Special Article
Comparative Studies of Structural and Functional Properties of Snake Venom Metalloproteinases
Anuwat Pinyachat PhD*
* College of Medicine and Public Health (CMP), Ubon Ratchathani University, Ubon Ratchathani, Thailand
Snake venom metalloproteinases (SVMPs) induces local and systemic effects on patients suffering from snakebite, degrading extracellular matrix (ECM) proteins such as collagen, gelatin, elastin, laminin, fibronectin, nidogen (entactin), and thrombospondin that cause local hemorrhage and tissue damage. They cleave or activate coagulation factors such as fibrinogen, fibrin, prothrombin, factor V, factor IX, factor X and protein C that bring about systemic coagulopathy. SVMPs and their truncated forms cleave or interfere with platelet adhesive proteins such as vWF, fibrinogen and collagen, and cleave or interfere with platelet receptors such as GPVI, alpha2beta1, GPIb, GPIX, and GPIIbIIIa that result in platelet aggregation defect. SVMPs induce cancer cell line to form morphological changes and apoptosis in vitro concordant with skin necrosis after snakebite in some cases. These local effects caused by SVMPs have no certain treatments, even with commercial anti- venom. SVMPs researches are focusing on their inhibitors, measurement and replacement of blood coagulation factor defects, or anti-cancer drug.
Keywords: Snake venom metalloproteinase (SVMP), Extracellular matrix (ECM), Coagulation factor, Platelet aggregation, Anti-cancer drug
J Med Assoc Thai 2016; 99 (Suppl. 1): S76-S88 Full text. e-Journal: http://www.jmatonline.com
Snake venom metalloproteinases (SVMPs) The P-I SVMPs activity Snake venoms contain many toxic enzymes. The biological function of P-I SVMPs, as Snake venom metalloproteinases (SVMPs), known as shown in Table 1, have degradation of ECM proteins extracellular matrix (ECM) degradation enzyme, such as collagen, gelatin, elastin, laminin, fibronectin, constitutes a large proportion of snake venom and nidogen (entactin), and thrombospondin that cause cause local tissue damage followed by skin necrosis in local hemorrhages and tissue damage. The proteolytic some envenomed cases. In addition, they interfere activity to ECM proteins of some P-I SVMPs such as with blood coagulation system and hemostatic plug fibrolase, atroxase and ACLF, do not show the formation. SVMPs are classified into 3 groups by hemorrhagic activity but they have proteolytic activities their domain structures. A group P-I SVMP, Ia, is against fibrinogen, fibrin, fibronectin, laminin and composed of a single metalloproteinase domain. A thrombospondin, implying that in vitro activities may group P-II SVMP; IIa, IIb, IIc, IId and IIe, consists of not refer to in vivo effects, or P-I SVMPs may be metalloproteinase domain and disintegrin domain. A responsible for systemic effects but not local effects. group P-III SVMP; IIIa, IIIb, IIIc and IIId, consists of They also have fibrinogenolytic and fibrinolytic activity metalloproteinase domain and disintegrin-like cysteine- especially to alpha-chain. Some P-I SVMPs degrade rich domain. VLFXA, RVV X and VAFXA are P-III beta-chain, but almost all cannot degrade gamma-chain SVMPs that contain two additional disulfide-linked C- of human fibrinogen. In generally, the fibrinogenolytic type lectin-like domains. The active form and post- and fibrinolytic activity of P-I SVMPs does not cause translational modification of different types of SVMPs pro-coagulant activity. The researcher tried to apply was well described(1). the fibrolase as a commercial thrombolytic drug, but alfimeprase®, recombinant fibrolase from yeast, did not successful in phase III clinical trials(2). Interestingly, a Correspondence to: P-I SVMP rACLF induces Hela cells to form shape Pinyachat A, College of Medicine and Public Health, Ubon changes, detachment and reduction on cell viability, Ratchathani University, Ubon Ratchathani 34190, Thailand, Phone: +66-45-353900 which the mechanism is unclear. It could be possible E-mail: [email protected] that rACLF cleave cancer cell adhesion proteins(3). It is
S76 J Med Assoc Thai Vol. 99 Suppl. 1 2016 Reference (18,19) (20-22) (23) (24) active form in some cases. , (13-15) ® Other approaches Alfimeprase Cleave microbial collagenase Induce innate immune response (28) Not induce death of cancer cell lineNot activate plasminogen (25,26) (27) Fibrinogenolysis agent Induce innate immune responseNot inhibit platelet aggregation (29-33) Not induce death of cancer cell line degradation Alpha AlphaBeta Alpha - Alpha BetaAlpha Beta Induce death of cancer cell line Specific antibody developing Beta Not inhibit platelet aggregation Hemorrhagic Fibrinogen proteinsdegradation activity (kDa) Mass* ECM Class Fibrolase Ia 23 - No SVMPs LHF-IIAtroxase Ia Ia 22 23 Yes - Yes No Acutolysin AAdamalysin II Ia Ia 2HT 22Atrolysin-C 24 -Trimerelysin-2 Ia Ia - IaBlaH1 24 23 22 Yes Yes - Weak Ia - - 28 Yes - Yes Yes No - - - Alpha Yes - - - (16) (17) BaP1 Ia 22 Yes Weak ACLF Ia 23 Yes No Alpha The example of structural and functional properties P-I SVMPs Agkistrodon Lachesis m. muta Crotalus Agkistrodon acutus Crotalus adamanteus Crotalus ruber r. Crotalus atrox Protobothrops flavoviridis Bothrops lanceolatus Bothrops asper Agkistrodon c. laticinctus atrox c. contortrix 1 Table 1. Table No. Snake species or mass-spectrometry which is not referred to the mass of * The protein mass of SVMPs was determined from calculation, SDS-PAGE 8 9 2 3 4 5 6 7 11 10
