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BioMed Research International
Volume 2013 (2013), Article ID 243047, 2 pages
http://dx.doi.org/10.1155/2013/243047
Editorial

Understanding the Molecular Mechanism and Structure-Function Relationship of the Toxicity of PLA2 and K49 Homologs in Snake Venom

1Department of Biochemistry, Institute of Biology, State University of Campinas (UNICAMP), CP 6109, 13083-970 Campinas, SP, Brazil
2Laboratorio de Química Biológica, Departamento de Bioquímica, Facultad de Ciencias Exactas y Naturales y Agrimensura, Universidad Nacional del Nordeste (UNNE), Avenida Libertad 5470, Campus Universitario, CP 3400 Corrientes, Argentina
3Laboratório de Inflamação, Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), R. Tessália Vieira de Camargo, 126, Caixa Postal 6111, 13084-971 Campinas, SP, Brazil

Received 20 December 2012; Accepted 20 December 2012

Copyright © 2013 Luis Alberto Ponce-Soto et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


The snake venom PLA2s, in association with the catalytic function that defines them, have developed a diverse set of biological functions which go beyond the purely digestive. Striking examples are the PLA2 that have evolved as toxins, either in conjunction with other proteins or by themselves, and in spite of having a similar structural geometry, they exert an amazing variety of pharmacological effects, which include myotoxic, neurotoxic, hemolytic, edematogenic, hyperalgesic, pro- and anti-inflammatory, hypotensive, anticoagulant, platelet-aggregation inhibitory, and cytotoxic. Furthermore, since the first studies reported by Maraganore et al. [1] to the present, in homologous K49 PLA2 from snake venom, have increased significantly. Despite its inability to bind Ca2 ion co-factor crucial for catalytic activity, it is capable of triggering toxic or pharmacological effects independent of PLA2 activity, thus opening a new understanding of the involvement of independent regions or domains of the catalytic site, postulated from Condrea et al. [2] and reinforced by Majunatha Kini and Evans [3]. The present work highlights some of the most relevant contributions in the study of venom PLA2s, including the PLA2 homólogous K49.

This special issue of contains nine papers describing structural and functional analysis of different PLA2 and PLA2 homólogous K49 from snakes. The review by C. V. Carregari and colleagues discusses the importance of the proinflammatory activity that characterized this new venom from Bothriopsis bilineata snake venom. The fact that Bbil-TX elicited a stronger inflammatory reaction argues in favor of a role of enzymatic phospholipid hydrolysis in this phenomenon, either through the direct release of arachidonic acid from plasma membranes or through activation of intracellular processes in target cells. I. G. Rodríguez et al. analyze, the PLA2s isolated from Panama Bothrops asper venoms (pMTX-I, II, III, and IV), which are able to induce myotoxic activity, inflammatory reaction, and mainly leukocyte migration to the muscle and induce J774A.1 macrophages activation to start phagocytic activity and superoxide production. J. Nelson et al. make an important contribution to the study of synergistic effects of secretory PLA2 from the venom of Agkistrodon piscivorus piscivorus with cancer chemotherapeutic agents. Healthy cells typically resist hydrolysis catalyzed by snake venom secretory PLA2. However, during various forms of programmed cell death, they become vulnerable to attack by the enzyme. This observation raises the question of whether the specificity of the enzyme for dying cells could be used as a strategy to eliminate tumor cells that have been intoxicated but not directly killed by chemotherapeutic agents. This work suggests that exposure of lymphoma cells to these drugs universally causes changes to the cell membrane that render it susceptible to enzymatic attack and that the snake venom enzyme is not only capable of clearing cell corpses but can aid in the demise of tumor cells that have initiated but not yet completed the death process. L. Wei et al. present a valuable contribution to the study of induction in the accumulation of mast cells, promutoxin, a new variant of PLA2 R49. The action of an R49 PLA2s, promutoxin from Protobothrops mucrosquamatus venom on mast cell accumulation, has not been previously examined. The promutoxin-induced mast cell accumulation was inhibited by cyproheptadine, terfenadine, and ginkgolide B, indicating that histamine and platelet activation factor (PAF) are likely to contribute to the mast cells accumulation. Preinjection of antibodies against adhesion molecules ICAM-1, CD18, CD11a, and L-selectin showed that ICAM-1, CD18, and CD11a are key adhesion molecules of promutoxin-induced mast cell accumulation. Promutoxin, as a novel member of minor subgroup of PLA2, is an enzymatically inactive enzyme. It induced mast cell accumulation via a PAF and histamine H1 receptor-dependent mechanism and through a CD11a/CD18 and ICAM-1 associated adhesion pathway. F. A. Marangoni et al. present an important contribution to the study structure function of a new PLA2 isolated from Bothrops leucurus. Kinetic and pharmacological studies illustrate a behavior similar to other PLA2 from snake venom Viperidae; however from the structural point of view, in relation to the few differences in its sequence, the contribution of each region or domain, as well as each amino acid, has been crucial in the understanding of toxic or pharmacological activities.

