Dissociation of enzymatic activity from lethality and pharmacological properties by carbamylation of lysines in Naja nigricollis and Naja naja atra snake venom phospholipases A2

Condrea, Eleonora; Fletcher, Jeffrey E.; Rapuano, Bruce E.; Yang, Chen-Chung; Rosenberg, Philïp

doi:10.1016/0041-0101(81)90108-2

Cited by 102 publications

(19 citation statements)

References 32 publications

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“…The enzymatic and pharmacological activities of venom PLA 2 s were characterized by Rosenberg and colleagues in 1981 [93]. Their experimental approach included chemically modifying PLA 2 s of variable toxicity followed by performing a variety of biochemical assessments of the modified enzymes.…”

Section: Phospholipase A2mentioning

confidence: 99%

“…Their experimental approach included chemically modifying PLA 2 s of variable toxicity followed by performing a variety of biochemical assessments of the modified enzymes. In addition, this research team used a variety of in vivo pharmacological assays that included determining the LD 50 in vivo , analyzed the effects of PLA 2 on neuromuscular preparations, measured cardiotoxicity, coagulation, and hemolysis [93]. Overall, their findings along with other reports [94] proposed a model suggesting that PLA 2 s interact with other protein targets located in phospholipid bilayers as an alternate mechanism of toxicity that does not involve phospholipid hydrolysis.…”

Section: Phospholipase A2mentioning

confidence: 99%

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Snake Venom Cytotoxins, Phospholipase A2s, and Zn2+-dependent Metalloproteinases: Mechanisms of Action and Pharmacological Relevance

2014

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Snake venom toxins are responsible for causing severe pathology and toxicity following envenomation including necrosis, apoptosis, neurotoxicity, myotoxicity, cardiotoxicity, profuse hemorrhage, and disruption of blood homeostasis. Clinically, snake venom toxins therefore represent a significant hazard to snakebite victims which underscores the need to produce more efficient anti-venom. Some snake venom toxins, however, have great potential as drugs for treating human diseases. In this review, we discuss the biochemistry, structure/function, and pathology induced by snake venom toxins on human tissue. We provide a broad overview of cobra venom cytotoxins, catalytically active and inactive phospholipase A 2 s (PLA 2 s), and Zn 2+ -dependent metalloproteinases. We also propose biomedical applications whereby snake venom toxins can be employed for treating human diseases. Cobra venom cytotoxins, for example, may be utilized as anti-cancer agents since they are efficient at destroying certain types of cancer cells including leukemia. Additionally, increasing our understanding of the molecular mechanism(s) by which snake venom PLA 2 s promote hydrolysis of cell membrane phospholipids can give insight into the underlying biomedical implications for treating autoimmune disorders that are caused by dysregulated endogenous PLA 2 activity. Lastly, we provide an exhaustive overview of snake venom Zn 2+ -dependent metalloproteinases and suggest ways by which these enzymes can be engineered for treating deep vein thrombosis and neurodegenerative disorders.

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Section: Phospholipase A2mentioning

confidence: 99%

Section: Phospholipase A2mentioning

confidence: 99%

Snake Venom Cytotoxins, Phospholipase A2s, and Zn2+-dependent Metalloproteinases: Mechanisms of Action and Pharmacological Relevance

2014

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“…In recent years considerable experimental evidence has been accumulated in support of this model (Lambeau et al 1989(Lambeau et al , 1997Stefansson et al 1990;Yen and Tzeng 1991;Krizaj et al 1994). The specific binding of PLA 2 to its protein target is conferred by the presence of a ''pharmacological site'' on its surface which is independent of the catalytic site (Condrea et al 1981;Rosenberg 1986;Kini andEvans 1987, 1989). As shown here, the natural substitution in this group of proteins occurs predominantly in surface residues and hence contributes directly toward modifying the molecular surface.…”

Section: Accelerated Evolution and Pharmacological Effectsmentioning

confidence: 99%

Accelerated Evolution and Molecular Surface of Venom Phospholipase A2 Enzymes

1999

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Multiple phospholipase A2 (PLA2) isoenzymes found in a single snake venom induce a variety of pharmacological effects. These multiple forms are formed by gene duplication and accelerated evolution of exons. We examined the amino acid sequences of 127 snake venom PLA2 enzymes and their homologues to study in which location most natural substitutions occur. Our data show that hot spots of amino acid substitutions in this group of proteins occur mostly on the surface. A logistic model correlating the substitution rates of each amino acid residue with their surface accessibility indicates that the probability of natural substitutions occurring in the fully exposed residue is 2.6-3.5 times greater than that of substitutions occurring in buried residues. These surface substitutions play a significant role in the evolution of new PLA2 isoenzymes by altering the specificity of targeting to various tissues or cells, resulting in distinct pharmacological effects. Thus natural substitutions in PLA2 enzymes, in contrast to popular belief, are not random substitutions but appear to be directed toward modifying the molecular surface.

