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• W2140248001 abstract "Australian elapid snakes are among the most venomous in the world. Their venoms contain multiple components that target blood hemostasis, neuromuscular signaling, and the cardiovascular system. We describe here a comprehensive approach to separation and identification of the venom proteins from 18 of these snake species, representing nine genera. The venom protein components were separated by two-dimensional PAGE and identified using mass spectrometry and de novo peptide sequencing. The venoms are complex mixtures showing up to 200 protein spots varying in size from <7 to over 150 kDa and in pI from 3 to >10. These include many proteins identified previously in Australian snake venoms, homologs identified in other snake species, and some novel proteins. In many cases multiple trains of spots were typically observed in the higher molecular mass range (>20 kDa) (indicative of post-translational modification). Venom proteins and their post-translational modifications were characterized using specific antibodies, phosphoprotein- and glycoprotein-specific stains, enzymatic digestion, lectin binding, and antivenom reactivity. In the lower molecular weight range, several proteins were identified, but the predominant species were phospholipase A2 and α-neurotoxins, both represented by different sequence variants. The higher molecular weight range contained proteases, nucleotidases, oxidases, and homologs of mammalian coagulation factors. This information together with the identification of several novel proteins (metalloproteinases, vespryns, phospholipase A2 inhibitors, protein-disulfide isomerase, 5′-nucleotidases, cysteine-rich secreted proteins, C-type lectins, and acetylcholinesterases) aids in understanding the lethal mechanisms of elapid snake venoms and represents a valuable resource for future development of novel human therapeutics. Australian elapid snakes are among the most venomous in the world. Their venoms contain multiple components that target blood hemostasis, neuromuscular signaling, and the cardiovascular system. We describe here a comprehensive approach to separation and identification of the venom proteins from 18 of these snake species, representing nine genera. The venom protein components were separated by two-dimensional PAGE and identified using mass spectrometry and de novo peptide sequencing. The venoms are complex mixtures showing up to 200 protein spots varying in size from <7 to over 150 kDa and in pI from 3 to >10. These include many proteins identified previously in Australian snake venoms, homologs identified in other snake species, and some novel proteins. In many cases multiple trains of spots were typically observed in the higher molecular mass range (>20 kDa) (indicative of post-translational modification). Venom proteins and their post-translational modifications were characterized using specific antibodies, phosphoprotein- and glycoprotein-specific stains, enzymatic digestion, lectin binding, and antivenom reactivity. In the lower molecular weight range, several proteins were identified, but the predominant species were phospholipase A2 and α-neurotoxins, both represented by different sequence variants. The higher molecular weight range contained proteases, nucleotidases, oxidases, and homologs of mammalian coagulation factors. This information together with the identification of several novel proteins (metalloproteinases, vespryns, phospholipase A2 inhibitors, protein-disulfide isomerase, 5′-nucleotidases, cysteine-rich secreted proteins, C-type lectins, and acetylcholinesterases) aids in understanding the lethal mechanisms of elapid snake venoms and represents a valuable resource for future development of novel human therapeutics. The venomous land snakes of Australia belong to the Elapidae family that also includes the Afro-Asian cobras, the American coral snakes, the Asian kraits, and the African mambas (1Underwood G. Lee Y. Handbook of Experimental Pharmacology. Springer, Berlin1979: 15-40Google Scholar). The venoms are complex mixtures of proteins and peptides possessing a variety of biological activities, and because the amount of venom injected into an animal that reaches the bloodstream may be minute, venom