S. Huancahuire-Vega et al. analyze the use of chemical modifications of a new PLA2 from Porthidium hyoprora snake venom in the study structure-function relationships. The results supported the hypothesis that both the catalytic sites as the hypothetical pharmacological sites are relevant to the pharmacological profile of PhTX-I. K. Giannotti et al. discuss an interesting study on the pathogenesis of the inflammatory process induced by a homologous K49 PLA2 from the venom of the snake Bothrops asper. The MT-II (PLA2 homologous K49) induces lipid droplet formation in macrophages that depends on distinct signaling pathways and the C-terminal region. MT-II directly activates murine macrophages to form LDs by a mechanism independent of enzymatic activity. This effect is related to the C-terminal loop of the MT-II molecule since a synthetic peptide corresponding to region 115–129 induced LD formation similarly to MT-II. Moreover, MT-II-induced LD formation is related to increased expression and recruitment of PLIN2 from its constitutive pools and regulated by distinct signaling pathways that include PKC, PI3K, ERK1/2, and iPLA2. In addition, MT-II induced synthesis and compartmentalization of PGE2 within LDs. Therefore, LDs may represent an important platform for the synthesis and accumulation of lipid mediators under MT-II stimulus, that takes place in the mechanisms whereby this PLA2 homologous K49 triggers inflammation. M. A. G. Heleno et al. conduct a major study on the structure-function basis of a new PLA2 from Bothrops roedingerii, indicating that their enzyme profiles as toxic or pharmacological show similar behavior to other PLA2. BrTX-I caused a neuromuscular blockade in biventer cervicis preparations in a similar way to other Bothrops species. BrTX-I induced myonecrosis and oedema-forming activity analyzed through injection of the purified BrTX-I in mice. Since BrTX-I exert a strong proinflammatory effect, the enzymatic phospholipids hydrolysis might be relevant for these phenomena, incrementing levels of IL-1, IL-6, and TNFα.

The best approach to understanding structure-function mechanisms of PLA2 from snake venoms will present a comprehensive view of toxinologists in different research fields, including biochemistry, biophysics, pharmacology, toxicology, and medicine. We hope that this special issue will encourage researchers to take on this challenge and increasingly elucidate structure-function behavior of PLA2 and K49 counterparts in snake venom.

Luis Alberto Ponce-Soto
Laura Leiva
Elen Cristina Teizem Landucci

References

  1. J. M. Maraganore, G. Merutka, W. Cho, et al., “A new class of phospholipases A2 with lysine in place of aspartate 49. Functional consequences for calcium and substrate binding,” Journal of Biological Chemistry, vol. 259, no. 22, pp. 13839–13843, 1984.
  2. E. Condrea, J. E. Fletcher, B. E. Rapuano, C. C. Yang, and P. Rosenberg, “Dissociation of enzymatic activity from lethality and pharmacological properties by carbamylation of lysines in Naja nigricollis and Naja naja atra snake venom phospholipases A2,” Toxicon, vol. 19, no. 5, pp. 705–720, 1981. View at Scopus
  3. R. Majunatha Kini and H. J. Evans, “A model to explain the pharmacological effects of snake venom phospholipases A2,” Toxicon, vol. 27, no. 6, pp. 613–635, 1989. View at Scopus