Phospholipase A2 myotoxins from Bothrops snake venoms

Gutiérrez, José Marı́a; Lomonte, Bruno

doi:10.1016/0041-0101(95)00085-z

Cited by 474 publications

(288 citation statements)

References 116 publications

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“…Previous studies had shown that other participants of the infl ammatory reaction, i. e. neutrophils, matrix metalloproteinases and the cytokines TNF-α, IL-1β and IL-6, are not directly involved in acute myonecrosis in a similar experimental model of B. asper envenomation [14,18,26]. Hence, local myonecrosis induced by this venom very likely depends on the direct toxic effects of myotoxic phospholipases A 2 [5,28] and hemorrhagic metalloproteinases [38,39]. The former infl ict muscle damage by directly affecting the integrity of skeletal muscle cell plasma membrane [7,28], whereas myonecrosis induced by hemorrhagic proteinases is likely to be secondary to the ischemia resultant in the tissue from the deleterious effects on blood supply [39].…”

Section: Discussionmentioning

confidence: 94%

“…The pathogenesis of local and systemic effects induced by B. asper venom has been partially investigated. Various locallyacting toxins, mostly metalloproteinases and phospholipases A 2 , are responsible for the acute local pathological effects [5][6][7]. In addition, a variety of venom components, such as metalloproteinases, serine proteinases and proteins of the Ctype lectin family, induce defi brination, systemic bleeding and thrombocytopenia, therefore promoting profuse bleeding and coagulopathy [8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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Role of nitric oxide in the local and systemic pathophysiological effects induced by Bothrops asper snake venom in mice

2006

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Abstract.Objective: To assess the role of nitric oxide in the most relevant local and systemic manifestations in mice injected with the venom of the snake Bothrops asper. Mice were pretreated with nitric oxide synthase inhibitors, and the modifi cations of the pathological effects induced by the venom were tested. Results: Inhibition of NO synthesis did not affect acute local myonecrosis and hemorrhage in muscle tissue upon intramuscular injection of venom. Local footpad edema was reduced in mice pretreated with the NO synthase inhibitor L-NAME, and a reduction in the extent of infl ammatory infi ltrate in muscle tissue was observed after envenomation in mice pretreated with L-NAME and aminoguanidine. The most pronounced effect of NOS inhibition by L-NAME was an increment in the lethal activity of the venom, when injected by the intraperitoneal route. Conclusion: Nitric oxide does not seem to play a signifi cant role in the local acute pathological alterations (hemorrhage and myonecrosis) induced by B. asper venom in mice, although it contributes to edema and infl ammatory infi ltrate. Nitric oxide exerts a protective role in the systemic pathophysiological manifestations leading to lethality.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Role of nitric oxide in the local and systemic pathophysiological effects induced by Bothrops asper snake venom in mice

2006

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“…These enzymes are widely distributed in pancreatic secretions, inflammatory exudates, and in snake and arthropod venoms (Balsinde et al, 1999) and in some invertebrates (Nevalainen et al, 2004a,b;Foradori et al, 2005). A variety of actions are attributed to venom sPLA 2 s, which include neurotoxic, myotoxic, edema-inducing, platelet-aggregating, cardiotoxic and anticoagulant effects (Gutierrez and Lomonte, 1995;Arni and Ward, 1996;Lomonte et al, 2003b). Venom sPLA 2 s belong to groups I (terrestrial elapids and sea snake venoms), II (viperid snake venoms) and III (bee and lizard venoms) (Six and Dennis, 2000;Valentin and Lambeau, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Although unable to hydrolyze the ester bond in the sn-2 position of glycerophospholipids, a host of studies have shown evidence that Lys-49 PLA 2 s are able to destabilize cell membranes by catalytically independent mechanisms (Rufini et al, 1992;Falconi et al, 2000;Ward et al, 2002;Lomonte et al, 2003b). Myotoxins II (Mt II) and III (Mt III) are well-characterized Lys-49 and Asp-49 myotoxic PLA 2 s, respectively, present in Bothrops asper venom (Kaiser et al, 1990;Francis et al, 1991;Gutierrez and Lomonte, 1995). Similar myotoxic PLA 2 s have been described in many Bothrops sp.…”

