{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T07:57:02Z","timestamp":1780473422208,"version":"3.54.1"},"reference-count":56,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2017,8,4]],"date-time":"2017-08-04T00:00:00Z","timestamp":1501804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Snake venom metalloproteinases (SVMP) are widely distributed among the venoms of Crotalinae and Viperidae, and are organized into three classes (P-I, P-II and P-III) according to their size and domain structure. P-I SVMP are the smallest SVMP, as they only have a metalloproteinase (M) domain. P-II SVMP contain a disintegrin-like (D) domain, which is connected by a short spacer region to the carboxyl terminus of the M domain. P-III SVMP contain a cysteine-rich (C) domain, which is attached to the carboxyl terminus of the D domain. Some SVMP exhibit hemorrhagic activity, whereas others do not. In addition, SVMP display fibrinolytic\/fibrinogenolytic (FL) activity, and the physiological functions of SVMP are controlled by their structures. Furthermore, these proteinases also demonstrate fibrinogenolytic and proteolytic activity against synthetic substrates for matrix metalloproteinases and ADAM (a disintegrin and metalloproteinase). This article describes the structures and FL, hemorrhagic, and platelet aggregation-inhibiting activity of SVMP derived from Protobothrops snake venom that was collected in Japan.<\/jats:p>","DOI":"10.3390\/molecules22081305","type":"journal-article","created":{"date-parts":[[2017,8,4]],"date-time":"2017-08-04T11:07:08Z","timestamp":1501844828000},"page":"1305","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Structures and Functions of Snake Venom Metalloproteinases (SVMP) from Protobothrops venom Collected in Japan"],"prefix":"10.3390","volume":"22","author":[{"given":"Etsuko","family":"Oyama","sequence":"first","affiliation":[{"name":"Department of Hygienic Chemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose-shi, Tokyo 204-8588, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidenobu","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Hygienic Chemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose-shi, Tokyo 204-8588, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1042\/BJ20060302","article-title":"Anticoagulant proteins from snake venoms: Structure, function, and mechanism","volume":"397","author":"Kini","year":"2006","journal-title":"Biochem. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1006\/abbi.1999.1517","article-title":"Inhibition of platelet aggregation by the recombinant cysteine-rich domain of the hemorrhagic snake venom metalloproteinase, atrolysin A","volume":"373","author":"Jia","year":"2000","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.bbapap.2011.04.009","article-title":"Snake venom metalloproteinases: Structure, function and relevance to the mammalian ADAM\/ADAMTS family proteins","volume":"1824","author":"Takeda","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6203","DOI":"10.1006\/abbi.1994.1026","article-title":"cDNA sequences for four snake venom metalloproteinases: Structure, classification, and their relationship to mammalian reproductive proteins","volume":"308","author":"Hite","year":"1994","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/978-3-642-66913-2_4","article-title":"Enzymes in snake venom","volume":"Volume 52","author":"Born","year":"1979","journal-title":"Handbook of Experimental Pharmacology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/0163-7258(94)90049-3","article-title":"Hemorrhagic metalloproteinases from snake venoms","volume":"62","author":"Bjarnason","year":"1994","journal-title":"Pharmacol. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/j.toxicon.2005.02.012","article-title":"Structural considerations of the snake venom metalloproteinases, key members of the M12 reprolysin family of metalloproteinases","volume":"45","author":"Fox","year":"2005","journal-title":"Toxicon"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.jprot.2009.01.015","article-title":"Timeline of key events in snake venom metalloproteinase research","volume":"72","author":"Fox","year":"2009","journal-title":"J. Proteom."},{"key":"ref_9","unstructured":"Bailey, G.S. (1998). Proteases that induce hemorrhagic. Enzymes from Snake Venom, Alaken."