Crystal structures of BnSP-7 and BnSP-6, two Lys49-phospholipases A2: quaternary structure and inhibition mechanism insights

Magro, Ângelo J.; Soares, Andreimar M.; Giglio, José Roberto; Fontes, Marcos R.M.

doi:10.1016/j.bbrc.2003.10.047

Cited by 70 publications

(57 citation statements)

References 32 publications

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“…The presence of a presynaptic PLA 2 in B. n. pauloensis venom was expected, since several reports had already indicated that this venom had presynaptic neurotoxicity (4,5,12,44,53). NeuTX-I and NeuTX-II have Gly-30 and Gly-32, but Lys-49 toxins such as BnSP-7, a myotoxic PLA 2 from B. n. pauloensis venom (13,32,46), besides bothropstoxin-I, piratoxins, Basp-II and Bneu, have Leu-32 (L-32) for Gly-32. In addition, the fraction that originated NeuTX-I and NeuTX-II, third peak from HPLC molecular exclusion elution profile, had PLA 2 activity and its blocking action was temperature-dependent.…”

Section: Discussionmentioning

confidence: 98%

Purification and n-terminal sequencing of two presynaptic neurotoxic PLA2, neuwieditoxin-I and neuwieditoxin-II, from Bothrops neuwiedi pauloensis (jararaca pintada) venom

Oliveira¹,

Kassab²,

Soares³

et al. 2007

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

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ABSTRACT:Two presynaptic phospholipases A 2 (PLA 2 ), neuwieditoxin-I (NeuTX-I) and neuwieditoxin-II (NeuTX-II), were isolated from the venom of Bothrops neuwiedi pauloensis (BNP). The venom was fractionated using molecular exclusion HPLC (Protein-Pak 300SW column), followed by reverse phase HPLC (μBondapak C18 column). Tricine-SDS-PAGE in the presence or absence of dithiothreitol showed that NeuTX-I and NeuTX-II had a molecular mass of approximately 14 kDa and 28kDa, respectively. At 10μg/ml, both toxins produced complete neuromuscular blockade in indirectly stimulated chick biventer cervicis isolated preparation without inhibiting the response to acetylcholine, but NeuTX-II reduced the response to KCl by 67.0±8.0% (n=3; p<0.05). NeuTX-I and NeuTX-II are probably responsible for the presynaptic neurotoxicity of BNP venom in vitro. In fact, using loose patch clamp technique for mouse phrenic nerve-diaphragm preparation, NeuTX-I produced a calcium-dependent blockade of acetylcholine release and caused appearance of giant miniature end-plate potentials (mepps), indicating a pure presynaptic action. The N-terminal sequence of NeuTX-I was DLVQFGQMILKVAGRSLPKSYGAYGCYCGWGGRGK (71% homology with bothropstoxin-II and 54% homology with caudoxin) and that of NeuTX-II was SLFEFAKMILEETKRLPFPYYGAYGCYCGWGGQGQPKDAT (92% homology with Basp-III and 62% homology with crotoxin PLA2). The fact that NeuTX-I has Q-4 (Gln-4) and both toxins have F-5 (Phe-5) and Y-28 (Tyr-28) strongly suggests that NeuTX-I and NeuTX-II are Asp49 PLA 2 .

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Section: Discussionmentioning

confidence: 98%

Purification and n-terminal sequencing of two presynaptic neurotoxic PLA2, neuwieditoxin-I and neuwieditoxin-II, from Bothrops neuwiedi pauloensis (jararaca pintada) venom

Oliveira¹,

Kassab²,

Soares³

et al. 2007

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

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“…This region is able to disorganize lipid bilayers owing to its cationic-hydrophobic property. The dimeric character of many Lys49 PLA 2 s may contribute to their mechanism of action by allowing a change in quaternary structure that favours membrane contact and penetration [93,94]. In addition, the dimeric character of these toxins may enhance their membrane-damaging effects by increasing binding affinity owing to the divalent interaction, as opposed to the monovalent binding of monomers; the latter ones are still capable of exerting myotoxicity and cytotoxicity, though with a lower potency than the dimers [22,95].…”

Section: Membrane Damagementioning

confidence: 95%

Cellular pathology induced by snake venom phospholipase A2 myotoxins and neurotoxins: common aspects of their mechanisms of action

Montecucco

Gutiérrez

Lomonte

2008

Cell. Mol. Life Sci.

261

163

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A large variety of snake toxins evolved from PLA(2) digestive enzymes through a process of 'accelerated evolution'. These toxins have different tissue targets, membrane receptors and mechanisms of alteration of the cell plasma membrane. Two of the most commonly induced effects by venom PLA(2)s are neurotoxicity and myotoxicity. Here, we will discuss how these snake toxins achieve a similar cellular lesion, which is evolutionarily highly conserved, despite the differences listed above. They cause an initial plasma membrane perturbation which promotes a large increase of the cytosolic Ca(2+) concentration leading to cell degeneration, following modes that we discuss in detail for muscle cells and for the neuromuscular junction. The different systemic pathophysiological consequences caused by these toxins are not due to different mechanisms of cell toxicity, but to the intrinsic anatomical and physiological properties of the targeted tissues and cells.

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“…Poucos estudos já foram publicados com PLA 2 s ácidas de peçonhas de serpentes brasileiras (FULY et al, 1997;SERRANO et al, 1999;ANDRIÃO-ESCARSO et al, 2002;KETELHUT et al, 2003;ROBERTO et al, 2004a, b ;MAGRO et al, 2003;2005;COGO et al, 2006;MODESTO et al, 2006;RODRIGUES et al, 2007 …”

Section: Discussão E Conclusãounclassified

Caracterização funcional e estrutural de uma fosfolipase A2 ácida tóxica isolada da peçonha de Bothrops moojeni

Filho¹,

Alves²

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Crystal structures of BnSP-7 and BnSP-6, two Lys49-phospholipases A2: quaternary structure and inhibition mechanism insights

Cited by 70 publications

References 32 publications

Purification and n-terminal sequencing of two presynaptic neurotoxic PLA2, neuwieditoxin-I and neuwieditoxin-II, from Bothrops neuwiedi pauloensis (jararaca pintada) venom

Purification and n-terminal sequencing of two presynaptic neurotoxic PLA2, neuwieditoxin-I and neuwieditoxin-II, from Bothrops neuwiedi pauloensis (jararaca pintada) venom

Cellular pathology induced by snake venom phospholipase A2 myotoxins and neurotoxins: common aspects of their mechanisms of action

Caracterização funcional e estrutural de uma fosfolipase A2 ácida tóxica isolada da peçonha de Bothrops moojeni

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