J Med Assoc Thai Vol. 99 Suppl. 1 2016 S77 noteworthy that P-I SVMPs cannot inhibit platelet that the conserve tri-peptide sequences are vital for aggregation. This may due to P-I SVMPs lack other platelet aggregation inhibition. There are some P-II additional domains to bind platelet receptors and related SVMPs have no hemorrhagic activity, jerdonitin and proteins. insularinase-A. Interestingly, insularinase-A can Platelet aggregation contributes to hemostasis activate prothrombin similar to group A prothrombin using complex mechanisms. Binding of subendothelial activator. It also activate factor X which cause pro- collagen with platelet receptor glycoprotein (GP) VI coagulant activity. (non-integrin) stimulates the signaling pathways and up-regulates platelet integrin expression (inside-out The P-III SVMPs activity signaling), such as alphaIIbbeta3and alpha2beta1. In As shown in Table 3, a group P-III SVMP; addition, stimulated platelets secrete the granule IIIa, IIIb, IIIc and IIId, consists of metalloproteinase contents, particularly ADP which promotes platelet domain and disintegrin-like cysteine-rich domain. The activations. Like GPVI, the alpha2beta1 intergrin disintegrin-like cysteine-rich domain of P-III SVMPs also binds collagen fibers activating platelet adhesion contains the hyper-variable-region (HVR). The ECM and spreading, as well as thrombus formation. The proteins proteolysis of P-III SVMPs contributes to the integrin alphaIIbbeta3 plays an exclusive role in hemorrhagic activity. Non-hemorrhagic P-III SVMPs linking platelets to one another through the adhesive were reported such as berythractivase, ecarin and action of fibrinogen. Engagements of this receptor HV1. The fibrinolysis and fibrinogenolysis of P-III further activate platelet spreading and enhance platelet SVMPs mostly degrade alpha-chain of human aggregation(4). fibrinogen and fibrin, and some of them degrade beta- chain subsequently. Nevertheless, that activity cannot The P-II SVMPs activity be a pro-coagulant activity in human blood coagulation As shown in Table 2, a group P-II SVMP; IIa, system. Ecarin, the RDD P-III SVMP is not only a non- IIb, IIc, IId and IIe, consists of metalloproteinase domain hemorrhagic venom, but also non-platelet aggregation and disintegrin domain, not only has proteolytic inhibitor. It can activate prothrombin that cause blood activity to ECM proteins, fibronogen and fibrin, but clot, and was developed to the Ecarin chromogenic also has hemorrhagic activity. In generally, the assay. The usefulness of this assay is for quantitative fibrinogenolytic and fibrinolytic activity of P-II SVMPs determination of direct thrombin inhibitors such as does not cause pro-coagulant activity. They can inhibit hirudin, argatroban and melagatran(6). platelet aggregation using conserve tri-peptide Interestingly, there are some high molecular sequences located in disintegrin domain. The conserve weight P-III SVMPs that can activate factor IX, X or tri-peptide sequences are either the Arg-Gly-Asp (RGD) protein C such as VAFXA-I, VAFXA-II, RVV X and or Lys-Gly-Asp (KGD), both of them are a potent VLFXA. The active form of VLFXA is heterotrimer inhibitor of integrins. The intergrin-constituent (disulfide-linked) which consists of one heavy chain proteins found in human are fibrinogen, vWF, collagen, (metalloproteinase and disintegrin-like cysteine-rich vitronectin, thrombospondin and also fibronectin. domain) and two light chains of lectin-like domain (LC1 Thus, the venom disintegrins may appear to inhibit and LC2). The additional two lectin-like domains found platelet aggregation using competitive binding between in P-IIId SVMP may responsible for factor V, factor IX, platelet GPIIbIIIa and fibrinogen as well as between factor X and protein C binding and/or activating. The vWF and GPIbIX, collagen and GPVI, and vitronectin/ usefulness of RVV X, P-IIId which can inhibit platelet fibronectin and GPIIbIIIa. However, the tri-peptide aggregation, was developed to be Lupus Anticoagulant sequences of bilitoxin-1 contain Met-Gly-Asp (MGD) test. The indications for this test are detection of which it cannot inhibit platelet aggregation. In addition, antiphospholipid antibody or detection of some snake venom disintegrins may have a therapeutic inhibitors that cause APTT prolong(7). The example of potential for the treatment of tumor metastasis, a process prothrombin activator from P-IIIc is HV1. The active requiring cell-ECM interaction via integrins. Many form of HV1 is homodimer suggesting that high reports showed that snake venom disintegrins can block molecular weight P-III SVMP can activate prothrombin. RGD-dependent integrins such as the vitronectin However, VaH3 P-IIIc SVMP cleaves prothrombin receptors (alphaVbeta3 and alphaVbeta5) and and factor X without activating them. P-IIIa SVMP, fibronectin receptor (alphaVbeta3) involved in cell berythractivase can activate prothrombin, but migration and invasion of tumor cells(5). This confirms jerdohagin can only cleave without activating.
