Snake venom metalloproteinases.
TL;DR: This chapter discusses the multiple activities of the SVMPs, which have fibrin(ogen)olytic activity, act as prothrombin activators, activate blood coagulation factor X, possess apoptotic activity, inhibit platelet aggregation, are pro-inflammatory and inactivate blood serine proteinase inhibitors.
About: This article is published in Toxicon.The article was published on 2013-02-01. It has received 284 citations till now.
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TL;DR: This work has provided the most complete characterization of the genes expressed in an active snake venom gland to date, producing insights into snakebite pathology and guidance for snakebite treatment for the largest rattlesnake species and arguably the most dangerous snake native to the United States of America, C. adamanteus.
Abstract: Snake venoms have significant impacts on human populations through the morbidity and mortality associated with snakebites and as sources of drugs, drug leads, and physiological research tools. Genes expressed by venom-gland tissue, including those encoding toxic proteins, have therefore been sequenced but only with relatively sparse coverage resulting from the low-throughput sequencing approaches available. High-throughput approaches based on 454 pyrosequencing have recently been applied to the study of snake venoms to give the most complete characterizations to date of the genes expressed in active venom glands, but such approaches are costly and still provide a far-from-complete characterization of the genes expressed during venom production. We describe the de novo assembly and analysis of the venom-gland transcriptome of an eastern diamondback rattlesnake (Crotalus adamanteus) based on 95,643,958 pairs of quality-filtered, 100-base-pair Illumina reads. We identified 123 unique, full-length toxin-coding sequences, which cluster into 78 groups with less than 1% nucleotide divergence, and 2,879 unique, full-length nontoxin coding sequences. The toxin sequences accounted for 35.4% of the total reads, and the nontoxin sequences for an additional 27.5%. The most highly expressed toxin was a small myotoxin related to crotamine, which accounted for 5.9% of the total reads. Snake-venom metalloproteinases accounted for the highest percentage of reads mapping to a toxin class (24.4%), followed by C-type lectins (22.2%) and serine proteinases (20.0%). The most diverse toxin classes were the C-type lectins (21 clusters), the snake-venom metalloproteinases (16 clusters), and the serine proteinases (14 clusters). The high-abundance nontoxin transcripts were predominantly those involved in protein folding and translation, consistent with the protein-secretory function of the tissue. We have provided the most complete characterization of the genes expressed in an active snake venom gland to date, producing insights into snakebite pathology and guidance for snakebite treatment for the largest rattlesnake species and arguably the most dangerous snake native to the United States of America, C. adamanteus. We have more than doubled the number of sequenced toxins for this species and created extensive genomic resources for snakes based entirely on de novo assembly of Illumina sequence data.
269 citations
TL;DR: The present review will highlight the non-catalytic ancillary domains of P-III SVMPs and ADAMs that may target the enzymes to specific substrates that may facilitate loss of blood from the vasculature of the prey.
172 citations
TL;DR: Recent findings on the regulation of platelet function by ROS are discussed, focusing on GPVI-dependent platelet activation and thrombus formation.
Abstract: Reactive oxygen species (ROS) are generated within activated platelets and play an important role in regulating platelet responses to collagen and collagen-mediated thrombus formation. As a major collagen receptor, platelet-specific glycoprotein (GP)VI is a member of the immunoglobulin (Ig) superfamily, with two extracellular Ig domains, a mucin domain, a transmembrane domain and a cytoplasmic tail. GPVI forms a functional complex with the Fc receptor γ-chain (FcRγ) that, following receptor dimerization, signals via an intracellular immunoreceptor tyrosine-based activation motif (ITAM), leading to rapid activation of Src family kinase signaling pathways. Our previous studies demonstrated that an unpaired thiol in the cytoplasmic tail of GPVI undergoes rapid oxidation to form GPVI homodimers in response to ligand binding, indicating an oxidative submembranous environment in platelets after GPVI stimulation. Using a redox-sensitive fluorescent dye (H2DCF-DA) in a flow cytometric assay to measure changes in intracellular ROS, we showed generation of ROS downstream of GPVI consists of two distinct phases: an initial Syk-independent burst followed by additional Syk-dependent generation. In this review, we will discuss recent findings on the regulation of platelet function by ROS, focusing on GPVI-dependent platelet activation and thrombus formation.