components must achieve their effects at very low concentrations. The use of snake venom in different pathophysiological conditions has been mentioned in homeopathy and folk medicine for centuries. Recently there have been a number of examples of snake venoms used in the development of novel human therapeutics. These include the antihypertensive drug captopril (2Cushman D.W. Ondetti M.A. Design of angiotensin converting enzyme inhibitors.Nat. Med. 1999; 5: 1110-1112Crossref PubMed Scopus (180) Google Scholar), modeled from the venom of the Brazilian arrowhead viper (Bothrops jaracusa); the anticoagulant Integrilin (eptifibatide (3O'Shea J.C. Tcheng J.E. Eptifibatide: a potent inhibitor of the platelet receptor integrin glycoprotein IIb/IIIa.Expert Opin. Pharmacother. 2002; 3: 1199-1210Crossref PubMed Scopus (39) Google Scholar)), a heptapeptide derived from a protein found in the venom of the American southeastern pygmy rattlesnake (Sistrurus miliarius barbouri); Ancrod (4Burger K.M. Tuhrim S. Antithrombotic trials in acute ischaemic stroke: a selective review.Expert Opin. Emerg. Drugs. 2004; 9: 303-312Crossref PubMed Scopus (8) Google Scholar), a compound isolated from the venom of the Malaysian pit viper (Agkistrodon rhodostoma) for use in the treatment of heparin-induced thrombocytopenia and stroke; and alfimeprase, a novel fibrinolytic metalloproteinase for thrombolysis derived from southern copperhead snake (Agkistrodon contortrix contortrix) venom (5Toombs C.F. Alfimeprase: pharmacology of a novel fibrinolytic metalloproteinase for thrombolysis.Haemostasis. 2001; 31: 141-147PubMed Google Scholar). Two venom proteins from the Australian brown snake, Pseudonaja textilis, are currently in development as human therapeutics (QRxPharma). The first is a single agent procoagulant that is a homolog of mammalian Factor Xa prothrombin activator (6Masci P.P. Whitaker A.N. de Jersey J. Purification and characterization of a prothrombin activator from the venom of the Australian brown snake, Pseudonaja textilis textilis.Biochem. Int. 1988; 17: 825-835PubMed Google Scholar), whereas the other is a plasmin inhibitor, named Textilinin-1, with antihemorrhagic properties (7Filippovich I. Sorokina N. Masci P.P. de Jersey J. Whitaker A.N. Winzor D.J. Gaffney P.J. Lavin M.F. A family of textilinin genes, two of which encode proteins with antihaemorrhagic properties.Br. J. Haematol. 2002; 119: 376-384Crossref PubMed Scopus (36) Google Scholar).Although there is much known about the protein compositions of venoms from Asian and American snakes, comparatively little is known of Australian snakes. This is despite the top 10 most toxic snakes (determined by LD50 (lethal dose in mice to kill 50%)) being Australian elapid snakes (8Sutherland S.K. Tibballs J. Australian Animal Toxins. Oxford University Press, Melbourne, Australia2001: 59-219Google Scholar). Australian snakes are most closely related to Asian snakes, and although they have significantly higher toxicity, they cause far fewer deaths by envenomation than their Asian counterparts, most likely due to lower population density and more widespread availability of suitable health care in Australia (8Sutherland S.K. Tibballs J. Australian Animal Toxins. Oxford University Press, Melbourne, Australia2001: 59-219Google Scholar). Proteins and peptides comprise the majority of the dry weight of elapid snake venoms, whereas other components include metallic cations, carbohydrates, nucleosides, biogenic amines, and low levels of free amino acids and lipids (9Russell F.E. Snake venom poisoning in the United States.Annu. Rev. Med. 1980; 31: 247-259Crossref PubMed Scopus (64) Google Scholar, 10Flight S. Mirtschin P. Masci P.P. Comparison of active venom components between eastern brown snakes collected from South Australia and Queensland.Ecotoxicology. 2006; 15: 133-141Crossref PubMed Scopus (17) Google Scholar). Venoms from Australian elapids can be loosely divided into procoagulant and anticoagulant types. The procoagulant venoms contain serine proteases (prothrombin activators) that cleave prothrombin to produce thrombin in the coagulation cascade resulting in coagulation. Snake venom prothrombin activators are classified into four groups based on functional characteristics, structural properties, and cofactor requirements (11Kini R.M. Morita T. Rosing J. Classification and nomenclature of prothrombin activators isolated from snake venoms—On behalf of the Registry of Exogenous Hemostatic Factors of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis.Thromb. Haemostasis. 