxin analogue from venom of the bushmaster snake (Lachesis muta muta). FEBS Lett. 329:116–20.PubMedCrossRefGoogle Scholar
  65. Magalhães, A., Magalhães, H.P.B., Richardson, M., Gontijo, S., Ferreira, R.N., Almeida, A.P., Sanchez, E.F., 2007. Purification and properties of a coagulant thrombin-like enzyme from the venom of Bothrops leucurus. Comp. Biochem. Physiol. 146A, 565–575.Google Scholar
  66. Marchler-Bauer, A., Anderson, J.B., Chitsaz, F., Derbyshire, M.K., DeWeese-Scott, C., Fong, J.H., Geer, L.Y., Geer, R.C., Gonzales, N.R., Gwadz, M., He, S., Hurwitz, D.I., Jackson, J.D., Ke, Z., Lanczycki, C.J., Liebert, C.A., Liu, C., Lu, F., Lu, S., Marchler, G.H., Mullokandov, M., Song, J.S., Tasneem, A., Thanki, N., Yamashita, R.A., Zhang, D., Zhang, N., Bryant, S.H. 2009. CDD: specific functional annotation with the Conserved Domain Database. Nucleic Acids Res. 37, 205–210.CrossRefGoogle Scholar
  67. Markland, F.S., Jr., 1976. Crotalase. Methods Enzymol. 45, 223–236.PubMedCrossRefGoogle Scholar
  68. Markland, F.S., Jr., 1998. Snake venoms and the hemostatic system. Toxicon 36, 1749–1800.PubMedCrossRefGoogle Scholar
  69. Markland, F.S., Jr., Kettner, C., Schiffman, S., Shaw, E., Bajwa, S.S., Reddy, K.N., Kirakossian, H., Patkos, G.B., Theodor, I., Pirkle, H., 1982. Kallikrein-like activity of crotalase, a snake venom enzyme that clots fibrinogen. Proc. Natl Acad. Sci. U.S.A. 79, 1688–1692.PubMedCrossRefGoogle Scholar
  70. Marrakchi, N., Zingali, R.B., Karoui, H., Bon, C., el Ayeb, M., 1995. Cerastocytin, a new thrombin-like platelet activator from the venom of the Tunisian viper Cerastes cerastes. Biochim. Biophys. Acta 1244, 147–156.PubMedCrossRefGoogle Scholar
  71. Marrakchi, N., Barbouche, R., Guermazi, S., Karoui, H., Bon, C., El Ayeb, M., 1997. Cerastotin, a serine protease from Cerastes cerastes venom, with platelet-aggregating and agglutinating properties. Eur. J. Biochem. 247, 121–128.PubMedCrossRefGoogle Scholar
  72. Marsh, N., Williams, V., 2005. Practical applications of snake venom toxins in haemostasis. Toxicon 45, 1171–1181.PubMedCrossRefGoogle Scholar
  73. Matsui, T., Sakurai, Y., Fujimura, Y., Hayashi, I., Oh-Ishi, S., Suzuki, M., Hamako, J., Yamamoto, Y., Yamazaki, J., Kinoshita, M., Titani, K., 1998. Purification and amino acid sequence of halystase from snake venom of Agkistrodon halys blomhoffii, a serine protease that cleaves specifically fibrinogen and kininogen. Eur. J. Biochem. 252, 569–575.PubMedCrossRefGoogle Scholar
  74. Mukherjee, A.K., 2008. Characterization of a novel pro-coagulant metalloprotease (RVBCMP) possessing α-fibrinogenase and tissue hemorrhagic activity from the venom of Daboia russelli russelli (Russell’s viper): evidence of distinct coagulant and haemorrhagic sites in RVBCMP. Toxicon 51, 923–933.PubMedCrossRefGoogle Scholar
  75. Nakashima, K., Nobuhisa, I., Deshimaru, M., Nakai, M., Ogawa, T., Shimohigashi, Y., Fukumaki, Y., Hattori, M., Sakaki, Y., Hattori, S., 1995. Accelerated evolution in the protein-coding regions is universal in crotalinae snake venom gland phospholipase A2 isozyme genes. Proc. Natl. Acad. Sci. U.S.A. 92, 5605–5609.PubMedCrossRefGoogle Scholar
  76. Nakashima, K., Ogawa, T., Oda, N., Hattori, M., Sakaki, Y., Kihara, H., Ohno, M., 1993. Accelerated evolution of Trimeresurus flavoviridis venom gland phospholipase A2 isozymes. Proc. Natl. Acad. Sci. U.S.A. 90, 5964–5968.PubMedCrossRefGoogle Scholar
