{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T11:10:08Z","timestamp":1792840208594,"version":"4.5.0"},"reference-count":66,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,10,6]],"date-time":"2024-10-06T00:00:00Z","timestamp":1728172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000923","name":"Australian Research Council Discovery Project","doi-asserted-by":"publisher","award":["DP190100304"],"award-info":[{"award-number":["DP190100304"]}],"id":[{"id":"10.13039\/501100000923","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Australian elapid snake venoms are uniquely procoagulant, utilizing blood clotting enzyme Factor Xa (FXa) as a toxin, which evolved as a basal trait in this clade. The subsequent recruitment of Factor Va (FVa) as a toxin occurred in the last common ancestor of taipans (Oxyuranus species) and brown snakes (Pseudonaja species). Factor II (prothrombin) activation has been stated as the primary mechanism for the lethal coagulopathy, but this hypothesis has never been tested. The additional activation of Factor VII (FVII) by Oxyuranus\/Pseudonaja venoms has historically been considered as a minor, unimportant novelty. This study aimed to investigate the significance of toxic FVII activation relative to prothrombin activation by testing a wide taxonomical range of Australian elapid species with procoagulant venoms. The activation of FVII or prothrombin, with and without the Factor Va as a cofactor, was assessed, along with the structural changes involved in these processes. All procoagulant species could activate FVII, establishing this as a basal trait. In contrast, only some lineages could activate prothrombin, indicating that this is a derived trait. For species able to activate both zymogens, Factor VII was consistently more strongly activated than prothrombin. FVa was revealed as an essential cofactor for FVII activation, a mechanism previously undocumented. Species lacking FVa in their venom utilized endogenous plasma FVa to exert this activity. The ability of the human FXa:FVa complex to activate FVII was also revealed as a new feedback loop in the endogenous clotting cascade. Toxin sequence analyses identified structural changes essential for the derived trait of prothrombin activation. This study presents a paradigm shift in understanding how elapid venoms activate coagulation factors, highlighting the critical role of FVII activation in the pathophysiological effects upon the coagulation cascade produced by Australian elapid snake venoms. It also documented the novel use of Factor Va as a cofactor for FVII activation for both venom and endogenous forms of FXa. These findings are crucial for developing better antivenoms and treatments for snakebite victims and have broader implications for drug design and the treatment of coagulation disorders. The research also advances the evolutionary biology knowledge of snake venoms.<\/jats:p>","DOI":"10.3390\/toxins16100430","type":"journal-article","created":{"date-parts":[[2024,10,7]],"date-time":"2024-10-07T07:30:18Z","timestamp":1728286218000},"page":"430","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["From Venom to Vein: Factor VII Activation as a Major Pathophysiological Target for Procoagulant Australian Elapid Snake Venoms"],"prefix":"10.3390","volume":"16","author":[{"given":"Uthpala","family":"Chandrasekara","sequence":"first","affiliation":[{"name":"Adaptive Biotoxicology Lab, School of the Environment, University of Queensland, St. Lucia, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhinandan","family":"Chowdhury","sequence":"additional","affiliation":[{"name":"Adaptive Biotoxicology Lab, School of the Environment, University of Queensland, St. Lucia, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Seneci","sequence":"additional","affiliation":[{"name":"Adaptive Biotoxicology Lab, School of the Environment, University of Queensland, St. Lucia, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0385-500X","authenticated-orcid":false,"given":"Christina N.","family":"Zdenek","sequence":"additional","affiliation":[{"name":"School of the Environment, University of Queensland, St. Lucia, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9707-7631","authenticated-orcid":false,"given":"Nathan","family":"Dunstan","sequence":"additional","affiliation":[{"name":"Venom Supplies Pty Ltd., Stonewell Rd., Tanunda, SA 5352, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6661-1283","authenticated-orcid":false,"given":"Bryan G.","family":"Fry","sequence":"additional","affiliation":[{"name":"Adaptive Biotoxicology Lab, School of the Environment, University of Queensland, St. Lucia, QLD 4072, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1159\/000321005","article-title":"Coagulation in vertebrates with a focus on evolution and inflammation","volume":"3","author":"Doolittle","year":"2011","journal-title":"J. Innate Immun."