2001; 86: 710-711Crossref PubMed Scopus (44) Google Scholar). Group A and B prothrombin activators are metalloproteinases, whereas Group C and D prothrombin activators are serine proteinases. Some Australian snake venoms are known to contain Group C or Group D prothrombin activators (12Kini R.M. The intriguing world of prothrombin activators from snake venom.Toxicon. 2005; 45: 1133-1145Crossref PubMed Scopus (92) Google Scholar). Group C prothrombin activators resemble the mammalian Factor Xa (FXa) 1The abbreviations used are: FXa, Factor Xa; FVa, Factor Va; 2D, two-dimensional; 1D, one-dimensional; Gla, γ-carboxyglutamate; PNGase F, peptidyl-N-glycosidase F; ConA, concanavalin A; WGA, wheat germ agglutinin; RCA120, Ricinus communis agglutinin 120; GalNAc, N-acetylgalactosamine; GlcNAc, N-acetylglu co sa mine; PLA2, phospholipase A2; NGF, nerve growth factor; CRISP, cysteine-rich secreted protein; PDI, protein-disulfide isomerase; SVMP, snake venom metalloproteinase; GRP78, glucose-regulated protein 78; ACTH, adrenocorticotropic hormone; clip, corticotropin-like intermediate lobe peptide; PMM, peptide mass mapping; SNA, Sambucus nigra lectin; UEA, Ulex europaeus agglutinin. 1The abbreviations used are: FXa, Factor Xa; FVa, Factor Va; 2D, two-dimensional; 1D, one-dimensional; Gla, γ-carboxyglutamate; PNGase F, peptidyl-N-glycosidase F; ConA, concanavalin A; WGA, wheat germ agglutinin; RCA120, Ricinus communis agglutinin 120; GalNAc, N-acetylgalactosamine; GlcNAc, N-acetylglu co sa mine; PLA2, phospholipase A2; NGF, nerve growth factor; CRISP, cysteine-rich secreted protein; PDI, protein-disulfide isomerase; SVMP, snake venom metalloproteinase; GRP78, glucose-regulated protein 78; ACTH, adrenocorticotropic hormone; clip, corticotropin-like intermediate lobe peptide; PMM, peptide mass mapping; SNA, Sambucus nigra lectin; UEA, Ulex europaeus agglutinin.-Factor Va (FVa) complex, whereas Group D activators are structurally and functionally similar to FXa alone (12Kini R.M. The intriguing world of prothrombin activators from snake venom.Toxicon. 2005; 45: 1133-1145Crossref PubMed Scopus (92) Google Scholar, 13Joseph J.S. Kini R.M. Snake venom prothrombin activators homologous to blood coagulation factor Xa.Haemostasis. 2001; 31: 234-240PubMed Google Scholar). The Group C prothrombin activator from the Australian brown snake, P. textilis, has been extensively studied and named Pseutarin C (14Rao V.S. Kini R.M. Pseutarin C, a prothrombin activator from Pseudonaja textilis venom: its structural and functional similarity to mammalian coagulation factor Xa-Va complex.Thromb. Haemostasis. 2002; 88: 611-619Crossref PubMed Scopus (77) Google Scholar). The 1461-amino acid FVa-like non-enzymatic subunit of Pseutarin C has been shown to share 50% sequence identity and significant structural homology with human FVa (15Rao V.S. Swarup S. Kini R.M. The nonenzymatic subunit of pseutarin C, a prothrombin activator from eastern brown snake (Pseudonaja textilis) venom, shows structural similarity to mammalian coagulation factor V.Blood. 2003; 102: 1347-1354Crossref PubMed Scopus (46) Google Scholar). Another hemostasis-related family of proteins identified in Australian snake venom is the textilinin family of plasmin inhibitors (16Masci P.P. Whitaker A.N. Sparrow L.G. de Jersey J. Winzor D.J. Watters D.J. Lavin M.F. Gaffney P.J. Textilinins from Pseudonaja textilis textilis. Characterization of two plasmin inhibitors that reduce bleeding in an animal model.Blood Coagul. Fibrinolysis. 2000; 11: 385-393Crossref PubMed Scopus (67) Google Scholar). These 7-kDa proteins share ∼45% identity with aprotinin, a bovine Kunitz-type serine protease inhibitor that acts on plasmin and kallikrein to reduce blood loss during surgery. Six isoforms of textilinin have been identified in P. textilis venom gland-derived cDNA (7Filippovich I. Sorokina N. Masci P.P. de Jersey J. Whitaker A.N. Winzor D.J. Gaffney P.J. Lavin M.F. A family of textilinin genes, two of which encode proteins with antihaemorrhagic properties.Br. J. Haematol. 