  77. Nakayama, D., Ben Ammar, Y., Takeda, S., 2009. Crystallization and preliminary X-ray crystallographic analysis of blood coagulation factor V-activating proteinase (RVV-V) from Russell’s viper venom. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 65, 1306–1308.PubMedCrossRefGoogle Scholar
  78. Nikai, T., Ohara, A., Komori, Y., Fox, J.W., Sugihara, H., 1995. Primary structure of a coagulant enzyme, bilineobin, from Agkistrodon bilineatus venom. Arch. Biochem. Biophys. 318, 89–96.PubMedCrossRefGoogle Scholar
  79. Nishida, S., Fujimura, Y., Miura, S., Ozaki, Y., Usami, Y., Suzuki, M., Tita´n, K., Yoshida, E., Sugimoto, M., Yoshioka, A., Fukui, H., 1994. Purification and characterization of bothrombin, a fibrinogen-clotting serine protease from the venom of Bothrops jararaca. Biochemistry 33, 1843–1849.PubMedCrossRefGoogle Scholar
  80. Nirthanan, S., Gwee, M.C.E., 2004. Three-finger α-neurotoxins and the nicotinic acetylcholine receptor, forty years on. J. Pharmacol. Sci. 94, 1–17.PubMedCrossRefGoogle Scholar
  81. Nobuhisa, I., Nakashima, K., Deshimaru, M., Ogawa, T., Shimohigashi, Y., Fukumaki, Y., Sakaki, Y., Hattori, S., Kihara, H., Ohno, M., 1996. Accelerated evolution of Trimeresurus okinavensis venom gland phospholipase A2 isozyme-encoding genes. Gene 172, 267–272.PubMedCrossRefGoogle Scholar
  82. Nolan, C., Hall, L.S., Barlow, G.H., 1976. Ancrod, the coagulating enzyme from Malayan pit viper (Agkistrodon rhodostoma) venom. Methods Enzymol. 45, 205–213.PubMedCrossRefGoogle Scholar
  83. Ogawa, T., Nakashima, K., Nobuhisa, I., Deshimaru, M., Shimohigashi, Y., Fukumaki, Y., Sakaki, Y., Hattori, S., Ohno, M., 1996. Accelerated evolution of snake venom phospholipase A2 isozymes for acquisition of diverse physiological functions. Toxicon 34, 1229–1236.PubMedCrossRefGoogle Scholar
  84. Ohno, M., Menez, R., Ogawa, T., Danse, J.M., Shimohigashi, Y., Fromen, C., Ducancel, F., Zinn-Justin, S., Le Du, M.H., Boulain, J.C., Tamiya, T., Menez, A., 1998. Molecular evolution of snake toxins: is the functional diversity of snake toxins associated with a mechanism of accelerated evolution? Prog. Nucleic Acid Res. Mol. Biol. 59, 307–364.CrossRefGoogle Scholar
  85. Oyama, E., Takahashi, H., 2003. Purification and characterization of a thrombin like enzyme, elegaxobin II, with lys-bradykinin releasing activity from the venom of Trimeresurus elegans (Sakishima-Habu). Toxicon 41, 559–568.PubMedCrossRefGoogle Scholar
  86. Paes Leme, A.F., Prezoto, B.C., Yamashiro, E.T., Bertholim, L., Tashima, A.K., Klitzke, C.F., Camargo, A.C., Serrano, S.M., 2008. Bothrops protease A, a unique highly glycosylated serine proteinase, is a potent, specific fibrinogenolytic agent. J. Thromb. Haemost. 6, 1363–1372.PubMedCrossRefGoogle Scholar
  87. Pahari, S., Mackessy, S.P., Kini, M.R., 2007. The venom gland transcriptome of the Desert Massasauga Rattlesnake (Sistrurus catenatus edwardsii): towards an understanding of venom composition among advanced snakes (Superfamily Colubroidea). BMC Mol. Biol. 8, 115.PubMedCrossRefGoogle Scholar
  88. Pan, H., Du, X., Yang, G., Zhou, Y., Wu, X., 1999. cDNA cloning and expression of acutin. Biochem. Biophys. Res. Commun. 255, 412–415.PubMedCrossRefGoogle Scholar
  89. Parry MA, Jacob U, Huber R, Wisner A, Bon C, Bode, W. 1998. The crystal structure of the novel snake venom plasminogen activator TSV-PA: a prototype structure for snake venom serine proteinases. Structure 6, 1195–1206.PubMedCrossRefGoogle Scholar