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Ainsworth, S., Slagboom, J., Alomran, N., Pla, D., Alhamdi, Y., King, S.I., Bolton, F.M.S., Guti\u00e9rrez, J.M., Vonk, F.J., and Toh, C.-H. (2018). The paraspecific neutralisation of snake venom induced coagulopathy by antivenoms. Commun. Biol., 1.","DOI":"10.1038\/s42003-018-0039-1"},{"key":"ref_3","unstructured":"Fry, B.G. (2015). Snake venom metalloprotease enzymes. Venomous Reptiles and Their Toxins: Evolution, Pathophysiology and Biodiscovery, Oxford University Press."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Debono, J., Dobson, J., Casewell, N.R., Romilio, A., Li, B., Kurniawan, N., Mardon, K., Weisbecker, V., Nouwens, A., and Kwok, H.F. (2017). Coagulating colubrids: Evolutionary, pathophysiological and biodiscovery implications of venom variations between Boomslang (Dispholidus typus) and Twig Snake (Thelotornis mossambicanus). Toxins, 9.","DOI":"10.3390\/toxins9050171"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S0003-9861(02)00447-2","article-title":"A novel prothrombin activator from the venom of Micropechis ikaheka: Isolation and characterization","volume":"408","author":"Gao","year":"2002","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Komori, Y., Hifumi, T., Yamamoto, A., Sakai, A., Ato, M., Sawabe, K., and Nikai, T. (2017). Comparative study of biological activities of venom from colubrid snakes Rhabdophis tigrinus (Yamakagashi) and Rhabdophis lateralis. Toxins, 9.","DOI":"10.3390\/toxins9110373"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0003-9861(03)00385-0","article-title":"Characterization of \u2018basparin A,\u2019 a prothrombin-activating metalloproteinase, from the venom of the snake Bothrops asper that inhibits platelet aggregation and induces defibrination and thrombosis","volume":"418","author":"Loria","year":"2003","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1021\/bi00005a034","article-title":"cDNA cloning and deduced amino acid sequence of prothrombin activator (ecarin) from Kenyan Echis carinatus venom","volume":"34","author":"Nishida","year":"1995","journal-title":"Biochemistry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5200","DOI":"10.1074\/jbc.271.9.5200","article-title":"Isolation and characterization of carinactivase, a novel prothrombin activator in Echis carinatus venom with a unique catalytic mechanism","volume":"271","author":"Yamada","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.toxlet.2018.02.020","article-title":"Factor X activating Atractaspis snake venoms and the relative coagulotoxicity neutralising efficacy of African antivenoms","volume":"288","author":"Oulion","year":"2018","journal-title":"Toxicol. Lett."},{"key":"ref_11","first-page":"225","article-title":"Snake venom activators of factor X: An overview","volume":"31","author":"Tans","year":"2001","journal-title":"Haemostasis"},{"key":"ref_12","unstructured":"Bailey, G.S. (1998). Proteases which activate factor X. Enzymes from Snake Venom, Alaken Inc."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Jones, L., Youngman, N.J., Neri-Castro, E., Guadarrama-Martinez, A., Lewin, M.R., Carter, R., Frank, N., and Fry, B.G. (2022). Differential antivenom and small-molecule inhibition of novel coagulotoxic variations in Atropoides, Cerrophidion, Metlapilcoatlus, and Porthidium American Viperid Snake Venoms. Toxins, 14.","DOI":"10.3390\/toxins14080511"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"10294","DOI":"10.1021\/bi000145i","article-title":"A novel venombin B from Agkistrodon contortrix contortrix: Evidence for recognition properties in the surface around the primary specificity pocket different from thrombin","volume":"39","author":"Amiconi","year":"2000","journal-title":"Biochemistry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3570","DOI":"10.1021\/bi00583a021","article-title":"Thrombocytin, a serine protease from Bothrops atrox venom. 2. Interaction with platelets and plasma-clotting factors","volume":"18","author":"Niewiarowski","year":"1979","journal-title":"Biochemistry"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1021\/bi00832a014","article-title":"Separation from Russell\u2019s viper venom of one fraction reacting with factor X and another reacting with factor V","volume":"8","author":"Schiffman","year":"1969","journal-title":"Biochemistry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0167-4838(98)00232-5","article-title":"Isolation, properties and N-terminal amino acid sequence of a factor V activator from Vipera lebetina (Levantine viper) snake venom","volume":"1429","author":"Siigur","year":"1998","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"17471","DOI":"10.1016\/S0021-9258(19)77860-0","article-title":"The factor V-activating enzyme (RVV-V) from Russell\u2019s viper venom. Identification of isoproteins RVV-V alpha, -V beta, and -V gamma and their complete amino acid sequences","volume":"263","author":"Tokunaga","year":"1988","journal-title":"J. Biol. Chem."