2002; 119: 376-384Crossref PubMed Scopus (36) Google Scholar).Australian snake venoms are also known to contain PLA2s and peptidic neurotoxins (for a review, see Ref. 17Fry B.G. Structure-function properties of venom components from Australian elapids.Toxicon. 1999; 37: 11-32Crossref PubMed Scopus (79) Google Scholar). Australian elapid PLA2s have seven conserved disulfide bonds and molecular masses of 13–15 kDa. As well as phospholipase activity, individual PLA2s are known to have myotoxic, neurotoxic, and/or anticoagulant activities. The α-neurotoxins found in Australian elapids are postsynaptic blocking short or long chain neurotoxins (18Southcott R.N. Coulter A.R. Chubb I.W. Geffen L.B. Neurotoxins, Fundamental and Clinical Advances. Adelaide University Union Press, Adelaide, Australia1979: 272Google Scholar, 19Tyler M.I. Retson Yip K.V. Gibson M.K. Barnett D. Howe E. Stocklin R. Turnbull R.K. Kuchel T. Mirtschin P. Isolation and amino acid sequence of a new long-chain neurotoxin with two chromatographic isoforms (Aa e1 and Ae e2) from the venom of the Australian death adder (Acanthophis antarcticus).Toxicon. 1997; 35: 555-562Crossref PubMed Scopus (25) Google Scholar). Short and long chain neurotoxins have similar effects and bind with high affinity to skeletal nicotinic acetylcholine receptors. The short chain neurotoxins have four disulfide bonds and are ∼60 amino acids in length, whereas the long chain neurotoxins have five disulfide bonds and are ∼73 amino acids in length. More recently, neurotoxic cysteine-rich secreted proteins (CRISPs) have been identified and characterized from the Australian elapids Pseudechis australis and Pseudechis porphyriacus (20Brown R.L. Haley T.L. West K.A. Crabb J.W. Pseudechetoxin: a peptide blocker of cyclic nucleotide-gated ion channels.Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 754-759Crossref PubMed Scopus (113) Google Scholar, 21Yamazaki Y. Brown R.L. Morita T. Purification and cloning of toxins from elapid venoms that target cyclic nucleotide-gated ion channels.Biochemistry. 2002; 41: 11331-11337Crossref PubMed Scopus (89) Google Scholar). These 211-amino acid proteins show the ability to block cyclic nucleotide-gated ion channels involved in signaling from the visual and olfactory systems.Other proteins known to exist in Australian elapid venoms include l-amino-acid oxidase, nerve growth factor (NGF), and natriuretic peptides. l-Amino-acid oxidase was identified in P. australis venom and in purified form was found to be antibacterial when tested against the important pathogen Aeromonas hydrophila (22Stiles B.G. Sexton F.W. Weinstein S.A. Antibacterial effects of different snake venoms: purification and characterization of antibacterial proteins from Pseudechis australis (Australian king brown or mulga snake) venom.Toxicon. 1991; 29: 1129-1141Crossref PubMed Scopus (132) Google Scholar). This protein has also been identified in Viperidae snake venoms. NGF has been identified in multiple Asian and African snake venoms but has been reported only recently as a component of Australian elapid venoms (23Earl S.T. Birrell G.W. Wallis T.P. St Pierre L.D. Masci P.P. de Jersey J. Gorman J.J. Lavin M.F. Post-translational modification accounts for the presence of varied forms of nerve growth factor in Australian elapid snake venoms.Proteomics. 2006; 6: 6554-6565Crossref PubMed Scopus (29) Google Scholar). NGF from Oxyuranus scutellatus venom is gly co sylated and shows the ability to induce neurite outgrowth of PC12 cells, a standard assay for NGF activity (23Earl S.T. Birrell G.W. Wallis T.P. St Pierre L.D. Masci P.P. de Jersey J. Gorman J.J. Lavin M.F. Post-translational modification accounts for the presence of varied forms of nerve growth factor in Australian elapid snake venoms.Proteomics. 2006; 6: 6554-6565Crossref PubMed Scopus (29) Google Scholar). Natriuretic peptides from Oxyuranus microlepidotus venom show potent arterial smooth muscle relaxant effects (24Fry B.G. Wickramaratana J.C. Lemme S. Beuve A. Garbers D. Hodgson W.C. Alewood P. Novel natriuretic peptides from the venom of the Inland Taipan (Oxyuranus microlepidotus): isolation, chemical and biological characterisation.Biochem. Biophys. Res. Commun. 