  90. Pawlak, J., Kini, R.M., 2008. Unique gene organization of colubrid three-finger toxins: complete cDNA and gene sequences of denmotoxin, a bird-specific toxin from colubrid snake Boiga dendrophila (Mangrove Catsnake). Biochimie 90, 868–877.Google Scholar
  91. Phillips, D.J., Swenson, S.D., Markland, F.S., Jr. 2009. Thrombin-like snake venom serine proteinases, in: Mackessy, S.P. (Ed.), Handbook of Venoms and Toxins of Reptiles. CRC Press/Taylor & Francis Group, Boca Raton, FL, pp. 139–154.CrossRefGoogle Scholar
  92. Philipps, J., Thomalla, G., Glahn, J., Schwarze, M., Rother, J., 2009. Treatment of progressive stroke with tirofiban – experience in 35 patients. Cerebrovasc. Dis. 28, 435–438.PubMedCrossRefGoogle Scholar
  93. Polaskova, V., Kapur, A., Khan, A., Molloy, M.P., Baker, M.S., 2010. High-abundance protein depletion: comparison of methods for human plasma biomarker discovery. Electrophoresis 31, 471–482.PubMedCrossRefGoogle Scholar
  94. Polgár, L., 1971. On the mechanism of proton transfer in the catalysis by serine proteases. J. Theor. Biol. 31, 165–169.PubMedCrossRefGoogle Scholar
  95. Polgár, L., Bender, M.L., 1969. The nature of general base-general acid catalysis in serine proteases. Proc. Natl. Acad. Sci. USA 64, 1335–1342.PubMedCrossRefGoogle Scholar
  96. Rawlings, N.D., Tolle, D.P., Barrett A.J., 2004a. MEROPS: the peptidase database. Nucleic Acids Res. 32, D160–164.PubMedCrossRefGoogle Scholar
  97. Rawlings, N.D., Tolle, D.P., Barrett A.J., 2004b. Evolutionary families of peptidase inhibitors. Biochem. J. 378, 705–716.PubMedCrossRefGoogle Scholar
  98. Rowe, S.L., Stegemann, J.P., 2009. Microstructure and mechanics of collagen-fibrin matrices polymerized using ancrod snake venom enzyme. J. Biomech. Eng. 131, 061012. doi: 10.1115/1.3128673.PubMedCrossRefGoogle Scholar
  99. Sanz, L., Gibbs, H.L., Mackessy, S.P., Calvete, J.J., 2006. Venom proteomes of closely related Sistrurus rattlesnakes with divergent diets. J. Proteome Res. 5, 2098–2112.PubMedCrossRefGoogle Scholar
  100. Segers, K., Rosing, J., Nicolaes, G.A., 2006. Structural models of the snake venom factor V activators from Daboia russelli and Daboia lebetina. Proteins 64, 968–984.PubMedCrossRefGoogle Scholar
  101. Serrano, S.M., Hagiwara, Y., Murayama, N., Higuchi, S., Mentele, R., Sampaio, C.A., Camargo, A.C., Fink, E., 1998. Purification and characterization of a kinin-releasing and fibrinogen-clotting serine proteinase (KN-BJ) from the venom of Bothrops jararaca, and molecular cloning and sequence analysis of its cDNA. Eur. J. Biochem. 251, 845–853.PubMedCrossRefGoogle Scholar
  102. Serrano, S.M.T., Maroun, R.C. 2005. Snake venom serine proteinases: sequence homology vs. substrate specificity, a paradox to be solved. Toxicon 45, 1115–1132.PubMedCrossRefGoogle Scholar
  103. Sherman, D.G., 2002. Ancrod. Curr. Med. Res. Opin. 18, s48–s52.CrossRefGoogle Scholar
  104. Shieh, T.-C., Kawabata, S., Kihara, H., Ohno, M., Iwanaga, S., 1988. Amino acid sequence of a coagulant enzyme, flavoxobin, from Trimeresurus flavoviridis venom. J. Biochem. 103, 596–605.PubMedGoogle Scholar
  105. Shieh, T.C., Tanaka, S., Kihara, H., Ohno, M., Makisumi, S., 1985. Purification and characterization of a coagulant enzyme from Trimeresurus flavoviridis venom. J. Biochem. (Tokyo) 98, 713–721.Google Scholar
  106. Shimokawa, K., Takahashi, H., 1993a. Purification of a capillary permeability-increasing enzyme-2 from the venom of Agkistrodon caliginosus (Kankoku-Mamushi). Toxicon 31, 1213–1219.PubMedCrossRefGoogle Scholar