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/S0041-0101(01)00249-5","article-title":"Involvement of specific integrins in apoptosis induced by vascular apoptosis-inducing protein 1","volume":"40","author":"Araki","year":"2002","journal-title":"Toxicon"},{"key":"ref_11","unstructured":"Mackessy, S.P. (2010). Snake venom metalloproteinase. Handbook of Venoms and Toxins of Reptiles, CRC Press."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4544","DOI":"10.1111\/j.1742-4658.2011.08115.x","article-title":"Enzymatic toxins from snake venom: Structural characterization and mechanism of catalysis","volume":"278","author":"Kang","year":"2011","journal-title":"FEBS"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/0076-6879(95)48023-4","article-title":"Snake venom metalloproteinases: Reprolysins","volume":"248","author":"Bjarnason","year":"1995","journal-title":"Methods Enzymol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1016\/S0041-0101(02)00179-4","article-title":"Molecular cloning of HR1a and HR1b, high molecular hemorrhagic factors, from Trimeresurus flavoviridis venom","volume":"40","author":"Kishimoto","year":"2002","journal-title":"Toxicon"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"16068","DOI":"10.1016\/S0021-9258(17)46189-8","article-title":"The complete amino acid sequence of the high molecular mass hemorrhagic protein HR1B isolated from the venom of Trimeresurus flavoviridis","volume":"265","author":"Takeya","year":"1990","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"14109","DOI":"10.1016\/S0021-9258(19)49685-3","article-title":"A novel metalloproteinase with disintegrin (platelet aggregation inhibitor)-like and C-type lectin-like domains","volume":"267","author":"Takeya","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"10644","DOI":"10.1016\/S0021-9258(17)34108-X","article-title":"Factor X-activating glycoprotein of Russell\u2019s viper venom. Polypeptide composition and characterization of the carbohydrate moieties","volume":"269","author":"Gowda","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1385\/MB:24:2:157","article-title":"Structural aspects of the metzincin clan of metalloendopeptidases","volume":"24","year":"2003","journal-title":"J. Mol. Biotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1093\/oxfordjournals.jbchem.a021215","article-title":"Crystal structure of H2-proteinase from the venom of Trimeresurus flavoviridis","volume":"119","author":"Kumasaka","year":"1996","journal-title":"J. Biochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.toxicon.2013.04.004","article-title":"Primary structure and characterization of a non hemorrhagic metalloproteinase with fibrinolytic activity, from the snake venom of Protobothrops tokarensis (Tokara-habu)","volume":"70","author":"Oyama","year":"2013","journal-title":"Toxicon"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1093\/oxfordjournals.jbchem.a122805","article-title":"Primary structure of H2-proteinase, a non-hemorrhagic proteinase, isolated from the venom of the habu snake, Trimeresurus flavoviridis","volume":"106","author":"Takeya","year":"1989","journal-title":"J. Biochem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1093\/oxfordjournals.jbchem.a122756","article-title":"Primary structure of hemorrhagic protein, HR2a, isolated from the venom of Trimeresurus flavoviridis","volume":"105","author":"Miyata","year":"1989","journal-title":"J. Biochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/0041-0101(94)00147-Z","article-title":"The primary structure of a hemorrhagic factor, HR2b, from the venom of Okinawa habu (Trimeresurus flavoviridis)","volume":"33","author":"Iha","year":"1995","journal-title":"Toxicon"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/S0041-0101(02)00081-8","article-title":"Molecular cloning and sequence analysis of cDNA encoding flavoviridin, a disintegrin from the venom of Trimeresurus flavoviridis","volume":"40","author":"Kishimoto","year":"2002","journal-title":"Toxicon"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1042\/bj3190775","article-title":"Amino acid sequence and molecular modelling of glycoprotein IIb-IIIa and fibronectin receptor iso-antagonists from Trimeresurus elegans venom","volume":"313","author":"Scaloni","year":"1996","journal-title":"Biochem. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3339","DOI":"10.1046\/j.1432-1327.2001.02246.x","article-title":"Purification, cDNA cloning and characterization of the vascular apoptosis-inducing protein, HV1, from Trimeresurus flavoviridis","volume":"268","author":"Masuda","year":"2001","journal-title":"Eur. J. Biochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2388","DOI":"10.1038\/sj.emboj.7601131","article-title":"Crystal structure of VAP1 reveal ADAMs MDC domain architecture and its unique C-shaped scaffold","volume":"25","author":"Takeda","year":"2006","journal-title":"EMBO J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.semcdb.2008.07.009","article-title":"Three-dimensional domain architecture of the ADAM family proteinases","volume":"20","author":"Takeda","year":"2009","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1093\/oxfordjournals.jbchem.a124069","article-title":"Primary structures of platelet aggregation inhibitors (disintegrin) autoproteolytically released from snake venom hemorrhagic metalloproteinases and new fluorogenic peptide substrates for these enzyme","volume":"113","author":"Takeya","year":"1993","journal-title":"J. Biochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6203","DOI":"10.1021\/bi00142a005","article-title":"Sequence of a cDNA clone encoding the zinc metalloproteinase hemorrhagic toxin e from Crotalus atrox: Evidence for signal, zymogen, and disintegrin-like structures","volume":"31","author":"Hite","year":"1992","journal-title":"Biochemistry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/0041-0101(92)90869-7","article-title":"Structural domains in venom proteins: Evidence that metalloproteinases and nonenzymatic platelet aggregation inhibitors (disintegrins) from snake venom are derived by proteolysis from a common precursor","volume":"30","author":"Kini","year":"1992","journal-title":"Toxicon"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"14248","DOI":"10.1021\/bi025876s","article-title":"A new gene structure of the disintegrin family: A subunit of dimeric disintegrin has a short coding region","volume":"41","author":"Okuda","year":"2002","journal-title":"Biochemistry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"16157","DOI":"10.1016\/S0021-9258(18)47710-1","article-title":"Trigramin. A low molecular weight peptide inhibiting fibrinogen interaction with platelet receptors expressed on glycoprotein IIb-IIIa complex","volume":"262","author":"Huang","year":"1987","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/j.toxicon.2005.02.024","article-title":"Snake venom disintegrins: Evolution of structure and function","volume":"45","author":"Calvete","year":"2005","journal-title":"Toxicon"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/0304-4165(91)90156-B","article-title":"Purification and characterization of lebetase, a fibrinolytic enzyme from Vipera lebetina (snake) venom","volume":"1074","author":"Siigur","year":"1991","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1111\/j.1365-2141.1967.tb00765.x","article-title":"The isolation and properties of the thrombin-like activity from Angistrodon rhodostoma venom","volume":"13","author":"Esnouf","year":"1967","journal-title":"Br. J. Haematol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6460","DOI":"10.1016\/S0021-9258(19)34138-9","article-title":"Purification and properties of a thrombin-like enzyme from the venom of Crotalus adamanteus (Eastern diamondback rattlesnake)","volume":"246","author":"Markland","year":"1971","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.toxicon.2005.08.007","article-title":"Substrate specificity of two thrombin like enzymes (elegaxobin, elegaxobinII) from the venom of Trimeresurus elegans (Sakishima-habu), using neutralizing antibody","volume":"48","author":"Oyama","year":"2006","journal-title":"Toxicon"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"20531","DOI":"10.1074\/jbc.272.33.20531","article-title":"Trimeresurus stejnegeri snake venom plasminogen activator","volume":"272","author":"Zhang","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1006\/abbi.2000.1781","article-title":"Isolation of a proteinase with plasminogen-activating activity from Lachesis muta muta (Bushmaster) snake venom","volume":"378","author":"Sanchez","year":"2000","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1016\/S0021-9258(18)95967-3","article-title":"The peptide chains of human plasmin. Mechanism of activation of human plasminogen to plasmin","volume":"242","author":"Robbins","year":"1967","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/0014-5793(87)81501-6","article-title":"Molecular cloning and characterization of a full-lengh cDNA clone for human