Section: Introductionmentioning

confidence: 99%

“…Similar myotoxic PLA 2 s have been described in many Bothrops sp. venoms (Gutierrez and Lomonte, 1995). Although it is well accepted that most of the skeletal muscle fiber deleterious effects of Mt II and Mt III are a direct result of cell membrane damage (delta-lesions, hypercontraction of myofilaments, mitochondrial swelling, flocculent densities and rupture of mitochondrial membranes, disruption of intracellular membranes and pycnosis of nuclei) (Gutierrez and Ownby, 2003), it is reasonable to consider that these proteins might also trigger specific intracellular biochemical pathways that lead to cell modifications in structure and function.…”

Section: Introductionmentioning

confidence: 99%

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Effect of calcineurin inhibitors on myotoxic activity of crotoxin and Bothrops asper phospholipase A2 myotoxins in vivo and in vitro

Miyabara¹,

Baptista²,

Lomonte³

et al. 2006

Comparative Biochemistry and Physiology Part C: Toxicology &

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Previous studies have shown that calcineurin activity plays a critical role in the myotoxic activity induced by crotoxin (CTX), a group II phospholipase A 2 (PLA 2 ) with neurotoxic and myotoxic actions. In order to address whether calcineurin is also important for the activity of nonneurotoxic group II PLA 2 myotoxins we have compared the effects of calcineurin inhibition on the myotoxic capacity of CTX and the nonneurotoxic PLA 2 s, myotoxin II (Mt II) and myotoxin III (Mt III) from Bothrops asper venom. Rats were treated with cyclosporin A (CsA) or FK506, calcineurin inhibitors, and received an intramuscular injection of either CTX, Mt II or Mt III into the tibialis anterior. Animals were killed 24 h after injection of toxins. Tibialis anterior was removed and stored in liquid nitrogen. Myofibers in culture were also treated with CsA or FK506 and exposed to CTX, Mt II and Mt III. It was observed that, in contrast to CTX, CsA and FK506 do not attenuate myotoxic effects induced by both Mt II and Mt III in vivo and in vitro. The results of the present study suggest that calcineurin is not essential for the myotoxic activity of Mt II and Mt III, indicating that distinct intracellular pathways might be involved in myonecrosis induced by neurotoxic CTX and non-neurotoxic Bothrops sp. PLA 2 myotoxins. Alternatively, calcineurin dependent fast fiber type shift might render the muscle resistant to the action of CTX, without affecting its susceptibility to Bothrops sp. myotoxins.

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Crystallographic and spectroscopic characterization of a molecular hinge: Conformational changes in bothropstoxin I, a dimeric Lys49-phospholipase A2 homologue

Giotto¹,

Garratt²,

Oliva³

et al. 1998

Proteins

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Bothropstoxin I (BthTX-I) from the venom of Bothrops jararacussu is a myotoxic phospholipase A2 (PLA2) homologue which, although catalytically inactive due to an Asp49-->Lys substitution, disrupts the integrity of lipid membranes by a Ca2+-independent mechanism. The crystal structures of two dimeric forms of BthTX-I which diffract X-rays to resolutions of 3.1 and 2.1 angstroms have been determined. The monomers in both structures are related by an almost perfect twofold axis of rotation and the dimer interfaces are defined by contacts between the N-terminal alpha-helical regions and the tips of the beta-wings of partner monomers. Significant differences in the relative orientation of the monomers in the two crystal forms results in "open" and "closed" dimer conformations. Spectroscopic investigations of BthTX-I in solution have correlated these conformational differences with changes in the intrinsic fluorescence emission of the single tryptophan residues located at the dimer interface. The possible relevance of this structural transition in the Ca2+-independent membrane damaging activity is discussed.

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Phospholipase A2 myotoxins from Bothrops snake venoms

Cited by 474 publications

References 116 publications

Role of nitric oxide in the local and systemic pathophysiological effects induced by Bothrops asper snake venom in mice

Role of nitric oxide in the local and systemic pathophysiological effects induced by Bothrops asper snake venom in mice

Effect of calcineurin inhibitors on myotoxic activity of crotoxin and Bothrops asper phospholipase A2 myotoxins in vivo and in vitro

Crystallographic and spectroscopic characterization of a molecular hinge: Conformational changes in bothropstoxin I, a dimeric Lys49-phospholipase A2 homologue

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