Coagulation factor X activating enzyme from Russell's viper venom (RVV-X). A novel metalloproteinase with disintegrin (platelet aggregation inhibitor)-like and C-type lectin-like domains.

Takeya, Hiroyuki; Nishida, Shinji; Miyata, Toshiyuki; Kawada, Shin-ichiro; Y, Saisaka; Morita, Takashi; Iwanaga, Sadaaki

doi:10.1016/s0021-9258(19)49685-3

Cited by 205 publications

(26 citation statements)

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“…The study also showed that DrSL and DrI venoms were highly potent in inducing plasma coagulation, consistent with the substantial amount of procoagulant SVSP and SVMP in the venom proteomes. The findings revealed that the procoagulant activity of D. russelii venoms is calcium-dependent, in line with the model proposed by Morita [68] which suggested that Ca 2+ ions are needed to induce a conformational change in the gammacarboxyglutamate domain of Factor X for it to be recognized by the procoagulant toxin [67]. Interestingly, anticoagulant activity was not detected in the venoms of DrSL and DrI, consistent with the study reported by Prasad et al [71] (Southern and Western Indian D. russelii specimens).…”

Section: Discussionsupporting

confidence: 86%

“…Despite the variable protein abundance, the major SVMP reported in these Russell's viper venom proteomes consistently belonged to the SVMP PIII subclass. Of the PIII SVMP detected, Factor X activating enzyme (RVV-X) was the most wellcharacterized subtype for its hemotoxic role in Russell's viper envenomation [67]. The metalloproteinase proteolytically cleaves the target bond in the factor X molecule, while the light-chain snaclecs form a secondary binding site specific for interaction with the Gla domain of factor X, thus activating factor X and initiating blood coagulation [68].…”

Section: Discussionmentioning

confidence: 99%

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Proteomics, toxicity and antivenom neutralization of Sri Lankan and Indian Russell’s viper (Daboia russelii) venoms

Faisal

Tan

et al. 2021

J. Venom. Anim. Toxins incl. Trop. Dis

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Background: The western Russell's viper (Daboia russelii) is widely distributed in South Asia, and geographical venom variation is anticipated among distant populations. Antivenoms used for Russell's viper envenomation are, however, raised typically against snakes from Southern India. The present study investigated and compared the venom proteomes of D. russelii from Sri Lanka (DrSL) and India (DrI), the immunorecognition of Indian VINS Polyvalent Antivenom (VPAV) and its efficacy in neutralizing the venom toxicity. Methods: The venoms of DrSL and DrI were decomplexed with C 18 high-performance liquid chromatography and SDS-polyacrylamide gel electrophoresis under reducing conditions. The proteins fractionated were identified through nano-ESI-liquid chromatography-tandem mass spectrometry (LCMS/MS). The immunological studies were conducted with enzyme-linked immunosorbent assay. The neutralization of the venom procoagulant effect was evaluated in citrated human plasma. The neutralization of the venom lethality was assessed in vivo in mice adopting the WHO protocol. Results: DrSL and DrI venom proteomes showed comparable major protein families, with phospholipases A 2 (PLA 2 ) being the most abundant (> 60% of total venom proteins) and diverse (six protein forms identified). Both venoms were highly procoagulant and lethal (intravenous median lethal dose in mice, LD 50 = 0.24 and 0.32 µg/g, for DrSL and DrI, respectively), while lacking hemorrhagic and anticoagulant activities. VPAV was immunoreactive toward DrSL and DrI venoms, indicating conserved protein antigenicity in the venoms. The high molecular weight venom proteins were, however, more effectively immunorecognized than small ones. VPAV was able to neutralize the coagulopathic and lethal effects of the venoms moderately. Conclusion:Considering that a large amount of venom can be injected by Russell's viper during envenomation, the potency of antivenom can be further improved for optimal neutralization and effective treatment. Region-specific venoms and key toxins may be incorporated into the immunization procedure during antivenom production.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Proteomics, toxicity and antivenom neutralization of Sri Lankan and Indian Russell’s viper (Daboia russelii) venoms

Faisal

Tan

et al. 2021

J. Venom. Anim. Toxins incl. Trop. Dis

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“…The partial activation by RVV-X was observed for all variants including wild-type FX, and thus it appeared unlikely to be related to the introduced N-glycan. The Gla-domain has previously been proposed to be an important exosite for RVV-X interaction [19], however the Gla-domain characterization of the variants tested herein demonstrated high level of γ-carboxylation consistent with the employed purification strategy based on a capture anti-Gla immunoaffinity and polish anion-exchange chromatography. As the glycans in the activation peptide have been reported to promote optimal activation of FX [20,21], the lack of full activation by RVV-X could be ascribed as a possible heterogeneous level of sialylation of the putative N-linked and O-linked glycosylation sites in the activation peptide of FX.…”

Section: Preparative Activation Of Fx Variants By Rvv-x and Active-site Probingsupporting

confidence: 60%

Prolonging coagulant activity of factor Xa under hemophilic conditions by site-specific N-glycosylation of the surface-exposed autolysis loop