S78 J Med Assoc Thai Vol. 99 Suppl. 1 2016 48) (37) (42) (45) Reference (52-54) active form in some cases. ECM proteins degradationAutoactivation (22,38,39) ECM proteins degradation (43) Activate prothrombin and factor X (34-36) Induce death of cancer cell lineBlock HSV entry and cell fusion (49,50) ECM proteins degradation Induce death of cancer cell line (44) Autoactivation (47, Platelet Other approaches aggregation inhibition Tri- peptide Fibrinogen degradation Alpha RGD Yes Beta Not induce death of cancer cell line Alpha RGDAlpha Yes MGD No Beta Alpha VGD Yes - Hemor rhagic activity Mass (kDa) Class SVMPs Insularinase-A IIa 53 No Ussurin IIaFlavoridin 53HR2a IIaTrigramin - 54 IIa IIa - - 53 53 - Yes - RGD - - Yes RGD - RGD Yes RGD Yes - Yes - - (40) (41) Atrolysin-E IIa 53 YesAlbolamin AlphaJerdonitin IIa MVD IIb 36Agkistin Yes 54 -Bilitoxin-1 IIb No IIc No 60 48 - RGD Yes - Yes RGD Yes Induce death of cancer cell line (46) TJM-1 IIb 53 - - RGD Yes - Acostatin BLebetase IIe 54 IIe - 53 - Yes RGD - - (51) Contortrostatin IId 53 - - RGD Yes The example of structural and functional properties P-II SVMPs Bothrops Protobothrops Protobothrops flavoviridis flavoviridis Gloydius Protobothrops Agkistrodon halys ussuriensis Crotalus atrox gramineus Protobothrops albolabris Protobothrops jerdonii Agkistrodon Protobothrops Macrovipera c. contortrix Agkistrodon insularis Agkistrodon c. contortrix bilineatus jerdonii lebetina Table 2. Table No. Snake species or mass-spectrometry which is not referred to the mass of * The protein mass of SVMPs was determined from calculation, SDS-PAGE 1 5 6 2 4 11 3 7 8 10 9 14 13 12
J Med Assoc Thai Vol. 99 Suppl. 1 2016 S79 (56) (8,62-64) Reference (75) (72,73) (65,66) active form in some cases. cancer cell line Cleave vWF Induce death ofcancer cell line (57,58) immune response Autoactivation Ecarin chromogenic assay Cleve prothrombin (71) Activate prothrombin Induce innate immune response Not induce death of cancer cell lineBactericidal activity (67) (68) Yes Induce death of (22,59-61) PlateletAggregation Other approaches inhibition No Activate prothrombin (6,69,70) Tri- peptide ECD Yes Induce innate (55) ECD Yes DCD Yes Cleave vWF Alpha ECD Yes Alpha ECD Yes Fibrinogen degradation Alpha - - - Beta Induce death of cancer cell line AlphaAlpha ECD - - No - Alpha DCDAlpha Yes RGD Yes Hemor- rhagic activity degradation Mass ECM (kDa) proteins IIIa 51 Yes Yes IIIa 46 Yes Yes - ECD IIIa 66 Yes - Class IIIb 68 - Yes - IIIb 62 Yes - No DCD Yes - (74) IIIb 60 - - IIIa 60IIIa - 69 - Yes No - RDD IIIa 78 - No Acurhagin Atrolysin-A VaH2 Halysase SVMPs VaH1, IIIa 70 - Yes HF3 IIIa 52 - Yes - Bothropasin Kaouthiagin IIIa 51 - - No Catrocollastatin IIIb 55 Yes Yes - ECD Yes Induce death of cancer cell line (76-79) Albocollagenase JerdohaginAlborhagin IIIa 96 - Yes ractivase BjussuMP I Ecarin Beryth- The example of structural and functional properties P-III SVMPs Deinagkistrodon atrox Crotalus halys Gloydius a. ammodites Vipera Bothrops jararaca albolabris Bothrops Naja acutus atrox jararaca Crotalus albolabris Protobothrops Protobothrops jerdonii Protobothrops carinatus Bothrops erythromelas jararacussu Echis kaouthia Bothrops 5 4 Table 3. Table 3 No. Snake species 2 or mass-spectrometry which is not referred to the mass of * The protein mass of SVMPs was determined from calculation, SDS-PAGE 1 13 6 14 12 10 11 8 9 7
S80 J Med Assoc Thai Vol. 99 Suppl. 1 2016 (92) (90) (85) Reference active form in some cases ivate prothrombin (88) plasminogen Activate factor X Lupus anticoaggulant Activate factor IX, X and protein C Cleave factor V Not cleave prothrombin (91) Induce death of cancer cell line (89) Induce death of cancer cell line Induce death of cancer cell line (87) Cleave prothrombin and factor X (86) Induce death of cancer cell line Cleave vWFInduce innate immune responseInduce death of cancer cell line Jaracetin induce platelet aggregation No effect on platelet agglutination 80-84) Autoactivation Induce death of cancer cell line (60,76, Platelet Other approaches inhibition Aggregation ECD Yes Tri- peptide Beta Alpha ECD Yes - Alpha ECD Yes Act Alpha ECD - BetaAlpha ECD Yes Not bind vWF Alpha ECD Yes Fibrinogen degradation Alpha ECD Yes Hemor- rhagic activity degradation Mass ECM (kDa) proteins IIIb 60 - Yes - Class IIIb 52 Yes Yes RVV X RVV VLFXA IIId 98 IIId 102 - - - - - No ECD ECD Yes - Activate factor IX, X and protein C Not activate prothrombin (7,94,95) (96,97) VAFXA-I,VAFXA-II IIId 58, Weak 70 - Weak - Yes Not activate prothrombin and (93) Ohagin III 50 - - AAV1 III 50 No Alpha - Yes Hemorrhagin III 72 Yes Yes - - - - VaH4 III 65 Yes Yes Alpha ECD Yes HV1 IIIc 68 - No VAP1 IIIc 67 No Yes VaH3 IIIc 53 Yes Yes HR1A Graminelysin IIIb 48 - - SVMPs Jararhagin Cont. russelii lebetina Daboia Macrovipera a. ammodites hannah Vipera acutus Ophiophagus pupureomaculatus Deinagkistrodon a. ammodites Protobothrops flavoviridis Vipera atrox Protobothrops a. ammodites Crotalus gramineus Vipera jararaca Protobothrops flavoviridis Trimeresurus Bothrops 26 27 25 24 23 22 21 20 19 18 16 17 Table 3. Table No. Snake species or mass-spectrometry which is not referred to the mass of * The protein mass of SVMPs was determined from calculation, SDS-PAGE 15
J Med Assoc Thai Vol. 99 Suppl. 1 2016 S81 Notably, the P-III SVMPs, which can cleave SVMPs is the main part interacting with platelets. The vWF such as acurhagin, kaouthiagin and jararhagin, disintegrin-like cysteine-rich domain of jararhagin, was developing to anti-cancer drug, but it is not always jaracetin, was compared with jararhagin for platelet the case. Acurhagin, P-IIIa SVMP 51 kDa, can induce aggregation inhibition test. Both of them inhibit cell lines to form morphological changes, caspase 8/9, collagen-induced platelet aggregation with IC50 of 140 and finally to apoptosis similar to the reduction of cells’ and 40 nM, respectively. As well as halydin was viability, proliferation, adhesion, and migration in vitro. compared with halysase, both of them inhibited platelet
