A SequenceSpace analysis of Lys49 phopholipases A2: clues towards identification of residues involved in a novel mechanism of membrane damage and in myotoxicity

Ward, Richard J.; Alves, Annabelle; Neto, J Ruggiero; Arni, R.K.; Casari, Giorgio

doi:10.1093/protein/11.4.285

Cited by 57 publications

(34 citation statements)

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“…Amino acid substitutions in the active site or Ca 21 -binding loop have been also reported in Group I and II PLA2s (Valentin and Lambeau, 2000). Among them, several catalytically inactive PLA2s from snake, where the critical Asp49 residue is substituted with Lys, Ser, or Arg, have been demonstrated to retain Ca 21 -independent pharmacological and antibacterial activities (Murakami et al, 2007;Paramo et al, 1998;Petan et al, 2007;Ward et al, 1998). These studies reveal that biological activities of venom PLA2s are not simply correlated with their catalytic properties, suggesting that the PLA2 of O. drewseni could have the Ca 21 -independent venomous activity regardless of its lack of catalytic activity.…”

Section: Discussionmentioning

confidence: 98%

“…The basic function of PLA2 is the hydrolysis of phospholipids to lysophospholipids and free fatty acids using Ca 21 as a co-factor (Six and Dennis, 2000). In addition, some catalytic venom PLA2s are known to have other physiological functions, including presynaptic and postsynaptic neurotoxicity (Bon et al, 1979), myotoxicity (Krizaj et al, 1991;Mebs and Samejima, 1986;Ward et al, 1998), hemolytic activity (Costa and Palma, 2000;de Oliveira and Palma, 1998;Ho and Ko, 1988), anticoagulant activity (Andriao-Escarso et al, 2002;Jabeen et al, 2005), and antibacterial activity (Nevalainen et al, 2008). Secretory PLA2s typically have 5-8 intramolecular disulfide bridges and a highly conserved active site and Ca 21 -binding loop (Scott et al, 1990a,b;Verheij et al, 1980;White et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

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Differential gene expression profiles in the venom gland/sac of Orancistrocerus drewseni (Hymenoptera: Eumenidae)

Baek

Woo

Kim

et al. 2009

Arch Insect Biochem Physiol

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To determine differential gene expression profiles in the venom gland and sac (gland/sac) of a solitary hunting wasp species, Orancistrocerus drewseni Saussure (1857), a subtractive cDNA library was constructed by suppression subtractive hybridization. A total of 498 expressed sequence tags (EST) were clustered and assembled into 205 contigs (94 multiple sequences and 111 singletons). About 65% (134) of the contigs had matched BLASTx hits (E< or =10(-4)). Among these, 115 contigs had similarity to proteins with assigned molecular function in the Gene Ontology database, and most of them (112 contigs, 83%) were homologous to genes from Hymenoptera, particularly to Apis mellifera (98 contigs). The contigs encoding hyaluronidase and phospholipase A2, known to be main components of wasp venoms, were found in high frequencies (27 and 4%, respectively, as judged by the number of ESTs) in the gene ontology category of catalytic activity. Full-length open reading frames of hyaluronidase and phospholipase A2 were characterized and their abundance in the venom gland/sac was confirmed by quantitative real-time PCR. Several contigs encoding enzymes, including zinc-metallopeptidases that are likely involved in the processing and activation of venomous proteins or peptides, were also identified from the library. Discovery of venom gland/sac-specific genes should promote further studies on biologically active components in the venom of O. drewseni.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Differential gene expression profiles in the venom gland/sac of Orancistrocerus drewseni (Hymenoptera: Eumenidae)

Baek

Woo

Kim

et al. 2009

Arch Insect Biochem Physiol

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“…The PLA 2 family is classified into two forms; cytosolic isoforms and secretary isoforms, involved in signal transduction pathway and inflammation pathway [8]. The catalytic mechanism of PLA 2 is common throughout the family with the conserved three-dimensional structure, but only at the sequence level, differences can be observed [9,10]. PLA 2 exists as monomer, dimer and trimeric form depending on the source [11].…”