},{"key":"ref_19","unstructured":"Fry, B.G. (2015). Kallikrein Enzymes. Venomous Reptiles and Their Toxins: Evolution, Pathophysiology and Biodiscovery, Oxford University Press."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.toxicon.2022.08.017","article-title":"Keel venom: Rhabdophis subminiatus (Red-Necked Keelback) venom pathophysiologically affects diverse blood clotting pathways","volume":"218","author":"Chowdhury","year":"2022","journal-title":"Toxicon"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.cbpc.2017.04.007","article-title":"Correlation between ontogenetic dietary shifts and venom variation in Australian brown snakes (Pseudonaja)","volume":"197","author":"Cipriani","year":"2017","journal-title":"Comp. Biochem. Physiol. C Toxicol. Pharmacol."},{"key":"ref_22","unstructured":"Fry, B.G. (2015). Factor Va Enzymes. Venomous Reptiles and Their Toxins: Evolution, Pathophysiology and Biodiscovery, Oxford University Press."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1016\/j.jprot.2012.01.006","article-title":"Comparative proteomic analysis of the venom of the taipan snake, Oxyuranus scutellatus, from Papua New Guinea and Australia: Role of neurotoxic and procoagulant effects in venom toxicity","volume":"75","author":"Herrera","year":"2012","journal-title":"J. Proteom."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.cbpc.2017.07.005","article-title":"Catch a tiger snake by its tail: Differential toxicity, co-factor dependence and antivenom efficacy in a procoagulant clade of Australian venomous snakes","volume":"202","author":"Lister","year":"2017","journal-title":"Comp. Biochem. Physiol. C Toxicol. Pharmacol."},{"key":"ref_25","unstructured":"Fry, B.G. (2015). Factor Xa Enzymes. Venomous Reptiles and Their Toxins: Evolution, Pathophysiology and Biodiscovery, Oxford University Press."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1111\/j.1751-0813.1998.tb10128.x","article-title":"Snake bites recorded by veterinary practices in Australia","volume":"76","author":"Mirtschin","year":"1998","journal-title":"Aust. Vet. J."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Jackson, T.N., Koludarov, I., Ali, S.A., Dobson, J., Zdenek, C.N., Dashevsky, D., Op den Brouw, B., Masci, P.P., Nouwens, A., and Josh, P. (2016). Rapid Radiations and the race to redundancy: An investigation of the evolution of australian elapid snake venoms. Toxins, 8.","DOI":"10.3390\/toxins8110309"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.toxicon.2010.03.013","article-title":"Endogenous thrombin potential as a novel method for the characterization of procoagulant snake venoms and the efficacy of antivenom","volume":"56","author":"Isbister","year":"2010","journal-title":"Toxicon"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.toxlet.2019.08.014","article-title":"Clinical implications of convergent procoagulant toxicity and differential antivenom efficacy in Australian elapid snake venoms","volume":"316","author":"Zdenek","year":"2019","journal-title":"Toxicol. Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.tiv.2019.03.031","article-title":"Coagulotoxic effects by brown snake (Pseudonaja) and taipan (Oxyuranus) venoms, and the efficacy of a new antivenom","volume":"58","author":"Zdenek","year":"2019","journal-title":"Toxicol. Vitr."},{"key":"ref_31","first-page":"825","article-title":"Purification and characterization of a prothrombin activator from the venom of the Australian brown snake, Pseudonaja textilis textilis","volume":"17","author":"Masci","year":"1988","journal-title":"Biochem. Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1055\/s-0037-1613264","article-title":"Pseutarin C, a prothrombin activator from Pseudonaja textilis venom: Its structural and functional similarity to mammalian coagulation factor Xa-Va complex","volume":"88","author":"Rao","year":"2002","journal-title":"Thromb. Haemost."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1160\/TH04-03-0144","article-title":"The catalytic subunit of pseutarin C, a group C prothrombin activator from the venom of Pseudonaja textilis, is structurally similar to mammalian blood coagulation factor Xa","volume":"92","author":"Rao","year":"2004","journal-title":"Thromb. Haemost."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1160\/TH04-07-0435","article-title":"Two parallel prothrombin activator systems in Australian rough-scaled snake, Tropidechis carinatus. Structural comparison of venom prothrombin activator with blood coagulation factor X","volume":"93","author":"Reza","year":"2005","journal-title":"Thromb. Haemost."