157 citations
TL;DR: Experimental evidence suggests that degradation of type IV collagen, and perhaps also perlecan, is the key event in the onset of microvessel damage, and it is necessary to study this phenomenon from a holistic, systemic perspective in which the action of other venom components is also taken into consideration.
Abstract: The historical development of discoveries and conceptual frames for understanding the hemorrhagic activity induced by viperid snake venoms and by hemorrhagic metalloproteinases (SVMPs) present in these venoms is reviewed. Histological and ultrastructural tools allowed the identification of the capillary network as the main site of action of SVMPs. After years of debate, biochemical developments demonstrated that all hemorrhagic toxins in viperid venoms are zinc-dependent metalloproteinases. Hemorrhagic SVMPs act by initially hydrolyzing key substrates at the basement membrane (BM) of capillaries. This degradation results in the weakening of the mechanical stability of the capillary wall, which becomes distended owing of the action of the hemodynamic biophysical forces operating in the circulation. As a consequence, the capillary wall is disrupted and extravasation occurs. SVMPs do not induce rapid toxicity to endothelial cells, and the pathological effects described in these cells in vivo result from the mechanical action of these hemodynamic forces. Experimental evidence suggests that degradation of type IV collagen, and perhaps also perlecan, is the key event in the onset of microvessel damage. It is necessary to study this phenomenon from a holistic, systemic perspective in which the action of other venom components is also taken into consideration.
149 citations
Cites background from "Snake venom metalloproteinases."
...The detailed analysis of the biochemical characterization of SVMPs, as well their molecular evolution after the recruitment of an ADAM-like gene early on in the course of advanced snakes diversification are beyond the scope of this review; readers are referred to excellent publications on these topics [33,35,36]....
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...In turn, several subclasses have been described within each class, depending on whether they are monomers or homo- or heterodimers, and also on the variable patterns of post-translational cleavage of several domains [35]....
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TL;DR: Despite the proteomic variations, the use of Thai monovalent and polyvalent antivenoms for N. kaouthia envenomation in the three regions is appropriate as the different venoms were neutralized by the antivenom albeit at different degrees of effectiveness, supporting their uses in theThree populations.
141 citations
References
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TL;DR: X‐ray crystal structures of two zinc endopeptidases, astacin from crayfish and adamalysin II from snake venom, reveal a strong overall topological equivalence and virtually identical extended HEXXHXXGXXH zinc‐binding segments, but in addition a methionine‐containing turn of similar conformation (the ‘Met‐turn’), which forms a hydrophobic basis for the zinc ion and the three liganding histidine residues.
725 citations
TL;DR: This review is focused on those venom constituents which affect the blood coagulation pathway, endothelial cells, and platelets, and contains a large number of disintegrins, which act as fibrinogen receptor (integrin GPIIb/IIIa) antagonists.
607 citations
TL;DR: The history of hemorrhagic toxin research is discussed with emphasis on the Crotalus atrox proteinases, the structural similarities observed among the hemorrhagic toxins are outlined, and the structural relationships of the toxins to the mammalian reproductive proteins are described.
544 citations
TL;DR: What the reader will observe is that there are very interesting structural features displayed by the various SVMP classes and subclasses that provide insight into their functional characteristics.
488 citations
TL;DR: The three‐dimensional structure of the alkaline protease of Pseudomonas aeruginosa, a zinc metalloprotease, has been solved to a resolution of 1.64 A by multiple isomorphous replacement and non‐crystallographic symmetry averaging between different crystal forms.
Abstract: The three-dimensional structure of the alkaline protease of Pseudomonas aeruginosa, a zinc metalloprotease, has been solved to a resolution of 1.64 A by multiple isomorphous replacement and non-crystallographic symmetry averaging between different crystal forms. The molecule is elongated with overall dimensions of 90 x 35 x 25 A; it has two distinct structural domains. The N-terminal domain is the proteolytic domain; it has an overall tertiary fold and active site zinc ligation similar to that of astacin, a metalloprotease isolated from a European freshwater crayfish. The C-terminal domain consists of a 21-strand beta sandwich. Within this domain is a novel 'parallel beta roll' structure in which successive beta strands are wound in a right-handed spiral, and in which Ca2+ ions are bound within the turns between strands by a repeated GGXGXD sequence motif, a motif that is found in a diverse group of proteins secreted by Gram-negative bacteria.
474 citations