The well-known P-IIIb SVMP, jararhagin 52 kDa, can aggregation with IC50 of 178 and 87 nM, respectively. induce cell lines to increase caspase-3 pathway, to Furthermore, the disintegrin-like cysteine-rich domain reduce G0/G1 period, to form necrosis, and finally to of P-III HF3, DC-HF3, inhibits collagen-induced platelet reduce nodules tumor in vivo. The mechanisms of aggregation with IC50 of 768 nM. Therefore, the these are not clear and are believed to come from disintegrin-like cysteine-rich domain of SVMPs was metalloproteinase, disintegrins, or disintegrin-like hypothesized to inhibit collagen-induced platelet cysteine rich domain. They may cleave ECM proteins aggregation. The studies in P-III SVMPs revealed the that are vital for cell adhesion similar to previous results specific sequences that seem likely to react with that showed that vascular endothelial damages can platelets. The disintegrin-like cysteine-rich domain was induce endothelial cell anoikis, a specialized form of found to block alpha2beta1 integrin binding to collagen apoptosis(8) or they may directly induce cell lines to and apparently enhanced the hemorrhagic activity of apoptosis such asgraminelysin, a SVMP from SVMPs(1). The sequence SECDPA is involved in the Trimeresurus (Protobothrops) gramineus, that causes inhibition of alpha2beta1 integrin binding to collagen(11). endothelial apoptosis prior to cell detachment(9). P-III SVMPs can inhibit platelet aggregation It was shown that P-III SVMPs were more through several proposed mechanisms. First, they can active in inducing hemorrhage than enzymes degrade or interact with different platelet receptors. comprising only the metalloproteinase domain. In For example, jararhagin degraded the beta subunit of addition to the protease domain, the strong proteolytic integrin alpha2beta1. Atrolysin A bound to and blocked activity of the P-III SVMPs may result from a specific alpha2beta1. Acurhagin interacted with GPVI. Second, interaction between disintegrin-like cysteine-rich they can degrade or interact with adhesive proteins domain and basement membrane components. Several involved in hemostasis. For example, AAV1 and studies suggested that the cysteine-rich domain bind halysase degraded fibrinogen. Kaouthiagin and collagen receptor on platelet, alpha2beta1, and cleave jararhagin destroyed vWF. Jararhagin, atrolysin A von willebrand factor (vWF) contributing to the and catrocollastatin interacted with vWF domain. hemorrhagic activity. The recent crystal structure of Jararhagin, acurhagin and catrocollastatin bound catrocollastatin revealed the hyper-variable-region collagen fibers. Albocollagenase, albolamin, and (HVR) located at the C terminal part of the cysteine- catrocollastatin inhibited only collagen (not ADP)- rich domain, which may be a substrate recognition site induced platelet aggregation suggesting that the venom for binding of disintegrin-like cysteine-rich domain with protein specifically prevented collagen and collagen ECM proteins. Jararhagin binds collagen using receptor (GPVI and/or alpha2beta1 integrin) disintegrin-like cysteine rich domain. This data may interactions. Whether this is mediated by enzymatic imply that the mechanism of P-III SVMPs, to induce degradation or non-enzymatic binding mechanisms the local effects of snakebite patients uses disintegrin- remains to be determined. It was reported that jararhagin like cysteine rich domain attached to ECM proteins at was bound to collagen and alpha2beta1 integrin by the wound site. The attachment causes the P-III SVMPs two independent motifs located on disintegrin-like and degrade ECM proteins and induce inflammation, cysteine-rich domain respectively. The collagen binding apoptosis and necrosis using metalloproteinase and with jararahgin only appeared to inhibit collagen- disintegrin-like cysteine rich domain in envenomed induced platelet aggregation(12). patients. Therefore, cysteine-rich domain may function as substrate targeting to enhance metalloproteinase Conclusion domain activities. Furthermore, HVR may also play a SVMPs are ECM proteins degradation that role in triggering pro-inflammatory effects by promoting contributes to hemorrhage in envenomed patients using leukocyte rolling(10). metalloproteinase domain. The disintegrin domain of The disintegrin-like cysteine-rich domain of SVMPs consists of conserve RGD sequences
S82 J Med Assoc Thai Vol. 99 Suppl. 1 2016 responsible to inhibit platelet aggregation and to inhibit of rACLF, a recombinant snake venom cancer progression. The disintegrin-like cysteine rich metallopeptidase on cell viability, chemokine domain of SVMPs consists of conserve ECD sequences expression and degradation of extracellular matrix and HVR responsible to inhibit platelet aggregation, to proteins. Toxicon 2006; 48: 641-8. bind specifically with local substrates at snakebite site 4. Adam F, Kauskot A, Rosa JP, Bryckaert M. and to inhibit cancer progression. The additional two Mitogen-activated protein kinases in hemostasis lectin-like domains found in P-IIId SVMP may be and thrombosis. J Thromb Haemost 2008; 6: 2007- responsible for factor V, factor IX, factor X and protein 16. C binding and/or activating. 5. Kamiguti AS, Zuzel M, Theakston RD. Snake venom metalloproteinases and disintegrins: Ethics consideration interactions with cells. Braz J Med Biol Res 1998; The author has no financial or other 31: 853-62. relationship with people or organizations that may 6. Lange U, Olschewski A, Nowak G, Bucha E. Ecarin inappropriately influence the work. chromogenic assay: an innovative test for quantitative determination of direct thrombin What is already known on this topic? inhibitors in plasma. Hamostaseologie 2005; 25: We have examined the activity of recombinant 293-300. albocollagenase, P-III SVMP of Thai green pit viper, 7. Thiagarajan P, Pengo V, Shapiro SS. The use of the and found that albocollagenase digests collagen type dilute Russell viper venom time for the diagnosis IV and inhibits collagen-induced platelet aggregation of lupus anticoagulants. Blood 1986; 68: 869-74. in vitro. These results imply that P-III SVMP of Thai 8. Shih CH, Chiang TB, Wang WJ. Inhibition of green pit viper can induce local hemorrhage and integrins alphav/alpha5-dependent functions in systemic bleeding in envenomed patients. melanoma cells by an ECD-disintegrin acurhagin- C. Matrix Biol 2013; 32: 152-9. What this study adds? 9. Wu WB, Huang TF. Activation of MMP-2, cleavage This review paper clearly described the of matrix proteins, and adherens junctions during activities of P-I, P-II and P-III SVMPs using table a snake