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“…The basic enzyme is unique in its behavior toward natural substrates concerning the hydrolysis of E. coli membranes in the presence of a bactericidal permeability-increasing (BPI) protein from neutrophil sources (Chen et al, 1987;Forst et al, 1987). The acidic PLA 2 displays the ability to inhibit platelet aggregation (Chen et al, 1987); the neutral PLA 2 designated as agkistrodotoxin, is characterized by potent activity as a presynaptic neurotoxin (Kondo et al, 1989); while the basic PLA 2 , in common with some basic PLA 2 's from other sources, possesses the ability to hemolyze erythrocytes (Condrea et al, 1981;Shukla & Hanahan, 1981). The basic PLA 2 is highly homologous to the basic PLA 2 's from Agkistrodon halys Blomhof®i and from Trimeresurus¯avoviridis (95 and 83% sequence identity, respectively) (Pan et al, 1996;Forst et al, 1986;Kini et al, 1986) which show high anticoagulant activity (Verheij et al, 1980;Kini & Evans, 1987).…”

Section: Introductionmentioning

confidence: 99%

Structure of a Basic Phospholipase A₂fromAgkistrodon halysPallas at 2.13 Å Resolution

et al. 1998

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The basic phospholipase A 2 isolated from the venom of Agkistrodon halys Pallas (Agkistrodon blomhof®i Brevicaudus) is a hemolytic toxin and one of the few PLA 2 's capable of hydrolyzing the phospholipids of E. coli membranes in the presence of a bactericidal/ permeability-increasing protein (BPI) of neutrophils. The crystal structure has been determined and re®ned at 2.13 A Ê to a R factor of 16.5% (F > 3') with excellent stereochemistry. A superposition of the two molecules in the asymmetric unit gives an r.m.s. deviation of 0.326 A Ê for all C atoms. The re®ned structure allowed a detailed comparison with other PLA 2 species of known structures. The overall architecture is similar to those of other PLA 2 's with a few signi®cant differences. One of which is in the region connecting the N-terminal helix and the Ca 2+ -binding loop. Unexpectedly, the conformation of the peptide plane Cys29ÐGly30 in the Ca 2+ -binding loop is very different to that of other PLA 2 's. The amide NH of Gly30 does not point toward the proposed site for stabilization of the tetrahedral intermediate oxyanion of the substrate analogue. The structure includes four residues which occur less frequently in other PLA 2 's. His1, Arg6 and Trp70 located at the interfacial recognition site may play an important role in the interaction with aggregated substrates, while Trp77 contributes to the hydrophobic interactions between the -wing and the main body of the molecule. This structure analysis reveals that two clusters of basic residues are located at or near the interfacial recognition site, forming an asymmetric positively charge distribution. In contrast to the acidic isoform, the present enzyme is a dimer in the crystalline state. The special phospholipid hydrolysis behaviors are discussed in the light of the structure determined.

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Dissociation of enzymatic activity from lethality and pharmacological properties by carbamylation of lysines in Naja nigricollis and Naja naja atra snake venom phospholipases A2

Cited by 102 publications

References 32 publications

Snake Venom Cytotoxins, Phospholipase A2s, and Zn2+-dependent Metalloproteinases: Mechanisms of Action and Pharmacological Relevance

Snake Venom Cytotoxins, Phospholipase A2s, and Zn2+-dependent Metalloproteinases: Mechanisms of Action and Pharmacological Relevance

Accelerated Evolution and Molecular Surface of Venom Phospholipase A2 Enzymes

Structure of a Basic Phospholipase A₂fromAgkistrodon halysPallas at 2.13 Å Resolution

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Dissociation of enzymatic activity from lethality and pharmacological properties by carbamylation of lysines in Naja nigricollis and Naja naja atra snake venom phospholipases A2

Cited by 102 publications

References 32 publications

Snake Venom Cytotoxins, Phospholipase A2s, and Zn2+-dependent Metalloproteinases: Mechanisms of Action and Pharmacological Relevance

Snake Venom Cytotoxins, Phospholipase A2s, and Zn2+-dependent Metalloproteinases: Mechanisms of Action and Pharmacological Relevance

Accelerated Evolution and Molecular Surface of Venom Phospholipase A2 Enzymes

Structure of a Basic Phospholipase A2fromAgkistrodon halysPallas at 2.13 Å Resolution

Contact Info

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Structure of a Basic Phospholipase A₂fromAgkistrodon halysPallas at 2.13 Å Resolution