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Hindawi Publishing CorporationBioMed Research InternationalVolume 2013, Article ID 243047, 2 pageshttp://dx.doi.org/10.1155/2013/243047

EditorialUnderstanding theMolecular Mechanism andStructure-Function Relationship of the Toxicity of PLA2 andK49 Homologs in Snake Venom

Luis Alberto Ponce-Soto,1 Laura Leiva,2 and Elen Cristina Teizem Landucci3

1 Department of Biochemistry, Institute of Biology, State University of Campinas (UNICAMP),CP 6109, 13083-970 Campinas, SP, Brazil

2 Laboratorio 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

3 Laboratório de In�ama��o, Departamento de Farmacologia, Faculdade de Ci�ncias M�dicas, Universidade Estadual deCampinas (UNICAMP), R. Tessália Vieira de Camargo, 126, Caixa Postal 6111, 13084-971 Campinas, SP, Brazil

Correspondence should be addressed to Luis Alberto Ponce-Soto; [email protected]

Received 20 December 2012; Accepted 20 December 2012

Copyright © 2013 Luis Alberto Ponce-Soto et al.is is an open access article distributed under theCreativeCommonsAttributionLicense, which permits unrestricted use, distribution, and reproduction in anymedium, provided the originalwork is properly cited.

e snake venom PLA2s, in association with the catalyticfunction that de�nes them, have developed a diverse set ofbiological functions which go beyond the purely digestive.Striking examples are the PLA2 that have evolved as tox-ins, either in conjunction with other proteins or by them-selves, and in spite of having a similar structural geometry,they exert an amazing variety of pharmacological effects,which include myotoxic, neurotoxic, hemolytic, edemato-genic, hyperalgesic, pro- and anti-in�ammatory, hypotensive,anticoagulant, platelet-aggregation inhibitory, and cytotoxic.�urthermore, since the �rst studies reported by Maraganoreet al. [1] to the present, in homologous K49 LA2 from snakevenom, have increased signi�cantly. Despite its inability tobind Ca2 ion co-factor crucial for catalytic activity, it iscapable of triggering toxic or pharmacological effects inde-pendent of PLA2 activity, thus opening a new understandingof the involvement of independent regions or domains ofthe catalytic site, postulated from Condrea et al. [2] andreinforced by Majunatha Kini and Evans [3]. e presentwork highlights some of the most relevant contributions inthe study of venom PLA2s, including the PLA2 homólogousK49.

is special issue of contains nine papers describingstructural and functional analysis of different PLA2 and PLA2

homólogous K49 from snakes. e review by C. V. Carregariand colleagues discusses the importance of the proin�amma-tory activity that characterized this new venom from Both-riopsis bilineata snake venom. e fact that Bbil-TX eliciteda stronger in�ammatory reaction argues in favor of a roleof enzymatic phospholipid hydrolysis in this phenomenon,either through the direct release of arachidonic acid fromplasma membranes or through activation of intracellularprocesses in target cells. I. G. Rodríguez et al. analyze, thePLA2s isolated fromPanamaBothrops asper venoms (pMTX-I, II, III, and IV), which are able to induce myotoxic activity,in�ammatory reaction, and mainly leukocyte migration tothe muscle and induce J774A.1 macrophages activation tostart phagocytic activity and superoxide production. J. Nelsonet al. make an important contribution to the study ofsynergistic effects of secretory PLA2 from the venom of Agk-istrodon piscivorus piscivorus with cancer chemotherapeuticagents. Healthy cells typically resist hydrolysis catalyzedby snake venom secretory PLA2. However, during variousforms of programmed cell death, they become vulnerable toattack by the enzyme. is observation raises the question ofwhether the speci�city of the enzyme for dying cells couldbe used as a strategy to eliminate tumor cells that havebeen intoxicated but not directly killed by chemotherapeutic