venom metalloproteinase-induced presentation. In addition, this review contains the tri- endothelial cell apoptosis. Exp Cell Res 2003; 288: peptide conserve sequences of many SVMPs related 143-57. to their activities. Thus, we can use these data to 10. Menezes MC, Paes Leme AF, Melo RL, Silva CA, characterize the usefulness of recombinant Della CM, Bruni FM, et al. Activation of leukocyte albocollagenase to be the treatment target or drug rolling by the cysteine-rich domain and the hyper- discovery. variable region of HF3, a snake venom hemorrhagic metalloproteinase. FEBS Lett 2008; 582: 3915-21. Acknowledgement 11. Kamiguti AS, Moura-da-Silva AM, Laing GD, The author would like to thank the staff of the Knapp T, Zuzel M, Crampton JM, et al. Collagen- Office of International Relations at Ubon Ratchathani induced secretion-dependent phase of platelet University and also appreciation is expressed for the aggregation is inhibited by the snake venom help in English provided. metalloproteinase jararhagin. Biochim Biophys Acta 1997; 1335: 209-17. Potential conflicts of interest 12. Tanjoni I, Evangelista K, Della-Casa MS, Butera None. D, Magalhaes GS, Baldo C, et al. Different regions of the class P-III snake venom metalloproteinase References jararhagin are involved in binding to alpha2beta1 1. Jia LG, Shimokawa K, Bjarnason JB, Fox JW. Snake integrin and collagen. Toxicon 2010; 55: 1093-9. venom metalloproteinases: structure, function and 13. Ahmed NK, Tennant KD, Markland FS, relationship to the ADAMs family of proteins. Lacz JP. Biochemical characteristics of fibrolase, Toxicon 1996; 34: 1269-76. a fibrinolytic protease from snake venom. 2. Markland FS, Swenson S. Fibrolase: trials and Haemostasis 1990; 20: 147-54. tribulations. Toxins (Basel) 2010; 2: 793-808. 14. Guan AL, Retzios AD, Henderson GN, Markland 3. de Moraes CK, Selistre-de-Araujo HS. Effect FS Jr. Purification and characterization of a
J Med Assoc Thai Vol. 99 Suppl. 1 2016 S83 fibrinolytic enzyme from venom of the southern lanceolatus (Fer-de-lance) snake venom. Toxicon copperhead snake (Agkistrodon contortrix 2005; 45: 411-20. contortrix). Arch Biochem Biophys 1991; 289: 197- 25. Rucavado A, Flores-Sanchez E, Franceschi A, 207. Magalhaes A, Gutierrez JM. Characterization of 15. Egen NB, Russell FE, Sammons DW, Humphreys the local tissue damage induced by LHF-II, a RC, Guan AL, Markland FS Jr. Isolation by metalloproteinase with weak hemorrhagic activity preparative isoelectric focusing of a direct acting isolated from Lachesis muta muta snake venom. fibrinolytic enzyme from the venom of Agkistrodon Toxicon 1999; 37: 1297-312. contortrix contortrix (southern copperhead). 26. Sanchez EF, Magalhes A, Mandelbaum FR, Diniz Toxicon 1987; 25: 1189-98. CR. Purification and characterization of the 16. Xiang KJ, Yu HX, Zou CS, Yuan PH, Liu J. hemorrhagic factor II from the venom of the Expression, refolding and biological activity of Bushmaster snake (Lachesis muta muta). Biochim recombinant type-I metalloproteinase acutolysin Biophys Acta 1991; 1074: 347-56. a from Agkistrodon acutus. Sheng Wu Hua Xue 27. Willis TW, Tu AT. Purification and biochemical Yu Sheng Wu Wu Li Xue Bao (Shanghai) 2002; 34: characterization of atroxase, a nonhemorrhagic 675-9. fibrinolytic protease from western diamondback 17. Gomis-Ruth FX, Kress LF, Bode W. First structure rattlesnake venom. Biochemistry 1988; 27: 4769- of a snake venom metalloproteinase: a prototype 77. for matrix metalloproteinases/collagenases. EMBO 28. Selistre-de-Araujo HS, de Souza EL, Beltramini LM, J 1993; 12: 4151-7. Ownby CL, Souza DH. Expression, refolding, and 18. Mori N, Nikai T, Sugihara H, Tu AT. Biochemical activity of a recombinant nonhemorrhagic snake characterization of hemorrhagic toxins with venom metalloprotease. Protein Expr Purif 2000; fibrinogenase activity isolated from Crotalus ruber 19: 41-7. ruber venom. Arch Biochem Biophys 1987; 253: 29. Escalante T, Ortiz N, Rucavado A, Sanchez EF, 108-21. Richardson M, Fox JW, et al. Role of collagens 19. Takeya H, Onikura A, Nikai T, Sugihara H, Iwanaga and perlecan in microvascular stability: exploring S. Primary structure of a hemorrhagic metallo- the mechanism of capillary vessel damage by proteinase, HT-2, isolated from the venom of snake venom metalloproteinases. PLoS One 2011; Crotalus ruber ruber. J Biochem 1990; 108: 711-9. 6: e28017. 20. Tortorella MD, Pratta MA, Fox JW, Arner EC. The 30. Castro JM, Oliveira TS, Silveira CR, Caporrino MC, interglobular domain of cartilage aggrecan is Rodriguez D, Moura-da-Silva AM, et al. A cleaved by hemorrhagic metalloproteinase HT-d neutralizing recombinant single chain antibody, (atrolysin C) at the matrix metalloproteinase and scFv, against BaP1, A P-I hemorrhagic metallo- aggrecanase sites. J Biol Chem 1998; 273: 5846-50. proteinase from Bothrops asper snake venom. 21. Bjarnason JB, Fox JW. Characterization of two Toxicon 2014; 87: 81-91. hemorrhagic zinc proteinases, toxin c and toxin d, 31. Watanabe L, Shannon JD, Valente RH, Rucavado from western diamondback rattlesnake (Crotalus A, Alape-Giron A, Kamiguti AS, et al. Amino acid atrox) venom. Biochim Biophys Acta 1987; 911: sequence and crystal structure of BaP1, a 356-63. metalloproteinase from Bothrops asper snake 22. Baramova EN, Shannon JD, Bjarnason JB, Fox JW. venom that exerts multiple tissue-damaging Degradation of extracellular matrix proteins by activities. Protein Sci 2003; 12: 2273-81. hemorrhagic metalloproteinases. Arch Biochem 32. Escalante T, Rucavado A, Kamiguti AS, Theakston Biophys 1989; 275: 63-71. RD, Gutierrez JM. Bothrops asper metallo- 23. Takeya H, Arakawa M, Miyata T, Iwanaga S, Omori- proteinase BaP1 is inhibited by alpha(2)- Satoh T. Primary structure of H2-proteinase, a non- macroglobulin and mouse serum and does not hemorrhagic metalloproteinase, isolated from the induce systemic hemorrhage or coagulopathy. venom of the habu snake, Trimeresurus flavoviridis. Toxicon 2004; 43: 213-7. J Biochem 1989; 106: 151-7. 33. Brenes O, Munoz E, Roldan-Rodriguez R, Diaz C. 24. Stroka A, Donato JL, Bon C, Hyslop S, de Araujo Cell death induced by Bothrops asper snake venom AL. Purification and characterization of a metalloproteinase on endothelial and other cell hemorrhagic metalloproteinase from Bothrops lines. Exp Mol Pathol 2010; 88: 424-32.