  107. Shimokawa, K., Takahashi, H., 1993b. Some properties of a capillary permeability-increasing enzyme-2 from the venom of Agkistrodon caliginosus (Kankoku-Mamushi). Toxicon 31, 1221–1227.PubMedCrossRefGoogle Scholar
  108. Silva-Junior, F.P., Guedes, H.L., Garvey, L.C., Aguiar, A.S., Bourguignon, S.C., Di Cera, E., Giovanni-De-Simone, S., 2007. BJ-48, a novel thrombin-like enzyme from the Bothrops jararacussu venom with high selectivity for Arg over Lys in P1: role of N-glycosylation in thermostability and active site accessibility. Toxicon 50, 18–31.PubMedCrossRefGoogle Scholar
  109. Silveira, A.M.V., Magalhães, A., Diniz, C.R., Oliveira, E.B., 1989. Purification and properties of the thrombin-like enzyme from the venom of Lachesis muta muta. Int. J. Biochem. 21, 863–868.PubMedCrossRefGoogle Scholar
  110. Smith, C.G., Vane, J.R., 2003. The discovery of captopril. FASEB J. 17, 788–789.PubMedCrossRefGoogle Scholar
  111. Spyropoulos, A.C., 2008. Brave new worlds: the current and future use of novel anticoagulants. Thromb. Res. 123, S29-S35.PubMedCrossRefGoogle Scholar
  112. Stocker, K.F., 1998. Research, diagnostic and medicinal uses of snake venom enzymes, in: Bailey, G.S. (Ed.), Enzymes From Snake Venom. Alaken Press, Fort Collins, CO, pp. 705–736.Google Scholar
  113. Stocker, K., Meier, J., 1989. Snake venom proteins in hemostasis: new results. Folia Haematol. Int. Mag. Klin. Morphol. Blutforsch 116, 935–953.Google Scholar
  114. Stocker, K., Barlow, G.H., 1976. The coagulant enzyme from Bothrops atrox venom (batroxobin). Methods Enzymol. 45, 214–223.PubMedCrossRefGoogle Scholar
  115. Stocker, K., Fischer, H., Meier, J., 1982. Thrombin-like snake venom proteinases. Toxicon 20, 265–273.PubMedCrossRefGoogle Scholar
  116. Sturzebecher, J., Sturzebecher, U., Markwardt, F., 1986. Inhibition of batroxobin, a serine proteinase from Bothrops snake venom, by derivatives of benzamidine. Toxicon 24, 585–595.PubMedCrossRefGoogle Scholar
  117. Swenson, S., Markland, F.S., Jr., 2005. Snake venom fibrin(ogen)olytic enzymes. Toxicon 45, 1021–1039.PubMedCrossRefGoogle Scholar
  118. Takacs, Z., Wilhelmsen, K.C., Sorota, S., 2001. Snake α-neurotoxin binding site on the Egyptian Cobra (Naja haje) nicotinic acetylcholine receptor is conserved. Mol. Biol. Evol. 18, 1800–1809.PubMedCrossRefGoogle Scholar
  119. Tamiya, T., Ohno, S., Nishimura, E., Fujimi, T.J., Tsuchiya, T., 1999. Complete nucleotide sequences of cDNAs encoding long chain alpha-neurotoxins from sea krait, Laticauda semifasciata. Toxicon 37, 181–185.PubMedCrossRefGoogle Scholar
  120. Tanaka, N., Nakada, H., Itoh, N., Mizuno, Y., Takanishi, M., Kawasaki, T., Tate, S., Inagaki, F., Yamashina, I., 1992. Novel structure of the N-acetylgalactosamine containing N-glycosidic carbohydrate chain of batroxobin, a thrombin-like snake venom enzyme. J. Biochem. 112, 68–74.PubMedGoogle Scholar
  121. Thompson, J.D., Higgins, D.G., Gibson, T.J., 1994. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 22, 4673–4680.PubMedCrossRefGoogle Scholar
  122. Tsai, I.-H., Wang, Y.-M., 2001. Identification of geographic variations and cloning of venom proteins of Trimeresurus stejnegeri: serine proteases and phospholipases. EMBL/GenBank/DDBJ databases.Google Scholar
  123. Utaisincharoen, P., Mackessy, S.P., Miller, R.A., Tu, A.T. 1993. Complete primary structure and biochemical properties of gilatoxin, a serine protease with kallikrein-like and angiotensin-degrading activities. J. Biol. Chem. 268, 21975–21983.PubMedGoogle Scholar