2005; 327: 1011-1015Crossref PubMed Scopus (56) Google Scholar). Natriuretic peptides have been identified and characterized from several Australian elapid venoms and represent the smallest known proteins from these venoms at only 35–39 amino acids (25St Pierre L. Flight S. Masci P.P. Hanchard K.J. Lewis R.J. Alewood P.F. de Jersey J. Lavin M.F. Cloning and characterisation of natriuretic peptides from the venom glands of Australian elapids.Biochimie (Paris). 2006; 88: 1923-1931Crossref PubMed Scopus (33) Google Scholar).The present study describes a thorough screening and identification of the venom proteins present in 18 Australian elapid snake species representing nine genera of the most venomous snakes on earth. In addition, post-translational modifications such as glycosylation, phosphorylation, and γ-carboxylation were examined in the venom proteins using specific stains and antibodies. Glycoforms of multiple proteins were identified and characterized using lectin binding specificity. Also antivenom reactivity of venom proteins was examined using tiger snake (Notechis) antivenom raised in horses for clinical use in envenomated people. Many proteins previously unknown in Australian snake venoms were identified based on sequence matches to venom proteins from other snakes. This information sheds light on evolutionary relationships between the different snake species and the clinical manifestations of envenomation. This comprehensive proteomics analysis brings Australian elapid snakes in line with their well studied American and Asian counterparts and represents a valuable resource for the future development of novel human therapeutics.RESULTSSeparation and Comparative Analysis of Venom Proteins from 18 Australian Elapid Snake SpeciesProtein components of the venoms from the 18 species listed in Table I were initially separated by 1D SDS-PAGE and subsequently silver-stained (Fig. 1). A similarity of protein bands between individual species within a single genus was apparent. For example, a prominent band of 30–35 kDa corresponding in size to the heavy chain of FXa-like protease was observed in several venoms including the Notechis (lanes 1–3), Pseudonaja (lanes 4–6), and Oxyuranus (lanes 14 and 15) species. In addition, several venoms showed significant staining of proteins primarily between 13 and 15 kDa, which is consistent with the size of PLA2 isoforms known to be abundant in elapid snake venoms. Moreover the multiplicity of bands between 10 and 170 kDa for all species highlights the complexity of these venoms and necessitated the use of 2D PAGE to achieve resolution of individual protein isoforms.The results in Fig. 2 show representative 2D PAGE silver-stained maps for a single species from all nine genera with resolution of proteins in the size range of 6–160 kDa over a pI range of 3–10. Between 100 and 200 individual protein spots were resolved in the different maps. Horizontal trains of spots are apparent in the upper region of the 2D PAGE maps consistent with multiple isoforms of individual proteins. This phenomenon has been observed previously in 2D PAGE of venom proteins from other snake species (32Serrano S.M.T. Shannon J.D. Wang D.Y. Camargo A.C.M. Fox J.W. A multifaceted analysis of viperid snake venoms by two-dimensional gel electrophoresis: an approach to understanding venom proteomics.Proteomics. 2005; 5: 501-510Crossref PubMed Scopus (137) Google Scholar, 33Li S. Wang J. Zhang X. Ren Y. Wang N. Zhao K. Chen X. Zhao C. Li X. Shao J. Yin J. West M.B. Xu N. Liu S. Proteomic characterization of two snake venoms: Naja naja atra and Agkistrodon halys.Biochem. J. 2004; 384: 119-127Crossref PubMed Scopus (106) Google Scholar). Although up to 200 spots were resolved on each gel, only a limited number of protein families appeared to be present. The 2D PAGE maps for all 18 species without annotation appear in Supplemental Fig. 1, A-R, and with annotation in Supplemental Fig. 2, A-R. The mass spectrometry data corresponding to each identified protein spot appear in Supplemental Table 1. Comparison of the distinct protein spots on the maps showed features characteristic of species within the same genera. For example, comparison of the four Pseudechis species showed a high degree of similarity between P. australis, Pseudechis