Bonde

Lund

Hansen

et al. 2021

Preprint

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The regulation of Factor X (FX) is critical to maintain hemostasis. To gain insights to the regulation of the active and zymogen form of coagulation FX, we probed specific molecular interactions by introducing novel N-linked glycosylations on the surface-exposed loop spanning residues 143-150 (chymotrypsin numbering) of FX. Introduction of N-glycans in the autolysis loop of these FX variants decreased Factor VIIa (FVIIa)-mediated activation ~3-fold and prothrombin activation 2- to 10-fold presumably through steric hinderance. Prothrombin activation was, however, recovered in presence of cofactor Factor Va (FVa) despite a reduced prothrombinase assembly. The introduced N-glycans exhibited position-specific effects on the interaction with two FXa inhibitors: tissue factor pathway inhibitor (TFPI) and antithrombin (ATIII). Ki for the inhibition by full-length TFPI of these FXa variants was increased by 7- to 1150-fold, while ATIII inhibition in the presence of the heparin-analogue Fondaparinux was modestly increased by 2- to 15-fold compared to wild type. To probe the in vitro hemostatic effect of the FX variants, the thrombin generation potential in FX-depleted plasma was evaluated. When supplemented in zymogen form, the FX variants exhibited reduced thrombin generation activity relative to wild-type FX, whereas enhanced procoagulant activity was measured for activated FX variants with N-glycosylation at positions 148-150. These results indicate that residues of the surface-exposed autolysis loop and residues close by participate in FX activation, proteolytic activity and inhibition of FXa by TFPI and ATIII. In plasma-based assays, a modest decrease in FX-activation rate appeared to compensate for the collective reduction in inhibitor interactions.

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“…94,95 Factor X Assays Daboia russellii venom contains a snake venom metalloproteinase activator of FX, RVV-X, which is the FX activator employed in the Stypven time. 75,96 RVV-X activates FX by cleaving the Arg 194 -Ile 195 bond, the same cleavage site used by FIXa and FVIIa. 96,97 It is by far the most potent snake venom FX activator, other snakes whose venoms contain a FX activator include Bothrops atrox, Bothrops neuwiedi, Saharan horned viper (Cerastes cerastes), common European adder (Vipera berus berus), and Cleopatra's apparent accomplice in her suicide, the asp (Vipera aspis aspis).…”

Section: Factor V Assaymentioning

confidence: 99%

“…[144][145][146][147] Although LA are antiphospholipid antibodies, RVV-X (also known as russellysin) itself is not phospholipid dependent and requires only Ca 2þ to activate FX. 96,97 The FXa generated from RVV-X activation then enters the phospholipid-dependent prothrombinase assembly to generate thrombin and clot formation. The phospholipid is diluted in the dRVVT screening test to accentuate the inhibitory effect of any LA present and increase sensitivity, and is concentrated in the dRVVT confirmatory test to swamp the LA and shorten the clotting time relative to the screening test, thereby evidencing phospholipid dependence.…”

Section: Lupus Anticoagulantsmentioning

confidence: 99%

Snake Venoms in Diagnostic Hemostasis and Thrombosis

Moore

2021

Semin Thromb Hemost

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Snake venoms have evolved primarily to immobilize and kill prey, and consequently, they contain some of the most potent natural toxins. Part of that armory is a range of hemotoxic components that affect every area of hemostasis, which we have harnessed to great effect in the study and diagnosis of hemostatic disorders. The most widely used are those that affect coagulation, such as thrombin-like enzymes unaffected by heparin and direct thrombin inhibitors, which can help confirm or dispute their presence in plasma. The liquid gold of coagulation activators is Russell's viper venom, since it contains activators of factor X and factor V. It is used in a range of clotting-based assays, such as assessment of factor X and factor V deficiencies, protein C and protein S deficiencies, activated protein C resistance, and probably the most important test for lupus anticoagulants, the dilute Russell's viper venom time. Activators of prothrombin, such as oscutarin C from Coastal Taipan venom and ecarin from saw-scaled viper venom, are employed in prothrombin activity assays and lupus anticoagulant detection, and ecarin has a valuable role in quantitative assays of direct thrombin inhibitors. Snake venoms affecting primary hemostasis include botrocetin from the jararaca, which can be used to assay von Willebrand factor activity, and convulxin from the cascavel, which can be used to detect deficiency of the platelet collagen receptor, glycoprotein VI. This article takes the reader to every area of the diagnostic hemostasis laboratory to appreciate the myriad applications of snake venoms available in diagnostic practice.

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Coagulation factor X activating enzyme from Russell's viper venom (RVV-X). A novel metalloproteinase with disintegrin (platelet aggregation inhibitor)-like and C-type lectin-like domains.

Cited by 205 publications

References 50 publications

Proteomics, toxicity and antivenom neutralization of Sri Lankan and Indian Russell’s viper (Daboia russelii) venoms

Proteomics, toxicity and antivenom neutralization of Sri Lankan and Indian Russell’s viper (Daboia russelii) venoms

Prolonging coagulant activity of factor Xa under hemophilic conditions by site-specific N-glycosylation of the surface-exposed autolysis loop

Snake Venoms in Diagnostic Hemostasis and Thrombosis

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