  124. Wang, Y.M., Wang, S.R., Tsai, I.H., 2001. Serine protease isoforms of Deinagkistrodon acutus venom: cloning, sequencing and phylogenetic analysis. Biochem. J. 354, 161–168.PubMedCrossRefGoogle Scholar
  125. Wei, J.N., Wang, Q.C., Liu, G.F., Ezell, E.L., Quast, M.J., 2004. Reduction of brain injury by antithrombotic agent acutobin after middle cerebral artery ischemia/reperfusion in the hyperglycemic rat. Brain Res. 1022, 234–243.PubMedCrossRefGoogle Scholar
  126. Weldon, C.L., Mackessy, S.P., 2010. Biological and proteomic analysis of venom from the Puerto Rican Racer (Alsophis portoricensis: Dipsadidae). Toxicon 55, 558–569.PubMedCrossRefGoogle Scholar
  127. White, J., 2005. Snake venoms and coagulopathy. Toxicon 45, 951–967.PubMedCrossRefGoogle Scholar
  128. White, J., 2009. Envenomation: prevention and treatment in Australia, in: Mackessy, S.P. (Ed.), Handbook of Venoms and Toxins of Reptiles. CRC Press/Taylor & Francis Group, Boca Raton, FL, pp. 423–451.CrossRefGoogle Scholar
  129. Wisner, A., Braud, S., Bon, C., 2001. Snake venom proteinases as tools in hemostasis studies: structure-function relationship of a plasminogen activator purified from Trimeresurus stejnegeri venom. Haemostasis 31, 133–140.PubMedGoogle Scholar
  130. Yamamoto, C., Tsuru, D., Oda-Ueda, N., Ohno, M., Hattori, S., Kim, S.T., 2002. Flavoxobin, a serine protease from Trimeresurus flavoviridis (habu snake) venom, independently cleaves Arg726–Ser727 of human C3 and acts as a novel, heterologous C3 convertase. Immunology 107, 111–117.PubMedCrossRefGoogle Scholar
  131. Xu, G., Liu, X., Zhu, W., Yin, Q., Zhang, R., Fan, X., 2007. Feasibility of treating hyperfibrinogenemia with intermittently administered batroxobin in patients with ischemic stroke/transient ischemic attack for secondary prevention. Blood Coagul. Fibrinolysis 18, 193–197.PubMedCrossRefGoogle Scholar
  132. Zeng, Z., Xiao, P., Chen, J., Wei, Y., 2009. Are batroxobin agents effective for perioperative hemorrhage in thoracic surgery? A systematic review of randomized controlled trials. Blood Coagul. Fibrinolysis 20, 101–107.PubMedCrossRefGoogle Scholar
  133. Zhang, B., Liu, Q., Yin, W., Zhang, X., Huang, Y., Luo, Y., Qiu, P., Su, X., Yu, J., Hu, S., Yan, G., 2006. Transcriptome analysis of Deinagkistrodon acutus venomous gland focusing on cellular structure and functional aspects using expressed sequence tags. BMC Genomics, 7, 152.PubMedCrossRefGoogle Scholar
  134. Zhang, L., Lu, S.H., Li, L., Tao, Y.G., Wan, Y.L., Senga, H., Yang, R., Han, Z.C., 2009. Batroxobin mobilizes circulating endothelial progenitor cells in patients with deep vein thrombosis. Clin. Appl. Thromb. Hemost. 2009 Oct 13. [Epub ahead of print]Google Scholar
  135. Zhang, Y., Gao, R., Lee, W.-H., Zhu, S.-W., Xiong, Y.-L., Wang, W.-Y., 1998. Characterization of a fibrinogen-clotting enzyme from Trimeresurus stejnegeri venom, and comparative study with other venom proteases. Toxicon 36, 131–142.PubMedCrossRefGoogle Scholar
  136. Zhu, Z, Liang, Z, Zhang, T, Zhu, Z, Xu, W, Teng, M, Niu, L., 2005. Crystal structures and amidolytic activities of two glycosylated snake venom serine proteinases. J. Biol. Chem. 280:10524–10529.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.School of Biological SciencesUniversity of Northern ColoradoGreeleyUSA

Personalised recommendations