S84 J Med Assoc Thai Vol. 99 Suppl. 1 2016 34. Modesto JC, Junqueira-de-Azevedo IL, Neves- pit viper (Cryptelytrops albolabris). Toxicon 2014; Ferreira AG, Fritzen M, Oliva ML, Ho PL, et al. 79: 19-27. Insularinase A, a prothrombin activator from 44. Chen RQ, Jin Y, Wu JB, Zhou XD, Lu QM, Wang Bothrops insularis venom, is a metalloprotease WY, et al. A new protein structure of P-II class derived from a gene encoding protease and snake venom metalloproteinases: it comprises disintegrin domains. Biol Chem 2005; 386: 589-600. metalloproteinase and disintegrin domains. 35. Junqueira-de-Azevedo IL, Ho PL. A survey of gene Biochem Biophys Res Commun 2003; 310: 182-7. expression and diversity in the venom glands of 45. Zhou XD, Jin Y, Chen RQ, Lu QM, Wu JB, Wang the pitviper snake Bothrops insularis through the WY, et al. Purification, cloning and biological generation of expressed sequence tags (ESTs). characterization of a novel disintegrin from Gene 2002; 299: 279-91. Trimeresurus jerdonii venom. Toxicon 2004; 43: 69- 36. Della-Casa MS, Junqueira-de-Azevedo I, Butera 75. D, Clissa PB, Lopes DS, Serrano SM, et al. 46. Wang SH, Shen XC, Yang GZ, Wu XF. cDNA “Insularin, a disintegrin from Bothrops insularis cloning and characterization of Agkistin, a new venom: inhibition of platelet aggregation and metalloproteinase from Agkistrodon halys. endothelial cell adhesion by the native and Biochem Biophys Res Commun 2003; 301: 298-303. recombinant GST-insularin proteins”. Toxicon 47. Nikai T, Taniguchi K, Komori Y, Masuda K, Fox 2011; 57: 125-33. JW, Sugihara H. Primary structure and functional 37. Sun DJ, Gu HD, Yang CW, Hu CG, Yang TS, Yan characterization of bilitoxin-1, a novel dimeric P-II WQ. Molecular cloning and sequence analysis of snake venom metalloproteinase from Agkistrodon ussurin, a new metalloproteinases/disintegrin from bilineatus venom. Arch Biochem Biophys 2000; Gloydius ussuriensis. Sheng Wu Gong Cheng Xue 378: 6-15. Bao 2003; 19: 353-7. 48. Imai K, Nikai T, Sugihara H, Ownby CL. 38. Shimokawa K, Jia LG, Shannon JD, Fox JW. Hemorrhagic toxin from the venom of Agkistrodon Isolation, sequence analysis, and biological bilineatus (common cantil). Int J Biochem 1989; 21: activity of atrolysin E/D, the non-RGD disintegrin 667-73. domain from Crotalus atrox venom. Arch Biochem 49. Zhou Q, Hu P, Ritter MR, Swenson SD, Argounova Biophys 1998; 354: 239-46. S, Epstein AL, et al. Molecular cloning and 39. Shimokawa K, Jia LG, Wang XM, Fox JW. functional expression of contortrostatin, a Expression, activation, and processing of the homodimeric disintegrin from southern recombinant snake venom metalloproteinase, pro- copperhead snake venom. Arch Biochem Biophys atrolysin E. Arch Biochem Biophys 1996; 335: 283- 2000; 375: 278-88. 94. 50. Hubbard S, Choudhary S, Maus E, Shukla D, 40. Musial J, Niewiarowski S, Rucinski B, Stewart GJ, Swenson S, Markland FS Jr, et al. Contortrostatin, Cook JJ, Williams JA, et al. Inhibition of platelet a homodimeric disintegrin isolated from snake adhesion to surfaces of extracorporeal circuits by venom inhibits herpes simplex virus entry and cell disintegrins. RGD-containing peptides from viper fusion. Antivir Ther 2012; 17: 1319-26. venoms. Circulation 1990; 82: 261-73. 51. Okuda D, Koike H, Morita T. A new gene structure 41. Yamada D, Shin Y, Morita T. Nucleotide sequence of the disintegrin family: a subunit of dimeric of a cDNA encoding a common precursor of disintegrin has a short coding region. Biochemistry disintegrin flavostatin and hemorrhagic factor 2002; 41: 14248-54. HR2a from the venom of Trimeresurus flavoviridis. 52. Siigur E, Siigur J. Purification and characterization FEBS Lett 1999; 451: 299-302. of lebetase, a fibrinolytic enzyme from Vipera 42. Huang TF, Holt JC, Kirby EP, Niewiarowski S. lebetina (snake) venom. Biochim Biophys Acta Trigramin: primary structure and its inhibition of 1991; 1074: 223-9. von Willebrand factor binding to glycoprotein IIb/ 53. Siigur J, Tonismagi K, Tu AT, Siigur E. Cross- IIIa complex on human platelets. Biochemistry 1989; reactivities of polyclonal antibodies against 28: 661-6. lebetase, fibrinolytic enzyme of Levantine viper 43. Jangprasert P, Rojnuckarin P. Molecular cloning, (Vipera lebetina) venom. Toxicon 1996; 34: 608-13. expression and characterization of albolamin: a type 54. Siigur J, Samel M, Tonismagi K, Subbi J, Siigur E, P-IIa snake venom metalloproteinase from green Tu AT. Biochemical characterization of lebetase, a