Section: Inflammationmentioning

confidence: 99%

Phytochemical analysis, molecular docking and molecular dynamics simulations of selected phytoconstituents from four herbs as anti-dotes for snake bites

Subasri¹,

Viswanathan²,

Kesharwani³

et al. 2016

Clin Proteom Bioinform

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The Irula community constitutes a small tribal community living in different parts of India and their main occupation is snake catching. They have rich knowledge about medicinal plants and their uses against various ailments. Snake bites are the common acute medical emergency faced by rural people. Even though Anti Venom Serum (AVS) is used as a remedy for snake bites in hospitals and in primary health centres, the rural people still depend on antidotes from medicinal plants.To counter the emergencies due to snake bites, the plants/parts of the plants are used alone or in combinations with other plants to make anti-dotes. The survey reports thirty traditional medicinal plants which are used by Irula against snake bites. These plants must contain some compounds responsible for snake venom inhibition. Venom neutralization or anti-inflammatory properties of the compounds identified from these plants have not been reported. Our present study reports the phytochemical analysis of the extracts from four plants which are commonly found and some of these compounds are identified as anti-inflammatory agents. Screened compounds are chosen for finding the binding affinity with PLA2 targets using the commercial Schrodinger software. Molecular Dynamics simulations were also carried out for the most favourable compounds and stability was checked upto 50ns.

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“…A number of models have been proposed to account for the molecular basis of their pharmacological activities; however the structural determinants remain elusive [10,11,[14][15][16][17][18][19][20][21]. Lys49-PLA 2 homologues have also been implicated in the inhibition of the vascular endothelial growth factor [22] and exhibit broad antibacterial activities [23,24], indicating their clinical and biomedical relevance.…”

Section: Introductionmentioning

confidence: 99%

Crystallographic portrayal of different conformational states of a Lys49 phospholipase A2 homologue: Insights into structural determinants for myotoxicity and dimeric configuration

Ullah

Souza

Betzel

et al. 2012

International Journal of Biological Macromolecules

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Catalytically inactive phospholipase A(2) (PLA(2)) homologues play key roles in the pathogenesis induced by snake envenomation, causing extensive tissue damage via a mechanism still unknown. Although, the amino acid residues directly involved in catalysis are conserved, the substitution of Asp49 by Arg/Lys/Gln or Ser prevents the binding of the essential calcium ion and hence these proteins are incapable of hydrolyzing phospholipids. In this work, the crystal structure of a Lys49-PLA(2) homologue from Bothrops brazili (MTX-II) was solved in two conformational states: (a) native, with Lys49 singly coordinated by the backbone oxygen atom of Val31 and (b) complexed with tetraethylene glycol (TTEG). Interestingly, the TTEG molecule was observed in two different coordination cages depending on the orientation of the nominal calcium-binding loop and of the residue Lys49. These structural observations indicate a direct role for the residue Lys49 in the functioning of a catalytically inactive PLA(2) homologue suggesting a contribution of the active site-like region in the expression of pharmacological effects such as myotoxicity and edema formation. Despite the several crystal structures of Lys49-PLA(2) homologues already determined, their biological assembly remains controversial with two possible conformations. The extended dimer with the hydrophobic channel exposed to the solvent and the compact dimer in which the active site-like region is occluded by the dimeric interface. In the MTX-II crystal packing analysis was found only the extended dimer as a possible stable quaternary arrangement.

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A SequenceSpace analysis of Lys49 phopholipases A2: clues towards identification of residues involved in a novel mechanism of membrane damage and in myotoxicity

Cited by 57 publications

References 1 publication

Differential gene expression profiles in the venom gland/sac of Orancistrocerus drewseni (Hymenoptera: Eumenidae)

Differential gene expression profiles in the venom gland/sac of Orancistrocerus drewseni (Hymenoptera: Eumenidae)

Phytochemical analysis, molecular docking and molecular dynamics simulations of selected phytoconstituents from four herbs as anti-dotes for snake bites

Crystallographic portrayal of different conformational states of a Lys49 phospholipase A2 homologue: Insights into structural determinants for myotoxicity and dimeric configuration

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