guttatus, and Pseudechis colletti. Although most of the protein families present in these three species also appear to be represented in the fourth member of this group, P. porphyriacus, it is evident that the protein pI values have a different pattern of distribution across the range of separation. It is also notable that P. porphyriacus is the only member of this genus known to have procoagulant activity, and the data described here point to additional variation at the protein level (8Sutherland S.K. Tibballs J. Australian Animal Toxins. Oxford University Press, Melbourne, Australia2001: 59-219Google Scholar).Fig. 22D SDS-PAGE of crude venom from species representing all nine genera.A–I, 300-μg samples of crude venoms representing nine species of different genera were subjected to isoelectric focusing on 11-cm pH 3–10 IEF strips and subsequently separated by 12% SDS-PAGE and silver-stained. Protein spots were excised for identification by MALDI-TOF/TOF MS/MS, MALDI-TOF PSD, and de novo peptide sequencing. Complete data are contained in Supplemental Figs. 1 and 2 and Supplemental Table 1.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Identification of Proteins by Mass SpectrometryApproximately 60 spots were selected from 2D PAGE for each species across a range of molecular sizes and pI values for further analysis. Gel spots were excised and digested with trypsin, and peptides were collected for analysis by MALDI-TOF, MALDI-TOF PSD, and MALDI-TOF/TOF MS/MS. The mass spectra were matched to the NCBI non-redundant or Celera databases to identify the protein spots using the Mascot search engine. Spectra for those spots that were not identified by this approach were subjected to de novo peptide sequence analysis using the PEAKS software package (Bioinformatics Solutions Inc.). The de novo peptide sequences were used in homology searches using the NCBI protein BLAST facility (www.ncbi.nlm.nih.gov/BLAST/). Using this combined approach, between 24 and 51 spots for each species were confidently identified, representing a total of 17 different protein families (Table II). A number of protein spots were not identified using the above approach possibly because the peptide sequences derived were not sufficiently homologous to those in the sequence databases searched.Table IIProtein families identified in the 18 snake venoms Open table in a new tab A total of 724 protein identifications were made, and a complete list of these together with their protein and ion scores appears in Supplemental Table 1. Various combinations of the different protein families were present in the 18 species within the nine genera studied (Table II). Supplemental Fig. 3 contains annotated fragmentation spectra for those 131 of 724 (18.1%) protein identifications based on a single peptide. Supplemental Fig. 4 contains annotated MALDI-TOF spectra for the 34 of 724 (4.7%) protein identifications based on peptide mass mapping (PMM). In some of the PMM spectra several major peaks were not matched suggesting either more than one protein in the spot or incomplete homology with database entries. Although a range of protein and ion scores were obtained in the mass spectrometry analysis, overall the data provided a high level of confidence that the identifications were correct. This was evident by the generally high protein and ion scores for the PMM and MS/MS data as well as high levels of sequence homology in the protein BLAST results from de novo peptide sequencing where the former approach failed to identify the protein. Identities and characteristics of the 17 protein families are provided below.PLA2s and PLA2 Inhibitors—The most frequently encountered proteins identified across the species were PLA2s that were found in all 18 venoms. In all cases there were multiple PLA2 isoforms representing sequence variants. Because of the large number of isoforms and associated activities for these proteins, information on the specific PLA2s identified within the different species can be accessed through the NCBI accession numbers provided in Supplemental Table 1. In the majority of cases the PLA2 isoforms were in the molecular size range of 13–17 kDa as predicted from published data and in some cases their cDNA sequences (34St Pierre L. Woods R. Earl S. Masci