J Med Assoc Thai Vol. 99 Suppl. 1 2016 S85 direct-acting fibrinolytic enzyme from Vipera Y, Ito M, et al. Purification and characterization of lebetina snake venom. Thromb Res 1998; 90: 39- kaouthiagin, a von Willebrand factor-binding and 49. -cleaving metalloproteinase from Naha kaouthia 55. Silva CA, Zuliani JP, Assakura MT, Mentele R, cobra venom. Thromb Haemost 1998; 80: 499-505. Camargo AC, Teixeira CF, et al. Activation of 66. Ito M, Hamako J, Sakurai Y, Matsumoto M, alpha(M)beta(2)-mediated phagocytosis by HF3, Fujimura Y, Suzuki M, et al. Complete amino acid a P-III class metalloproteinase isolated from the sequence of kaouthiagin, a novel cobra venom venom of Bothrops jararaca. Biochem Biophys Res metalloproteinase with two disintegrin-like Commun 2004; 322: 950-6. sequences. Biochemistry 2001; 40: 4503-11. 56. Leonardi A, Gubensek F, Krizaj I. Purification and 67. Pereira AL, Fritzen M, Faria F, Motta G, Chudzinski- characterisation of two hemorrhagic Tavassi AM. Releasing or expression modulating metalloproteinases from the venom of the long- mediator involved in hemostasis by nosed viper, Vipera ammodytes ammodytes. Berythractivase and Jararhagin (SVMPs). Toxicon Toxicon 2002; 40: 55-62. 2006; 47: 788-96. 57. You WK, Jang YJ, Chung KH, Kim DS. A novel 68. Mazzi MV, Marcussi S, Carlos GB, Stabeli RG, disintegrin-like domain of a high molecular weight Franco JJ, Ticli FK, et al. A new hemorrhagic metalloprotease inhibits platelet aggregation. metalloprotease from Bothrops jararacussu snake Biochem Biophys Res Commun 2003; 309: 637-42. venom: isolation and biochemical characterization. 58. You WK, Jang YJ, Chung KH, Jeon OH, Kim DS. Toxicon 2004; 44: 215-23. Functional roles of the two distinct domains of 69. Morita T, Iwanaga S, Suzuki T. The mechanism of halysase, a snake venom metalloprotease, to activation of bovine prothrombin by an activator inhibit human platelet aggregation. Biochem isolated from Echis carinatus venon and Biophys Res Commun 2006; 339: 964-70. characterization of the new active intermediates. J 59. Jia LG, Wang XM, Shannon JD, Bjarnason JB, Fox Biochem 1976; 79: 1089-108. JW. Function of disintegrin-like/cysteine-rich 70. Dyr JE, Blomback B, Kornalik F. The action of domains of atrolysin A. Inhibition of platelet prothrombin activated by Ecarin on fibrinogen. aggregation by recombinant protein and peptide Thromb Res 1983; 30: 225-34. antagonists. J Biol Chem 1997; 272: 13094-102. 71. Chen RQ, Jin Y, Wu JB, Zhou XD, Li DS, Lu QM, 60. Kamiguti AS, Hay CR, Theakston RD, Zuzel M. et al. A novel high molecular weight metallo- Insights into the mechanism of haemorrhage proteinase cleaves fragment F1 of activated human caused by snake venom metalloproteinases. prothrombin. Toxicon 2004; 44: 281-7. Toxicon 1996; 34: 627-42. 72. Andrews RK, Gardiner EE, Asazuma N, Berlanga 61. Serrano SM, Jia LG, Wang D, Shannon JD, Fox JW. O, Tulasne D, Nieswandt B, et al. A novel viper Function of the cysteine-rich domain of the venom metalloproteinase, alborhagin, is an agonist haemorrhagic metalloproteinase atrolysin A: at the platelet collagen receptor GPVI. J Biol Chem targeting adhesion proteins collagen I and von 2001; 276: 28092-7. Willebrand factor. Biochem J 2005; 391: 69-76. 73. Wijeyewickrema LC, Gardiner EE, Moroi M, 62. Wang WJ, Huang TF. Purification and Berndt MC, Andrews RK. Snake venom metallo- characterization of a novel metalloproteinase, proteinases, crotarhagin and alborhagin, induce acurhagin, from Agkistrodon acutus venom. ectodomain shedding of the platelet collagen Thromb Haemost 2002; 87: 641-50. receptor, glycoprotein VI. Thromb Haemost 2007; 63. Wang WJ, Shih CH, Huang TF. Primary structure 98: 1285-90. and antiplatelet mechanism of a snake venom 74. Pinyachat A, Rojnuckarin P, Muanpasitporn C, metalloproteinase, acurhagin, from Agkistrodon Singhamatr P, Nuchprayoon S. Albocollagenase, acutus venom. Biochimie 2005; 87: 1065-77. a novel recombinant P-III snake venom metallo- 64. Wang WJ. Acurhagin-C, an ECD disintegrin, proteinase from green pit viper (Cryptelytrops inhibits integrin alphavbeta3-mediated human albolabris), digests collagen and inhibits platelet endothelial cell functions by inducing apoptosis aggregation. Toxicon 2011; 57: 772-80. via caspase-3 activation. Br J Pharmacol 2010; 160: 75. Assakura MT, Silva CA, Mentele R, Camargo AC, 1338-51. Serrano SM. Molecular cloning and expression of 65. Hamako J, Matsui T, Nishida S, Nomura S, Fujimura structural domains of bothropasin, a P-III