2 BioMed Research International

agents.is work suggests that exposure of lymphoma cells tothese drugs universally causes changes to the cell membranethat render it susceptible to enzymatic attack and that thesnake venom enzyme is not only capable of clearing cellcorpses but can aid in the demise of tumor cells that haveinitiated but not yet completed the death process. L. Wei etal. present a valuable contribution to the study of inductionin the accumulation of mast cells, promutoxin, a new variantof PLA2 R49. e action of an R49 PLA2s, promutoxin fromProtobothrops mucrosquamatus venom on mast cell accumu-lation, has not been previously examined. e promutoxin-inducedmast cell accumulationwas inhibited by cyprohepta-dine, terfenadine, and ginkgolide B, indicating that histamineand platelet activation factor (PAF) are likely to contributeto the mast cells accumulation. Preinjection of antibodiesagainst adhesion molecules ICAM-1, CD18, CD11a, andL-selectin showed that ICAM-1, CD18, and CD11a arekey adhesion molecules of promutoxin-induced mast cellaccumulation. Promutoxin, as a novel member of minorsubgroup of PLA2, is an enzymatically inactive enzyme. Itinduced mast cell accumulation via a PAF and histamine H1receptor-dependentmechanism and through a CD11a/CD18and ICAM-1 associated adhesion pathway. F. A. Marangoniet al. present an important contribution to the study structurefunction of a new PLA2 isolated from Bothrops leucurus.Kinetic and pharmacological studies illustrate a behaviorsimilar to other PLA2 from snake venom Viperidae; howeverfrom the structural point of view, in relation to the fewdifferences in its sequence, the contribution of each regionor domain, as well as each amino acid, has been crucial in theunderstanding of toxic or pharmacological activities.

S. Huancahuire-Vega et al. analyze the use of chemicalmodi�cations of a newPLA2 fromPorthidiumhyoprora snakevenom in the study structure-function relationships. eresults supported the hypothesis that both the catalytic sitesas the hypothetical pharmacological sites are relevant to thepharmacological pro�le of PhTX-I. K. Giannotti et al. discussan interesting study on the pathogenesis of the in�ammatoryprocess induced by a homologous K49 PLA2 from the venomof the snake Bothrops asper. e MT-II (PLA2 homologousK49) induces lipid droplet formation in macrophages thatdepends on distinct signaling pathways and the C-terminalregion. MT-II directly activates murine macrophages to formLDs by a mechanism independent of enzymatic activity. iseffect is related to the C-terminal loop of the MT-II moleculesince a synthetic peptide corresponding to region 115–129induced LD formation similarly to MT-II. Moreover, MT-II-induced LD formation is related to increased expression andrecruitment of PLIN2 from its constitutive pools and regu-lated by distinct signaling pathways that include PKC, PI3K,ERK1/2, and iPLA2. In addition, MT-II induced synthesisand compartmentalization of PGE2 within LDs. erefore,LDs may represent an important platform for the synthesisand accumulation of lipid mediators under MT-II stimulus,that takes place in the mechanisms whereby this PLA2homologous K49 triggers in�ammation. M. A. G. Heleno etal. conduct a major study on the structure-function basis ofa new PLA2 from Bothrops roedingerii, indicating that theirenzyme pro�les as toxic or pharmacological show similar

behavior to other PLA2. BrTX-I caused a neuromuscularblockade in biventer cervicis preparations in a similar wayto other Bothrops species. BrTX-I induced myonecrosis andoedema-forming activity analyzed through injection of thepuri�ed BrTX-I in mice. Since BrTX-I exert a strong proin-�ammatory effect, the enzymatic phospholipids hydrolysismight be relevant for these phenomena, incrementing levelsof IL-1, IL-6, and TNF𝛼𝛼.

e best approach to understanding structure-functionmechanisms of PLA2 from snake venoms will present acomprehensive view of toxinologists in different research�elds, including biochemistry, biophysics, pharmacology,toxicology, and medicine. We hope that this special issuewill encourage researchers to take on this challenge andincreasingly elucidate structure-function behavior of PLA2and K49 counterparts in snake venom.

Luis Alberto Ponce-SotoLaura Leiva

Elen Cristina Teizem Landucci

References

[1] J. M. Maraganore, G. Merutka, W. Cho et al., “A new class ofphospholipases A2 with lysine in place of aspartate 49. Func-tional consequences for calcium and substrate binding,” Journalof 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 lethalityand pharmacological properties by carbamylation of lysines inNaja nigricollis andNaja naja atra snake venom phospholipasesA2,” Toxicon, vol. 19, no. 5, pp. 705–720, 1981.

[3] R. Majunatha Kini and H. J. Evans, “A model to explain thepharmacological effects of snake venom phospholipases A2,”Toxicon, vol. 27, no. 6, pp. 613–635, 1989.

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