P.P. Lavin M.F. Identification and analysis of venom gland-specific genes from the coastal taipan (Oxyuranus scutellatus) and related species.Cell. Mol. Life Sci. 2005; 62: 2679-2693Crossref PubMed Scopus (45) Google Scholar). However, in other cases (for example Acanthophis, Fig. 2F) there was considerable size variation with PLA2s ranging from 13 to 30 kDa. Surprisingly we also detected a protein homologous to the α isoform of PLA2 inhibitor (35Hains P.G. Broady K.W. Purification and inhibitory profile of phospholipase A2 inhibitors from Australian elapid sera.Biochem. J. 2000; 346: 139-146Crossref PubMed Google Scholar) (NCBI accession number CAB56615) in both Pseudonaja nuchalis and O. microlepidotus. This is the first description of a PLA2 inhibitor in the venom of any snake. Previous reports have demonstrated that PLA2 inhibitors are present in the blood of Elapidae, Hydrophidae, Boidae, and Colubridae genera, and it was assumed that they were present to provide protection against any PLA2s appearing inadvertently in the blood (for a review, see Ref. 36Dunn R.D. Broady K.W. Snake inhibitors of phospholipase A2 enzymes.Biochim. Biophys. Acta. 2001; 1533: 29-37Crossref PubMed Scopus (59) Google Scholar).Neurotoxins and Protease Inhibitors—Australian snake venoms are known to contain a multitude of neurotoxins including short and long chain α-neurotoxins and neurotoxic PLA2s (8Sutherland S.K. Tibballs J. Australian Animal Toxins. Oxford University Press, Melbourne, Australia2001: 59-219Google Scholar). Long chain neurotoxins were found in the majority of venoms. These were readily identifiable in all species of Notechis and Pseudonaja but only in one (P. australis) of the Pseudechis species. On the other hand, short chain neurotoxins were only detected in three species (Table II). The Kunitz-type serine protease inhibitor textilinin was identified in all species of the Pseudonaja genus as expected. We have previously identified multiple forms of textilinin both at the protein and cDNA level in P. textilis (7Filippovich I. Sorokina N. Masci P.P. de Jersey J. Whitaker A.N. Winzor D.J. Gaffney P.J. Lavin M.F. A family of textilinin genes, two of which encode proteins with antihaemorrhagic properties.Br. J. Haematol. 2002; 119: 376-384Crossref PubMed Scopus (36) Google Scholar, 16Masci P.P. Whitaker A.N. Sparrow L.G. de Jersey J. Winzor D.J. Watters D.J. Lavin M.F. Gaffney P.J. Textilinins from Pseudonaja textilis textilis. Characterization of two plasmin inhibitors that reduce bleeding in an animal model.Blood Coagul. Fibrinolysis. 2000; 11: 385-393Crossref PubMed Scopus (67) Google Scholar). Proteins with homology to textilinin were also found in the Notechis, Acanthophis, Pseudechis, Tropidechis, and Oxyuranus genera. This molecule is an antifibrinolytic agent that inhibits plasmin (7Filippovich I. Sorokina N. Masci P.P. de Jersey J. Whitaker A.N. Winzor D.J. Gaffney P.J. Lavin M.F. A family of textilinin genes, two of which encode proteins with antihaemorrhagic properties.Br. J. Haematol. 2002; 119: 376-384Crossref PubMed Scopus (36) Google Scholar).Prothrombin Activators—Another snake protein known to affect hemostasis is the FXa-like prothrombin activator previously identified in Pseudonaja and other genera (37Rao V.S. Joseph J.S. Kini R.M. Group D prothrombin activators from snake venom are structural homologues of mammalian blood coagulation factor Xa.Biochem. J. 2003; 369: 635-642Crossref PubMed Google Scholar). The heavy chain of this protein was identified in all the Notechis, Oxyuranus, and Pseudonaja species along with Tropidechis carinatus, Hoplocephalus stephensii, Rhinoplocephalus nigrescens, and P. porphyriacus. This is consistent with the presence of procoagulant activity in all of these snakes (8Sutherland S.K. Tibballs J. Australian Animal Toxins. Oxford University Press, Melbourne, Australia2001: 59-219Google Scholar). The heavy chain was identified as" @default.
• W2140248001 created "2016-06-24" @default.
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• W2140248001 date "2007-06-01" @default.
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• W2140248001 title "The Diversity of Bioactive Proteins in Australian Snake Venoms" @default.
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