S86 J Med Assoc Thai Vol. 99 Suppl. 1 2016 metalloproteinase from the venom of Bothrops of platelet aggregation inhibitors (disintegrins) jararaca. Toxicon 2003; 41: 217-27. autoproteolytically released from snake venom 76. Serrano SM, Wang D, Shannon JD, Pinto AF, hemorrhagic metalloproteinases and new fluoro- Polanowska-Grabowska RK, Fox JW. Interaction genic peptide substrates for these enzymes. J of the cysteine-rich domain of snake venom Biochem 1993; 113: 473-83. metalloproteinases with the A1 domain of von 86. Sajevic T, Leonardi A, Kovacic L, Lang-Balija M, Willebrand factor promotes site-specific Kurtovic T, Pungercar J, et al. VaH3, one of the proteolysis of von Willebrand factor and inhibition principal hemorrhagins in Vipera ammodytes of von Willebrand factor-mediated platelet ammodytes venom, is a homodimeric P-IIIc aggregation. FEBS J 2007; 274: 3611-21. metalloproteinase. Biochimie 2013; 95: 1158-70. 77. Zhou Q, Smith JB, Grossman MH. Molecular 87. Masuda S, Ohta T, Kaji K, Fox JW, Hayashi H, cloning and expression of catrocollastatin, a snake- Araki S. cDNA cloning and characterization of venom protein from Crotalus atrox (western vascular apoptosis-inducing protein 1. Biochem diamondback rattlesnake) which inhibits platelet Biophys Res Commun 2000; 278: 197-204. adhesion to collagen. Biochem J 1995; 307 ( Pt 2): 88. Masuda S, Hayashi H, Atoda H, Morita T, Araki S. 411-7. Purification, cDNA cloning and characterization 78. Zhou Q, Dangelmaier C, Smith JB. The hemorrhagin of the vascular apoptosis-inducing protein, HV1, catrocollastatin inhibits collagen-induced platelet from Trimeresurus flavoviridis. Eur J Biochem 2001; aggregation by binding to collagen via its 268: 3339-45. disintegrin-like domain. Biochem Biophys Res 89. Leonardi A, Sajevic T, Kovacic L, Pungercar J, Lang Commun 1996; 219: 720-6. BM, Halassy B, et al. Hemorrhagin VaH4, a covalent 79. Igarashi T, Oishi Y, Araki S, Mori H, Takeda S. heterodimeric P-III metalloproteinase from Vipera Crystallization and preliminary X-ray crystallo- ammodytes ammodytes with a potential antitumour graphic analysis of two vascular apoptosis- activity. Toxicon 2014; 77: 141-55. inducing proteins (VAPs) from Crotalus atrox 90. Khow O, Chanhome L, Omori-Satoh T, venom. Acta Crystallogr Sect F Struct Biol Cryst Puempunpanich S, Sitprija V. A hemorrhagin as a Commun 2006; 62: 688-91. metalloprotease in the venom of Trimeresurus 80. Correa MC Jr, Maria DA, Moura-da-Silva AM, purpureomaculatus: purification and characteri- Pizzocaro KF, Ruiz IR. Inhibition of melanoma cells zation. Toxicon 2002; 40: 455-61. tumorigenicity by the snake venom toxin jararhagin. 91. Wang WJ. Purification and functional Toxicon 2002; 40: 739-48. characterization of AAV1, a novel P-III metallo- 81. Schattner M, Fritzen M, Ventura JS, Albuquerque proteinase, from Formosan Agkistrodon acutus Modesto JC, Pozner RG, Moura-da-Silva AM, venom. Biochimie 2007; 89: 105-15. et al. The snake venom metalloproteases bery- 92. Guo XX, Zeng L, Lee WH, Zhang Y, Jin Y. Isolation thractivase and jararhagin activate endothelial and cloning of a metalloproteinase from king cobra cells. Biol Chem 2005; 386: 369-74. snake venom. Toxicon 2007; 49: 954-65. 82. Moura-da-Silva AM, Baldo C. Jararhagin, a 93. Leonardi A, Fox JW, Trampus-Bakija A, Krizaj I. hemorrhagic snake venom metalloproteinase from Two coagulation factor X activators from Vipera a. Bothrops jararaca. Toxicon 2012; 60: 280-9. ammodytes venom with potential to treat patients 83. Maria DA, da Silva MG, Correia Junior MC, Ruiz with dysfunctional factors IXa or VIIa. Toxicon IR. Antiproliferative effect of the jararhagin toxin 2008; 52: 628-37. on B16F10 murine melanoma. BMC Complement 94. Takeya H, Nishida S, Miyata T, Kawada S, Saisaka Altern Med 2014; 14: 446. Y, Morita T, et al. Coagulation factor X activating 84. Moura-da-Silva AM, Linica A, Della-Casa MS, enzyme from Russell’s viper venom (RVV-X). A Kamiguti AS, Ho PL, Crampton JM, et al. Jararhagin novel metalloproteinase with disintegrin (platelet ECD-containing disintegrin domain: expression in aggregation inhibitor)-like and C-type lectin-like escherichia coli and inhibition of the platelet- domains. J Biol Chem 1992; 267: 14109-17. collagen interaction. Arch Biochem Biophys 1999; 95. Chen HS, Chen JM, Lin CW, Khoo KH, Tsai IH. 369: 295-301. New insights into the functions and N-glycan 85. Takeya H, Nishida S, Nishino N, Makinose Y, structures of factor X activator from Russell’s viper Omori-Satoh T, Nikai T, et al. Primary structures venom. FEBS J 2008; 275: 3944-58.
J Med Assoc Thai Vol. 99 Suppl. 1 2016 S87 96. Siigur E, Tonismagi K, Trummal K, Samel M, 97. Siigur J, Aaspollu A, Tonismagi K, Trummal K, Vija H, Subbi J, et al. Factor X activator from Vipera Samel M, Vija H, et al. Proteases from Vipera lebetina snake venom, molecular characterization lebetina venom affecting coagulation and and substrate specificity. Biochim Biophys Acta fibrinolysis. Haemostasis 2001; 31: 123-32. 2001; 1568: 90-8.
⌦⌫⌫..⌫⌫.⌫..
⌫..⌫.⌫. ⌫⌫⌫ ⌫ .⌦ ⌫ . ⌫ . . .⌦ . ⌫ . . . ..⌫ ⌫.. ⌫ . . . ⌫..⌫.⌫. ..... ⌫⌫..⌫⌫ ⌫⌫⌦.. .⌫⌫.⌫...⌫. ..⌫ .
S88 J Med Assoc Thai Vol. 99 Suppl. 1 2016