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1111\/j.1538-7836.2006.01969.x","article-title":"Molecular evolution caught in action: Gene duplication and evolution of molecular isoforms of prothrombin activators in Pseudonaja textilis (brown snake)","volume":"4","author":"Reza","year":"2006","journal-title":"J. Thromb. Haemost."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"13258","DOI":"10.1016\/S0021-9258(18)69299-3","article-title":"Prothrombin activation by an activator from the venom of Oxyuranus scutellatus (Taipan snake)","volume":"261","author":"Speijer","year":"1986","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1016\/S0041-0101(01)00168-4","article-title":"Preliminary characteristics of the prothrombin converting enzyme from venom of Stephen\u2019s banded snake (Hoplocephalus stephensii)","volume":"39","author":"Weinstein","year":"2001","journal-title":"Toxicon"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/j.1365-2141.2005.05744.x","article-title":"Cloning and functional expression of venom prothrombin activator protease from Pseudonaja textilis with whole blood procoagulant activity","volume":"131","author":"Filippovich","year":"2005","journal-title":"Br. J. Haematol."},{"key":"ref_39","first-page":"822","article-title":"Taipan viper venom and chromogenic substrate (chromozym Th). Prothrombin assay. No sensitivity to coumarin-induced prothrombin","volume":"108","author":"Girolami","year":"1981","journal-title":"Folia Haematol. Int. Mag. Klin. Morphol. Blutforsch."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"153","DOI":"10.4161\/bioe.22676","article-title":"Recombinant snake venom prothrombin activators","volume":"4","author":"Lovgren","year":"2013","journal-title":"Bioengineered"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1177\/0310057X9802600308","article-title":"Brown snakes (Pseudonaja genus): Venom yields, prothrombin activator neutralization and implications affecting antivenom usage","volume":"26","author":"Masci","year":"1998","journal-title":"Anaesth. Intensive Care"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1016\/0041-0101(94)90352-2","article-title":"Isolation and characterization of Textarin, a prothrombin activator from eastern brown snake (Pseudonaja textilis) venom","volume":"32","author":"Stocker","year":"1994","journal-title":"Toxicon"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9366","DOI":"10.1016\/S0021-9258(17)39373-0","article-title":"Purification and properties of a prothrombin activator from the venom of Notechis scutatus scutatus","volume":"260","author":"Tans","year":"1985","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1177\/0310057X9802600510","article-title":"The cardiovascular, coagulation and haematological effects of tiger snake (Notechis scutatus) prothrombin activator and investigation of release of vasoactive substances","volume":"26","author":"Tibballs","year":"1998","journal-title":"Anaesth. Intensive Care"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1021\/bi00546a029","article-title":"Characterization of the prothrombin activator from the venom of Oxyuranus scutellatus scutellatus (taipan venom)","volume":"19","author":"Walker","year":"1980","journal-title":"Biochemistry"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/0041-0101(89)90044-5","article-title":"Purification and properties of a procoagulant from peninsula tiger snake (Notechis ater niger) venom","volume":"27","author":"Williams","year":"1989","journal-title":"Toxicon"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1042\/bj20020889","article-title":"Group D prothrombin activators from snake venom are structural homologues of mammalian blood coagulation factor Xa","volume":"369","author":"Rao","year":"2003","journal-title":"Biochem. J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.toxicon.2005.05.001","article-title":"Full length nucleotide sequence of a Factor V-like subunit of oscutarin from Oxyuranus scutellatus scutellatus (coastal Taipan)","volume":"46","author":"Welton","year":"2005","journal-title":"Toxicon"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1160\/TH09-08-0050","article-title":"Prothrombinase complexes with different physiological roles","volume":"102","author":"Lavin","year":"2009","journal-title":"Thromb. Haemost."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/0041-0101(79)90245-9","article-title":"Lethality in mice of dangerous Australian and other snake venom","volume":"17","author":"Broad","year":"1979","journal-title":"Toxicon"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1182\/blood-2009-02-202663","article-title":"Venom factor V from the common brown snake escapes hemostatic regulation through procoagulant adaptations","volume":"114","author":"Bos","year":"2009","journal-title":"Blood"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/0049-3848(92)90230-8","article-title":"Activation of human factor VII by the prothrombin activator from the venom of Oxyuranus scutellatus (Taipan snake)","volume":"65","author":"Nakagaki","year":"1992","journal-title":"Thromb. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1101\/gr.3228405","article-title":"From genome to \u201cvenome\u201d: Molecular origin and evolution of the snake venom proteome inferred from phylogenetic analysis of toxin sequences and related body proteins","volume":"15","author":"Fry","year":"2005","journal-title":"Genome Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1074\/mcp.M700094-MCP200","article-title":"Evolution of an arsenal: Structural and functional diversification of the venom system in the advanced snakes (Caenophidia)","volume":"7","author":"Fry","year":"2008","journal-title":"Mol. Cell. Proteom."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/0049-3848(90)90399-W","article-title":"Fibrinolysis as a feature of disseminated intravascular coagulation (DIC) after Pseudonaja textilis textilis envenomation","volume":"59","author":"Masci","year":"1990","journal-title":"Thromb. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1093\/molbev\/msi181","article-title":"Comparative analysis of prothrombin activators from the venom of Australian elapids","volume":"22","author":"Masci","year":"2005","journal-title":"Mol. Biol. Evol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1177\/0310057X9202000105","article-title":"The cardiovascular and haematological effects of purified prothrombin activator from the common brown snake (Pseudonaja textilis) and their antagonism with heparin","volume":"20","author":"Tibballs","year":"1992","journal-title":"Anaesth. Intensive Care"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1182\/blood.V94.2.621","article-title":"Amino acid sequence of trocarin, a prothrombin activator from Tropidechis carinatus venom: Its structural similarity to coagulation factor Xa","volume":"94","author":"Joseph","year":"1999","journal-title":"Blood"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1093\/protein\/3.5.433","article-title":"Sequence differences between glycosylated and non-glycosylated Asn-X Thr\/Ser acceptor sites: Implications for protein engineering","volume":"3","author":"Gavel","year":"1990","journal-title":"Protein Eng."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"14756","DOI":"10.1074\/jbc.270.24.14756","article-title":"The hydroxy amino acid in an Asn-X-Ser\/Thr sequon can influence N-linked core glycosylation efficiency and the level of expression of a cell surface glycoprotein","volume":"270","author":"Kasturi","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"6833","DOI":"10.1021\/bi972217k","article-title":"The amino acid following an asn-X-Ser\/Thr sequon is an important determinant of N-linked core glycosylation efficiency","volume":"37","author":"Mellquist","year":"1998","journal-title":"Biochemistry"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"6363","DOI":"10.1074\/jbc.271.11.6363","article-title":"The amino acid at the X position of an Asn-X-Ser sequon is an important determinant of N-linked core-glycosylation efficiency","volume":"271","author":"Spitalnik","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"150277","DOI":"10.1098\/rsos.150277","article-title":"Diversification rates and phenotypic evolution in venomous snakes (Elapidae)","volume":"3","author":"Lee","year":"2016","journal-title":"R. Soc. Open Sci."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Seneci, L., Zdenek, C.N., Chowdhury, A., Rodrigues, C.F.B., Neri-Castro, E., Benard-Valle, M., Alagon, A., and Fry, B.G. (2021). A clot twist: Extreme variation in coagulotoxicity mechanisms in Mexican neotropical rattlesnake venoms. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.612846"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1093\/bioinformatics\/btg412","article-title":"APE: Analyses of phylogenetics and evolution in R language","volume":"20","author":"Paradis","year":"2004","journal-title":"Bioinformatics"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1111\/j.2041-210X.2011.00169.x","article-title":"phytools: An R package for phylogenetic comparative biology (and other things)","volume":"3","author":"Revell","year":"2012","journal-title":"Methods Ecol. Evol."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/16\/10\/430\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:11:42Z","timestamp":1760112702000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/16\/10\/430"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,6]]},"references-count":66,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["toxins16100430"],"URL":"https:\/\/doi.org\/10.3390\/toxins16100430","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,6]]}}}