plasminogen","volume":"213","author":"Forsgren","year":"1987","journal-title":"FEBS Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/0304-4165(85)90258-2","article-title":"Isolation and characterization of hemorrhagic factors and b from the venom of the Chinese habu snake (Trimeresurus mucrosquamatus)","volume":"838","author":"Nikai","year":"1985","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/0003-9861(84)90393-X","article-title":"Isolation and biochemical characterization of hemorrhagic toxin f from the venom of Crotalus atrox (western diamondback rattlesnake)","volume":"231","author":"Nikai","year":"1984","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"44","DOI":"10.3831\/KPI.2014.17.006","article-title":"Isolation and Characterization of a 32-kDa fibrinolytic enzyme (FE-32 kDa) from Gloydius blomhoffii siniticus venom","volume":"17","author":"Kim","year":"2014","journal-title":"Pharmacopuncture"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Lee, C.-Y. (1979). Handbook of Experimental Pharmacology, Snake Venoms, Springer-Verlag.","DOI":"10.1007\/978-3-642-66913-2"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/0005-2744(70)90062-8","article-title":"Purification and characterization of a proteinase in the venom of Trimeresurus flavoviridis. Complete separation of the enzyme from hemorrhagic activity","volume":"198","author":"Takahashi","year":"1970","journal-title":"Biochim. Biophys. Acts"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1016\/0041-0101(90)90155-Z","article-title":"Effects of snake venom proteins on blood platelets","volume":"28","author":"Kini","year":"1990","journal-title":"Toxicon"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"77","DOI":"10.3109\/09537109109113692","article-title":"Snake venom constituents that affect platelet function","volume":"2","author":"Teng","year":"1991","journal-title":"Platelets"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1093\/oxfordjournals.jbchem.a123437","article-title":"Primary structures of cytotoxic factors isolated from Habu (Trimeresurus flavoviridis) venom","volume":"109","author":"Yamakawa","year":"1991","journal-title":"J. Biochem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1161\/01.CIR.82.1.261","article-title":"Inhibition of platelet adhesion to surfaces of extracorporeal circuits by disintegrins. RGD-containing peptides from viper venoms","volume":"82","author":"Musial","year":"1990","journal-title":"Circulation"},{"key":"ref_52","first-page":"328","article-title":"Triflavin, an antiplatelet Arg-Gly-Asp-containing peptide, is a specific antagonist of platelet membrane glycoprotein IIb-IIIa complex","volume":"109","author":"Huang","year":"1991","journal-title":"J. Biochem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/0167-4838(90)90229-9","article-title":"Elegantin and albolabrin purified peptides from viper venoms: Homologies with the RGDS domain of fibrinogen and von Willebrand factor","volume":"31","author":"Williams","year":"1990","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.toxicon.2015.06.010","article-title":"Purification and characterization of two high molecular mass snake venom metalloproteinase (P-III SVMPs), named SV-PAD-2 and HR-Ele-1, from the venom of Protobothrops elegans (Sakishima-habu)","volume":"103","author":"Oyama","year":"2015","journal-title":"Toxicon"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"352420","DOI":"10.1155\/2014\/352420","article-title":"Rapid purification of a new P-I Crass metalloproteinase from Bothrops moojeni venom with antiplatelet activity","volume":"2014","author":"Queiroz","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1016\/j.bbagen.2015.12.021","article-title":"A novel fibrinolytic metalloproteinase, barnettlysin-1 from Bothrops barnetti (barnett\u2019s pitviper) snake venom with anti-platelet properties","volume":"1860","author":"Sanchez","year":"2016","journal-title":"Biochim. Biophys. Acta"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/22\/8\/1305\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:41:27Z","timestamp":1760208087000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/22\/8\/1305"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,4]]},"references-count":56,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2017,8]]}},"alternative-id":["molecules22081305"],"URL":"https:\/\/doi.org\/10.3390\/molecules22081305","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8,4]]}}}