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1.
J Proteome Res ; 18(5): 2287-2309, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31017792

RESUMO

The nose-horned viper, its nominotypical subspecies Vipera ammodytes ammodytes ( Vaa), in particular, is, medically, one of the most relevant snakes in Europe. The local and systemic clinical manifestations of poisoning by the venom of this snake are the result of the pathophysiological effects inflicted by enzymatic and nonenzymatic venom components acting, most prominently, on the blood, cardiovascular, and nerve systems. This venom is a very complex mixture of pharmacologically active proteins and peptides. To help improve the current antivenom therapy toward higher specificity and efficiency and to assist drug discovery, we have constructed, by combining transcriptomic and proteomic analyses, the most comprehensive library yet of the Vaa venom proteins and peptides. Sequence analysis of the venom gland cDNA library has revealed the presence of messages encoding 12 types of polypeptide precursors. The most abundant are those for metalloproteinase inhibitors (MPis), bradykinin-potentiating peptides (BPPs), and natriuretic peptides (NPs) (all three on a single precursor), snake C-type lectin-like proteins (snaclecs), serine proteases (SVSPs), P-II and P-III metalloproteinases (SVMPs), secreted phospholipases A2 (sPLA2s), and disintegrins (Dis). These constitute >88% of the venom transcriptome. At the protein level, 57 venom proteins belonging to 16 different protein families have been identified and, with SVSPs, sPLA2s, snaclecs, and SVMPs, comprise ∼80% of all venom proteins. Peptides detected in the venom include NPs, BPPs, and inhibitors of SVSPs and SVMPs. Of particular interest, a transcript coding for a protein similar to P-III SVMPs but lacking the MP domain was also found at the protein level in the venom. The existence of such proteins, also supported by finding similar venom gland transcripts in related snake species, has been demonstrated for the first time, justifying the proposal of a new P-IIIe subclass of ancestral SVMP precursor-derived proteins.


Assuntos
Metaloproteases/genética , Proteoma/genética , RNA Mensageiro/genética , Transcriptoma , Venenos de Víboras/química , Viperidae/genética , Sequência de Aminoácidos , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Antivenenos/química , Antivenenos/metabolismo , Desintegrinas/classificação , Desintegrinas/genética , Desintegrinas/metabolismo , Biblioteca Gênica , Ontologia Genética , Lectinas Tipo C/classificação , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Metaloproteases/classificação , Metaloproteases/metabolismo , Anotação de Sequência Molecular , Peptídeos Natriuréticos/classificação , Peptídeos Natriuréticos/genética , Peptídeos Natriuréticos/metabolismo , Fosfolipases A2 Secretórias/classificação , Fosfolipases A2 Secretórias/genética , Fosfolipases A2 Secretórias/metabolismo , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Proteoma/classificação , Proteoma/metabolismo , Proteômica/métodos , RNA Mensageiro/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Serina Proteases/classificação , Serina Proteases/genética , Serina Proteases/metabolismo , Venenos de Víboras/genética , Venenos de Víboras/metabolismo , Viperidae/metabolismo
2.
Arch Inst Pasteur Tunis ; 84(1-4): 29-37, 2007.
Artigo em Francês | MEDLINE | ID: mdl-19388581

RESUMO

Biochemistry and pharmacology of snake venoms reveal structural and functional polymorphisms of proteins they contain. These lead their effects by their enzymatic activities (proteases, phospholipases A2, L-amino acid oxydases...) or by binding to membrane receptors. Disintegrin from snake venoms play a role as antagonists of cell adhesion and migration by binding integrins and blocking their function. Characterization of integrin antagonists from snake venom allows us understanding the function of some integrins providing new information to develop new therapeutic agents. In this review, we report classification and therapeutic implications of disintegrins. In particular the structural and the functional characteristics of lebestatin; a short disintegrin isolated from Tunisian Macrovipera lebetina snake venom.


Assuntos
Desintegrinas/classificação , Desintegrinas/uso terapêutico , Inibidores da Agregação Plaquetária/classificação , Inibidores da Agregação Plaquetária/uso terapêutico , Venenos de Serpentes/química , Animais , Adesão Celular , Desintegrinas/química , Desintegrinas/farmacologia , Integrinas/antagonistas & inibidores , Modelos Químicos , Modelos Moleculares , Metástase Neoplásica/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Tunísia
3.
Toxicon ; 45(8): 1063-74, 2005 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-15922775

RESUMO

Disintegrins represent a family of polypeptides present in the venoms of various vipers that selectively block the function of integrin receptors. Here, we review our current view and hypothesis on the emergence and the structural and functional diversification of disintegrins by accelerated evolution and the selective loss of disulfide bonds of duplicated genes. Research on disintegrins is relevant for understanding the biology of viper venom toxins, but also provides information on new structural determinants involved in integrin recognition that may be useful in basic and clinical research. The role of the composition, conformation, and dynamics of the integrin inhibitory loop acting in concert with the C-terminal tail in determining the selective inhibition of integrin receptors is discussed.


Assuntos
Desintegrinas/química , Desintegrinas/genética , Evolução Molecular , Modelos Moleculares , Venenos de Serpentes/metabolismo , Serpentes , Motivos de Aminoácidos/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Desintegrinas/classificação , Genes Duplicados , Integrinas/metabolismo , Dados de Sequência Molecular , Filogenia , Estrutura Terciária de Proteína , Alinhamento de Sequência , Relação Estrutura-Atividade
4.
Biochim Biophys Acta ; 1702(1): 111-9, 2004 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-15450855

RESUMO

To explore the venom diversity and systematics of pit vipers under the genus Protobothrops, the venom phospholipases A2 (PLA2s) of P. mangshanensis, P. elegans and P. tokarensis were purified and characterized for the first time. The results were compared with the corresponding venom data of other co-generic species including P. mucrosquamatus, P. flavoviridis and P. jerdonii. Based on sequence features at the N-terminal regions, we identified five PLA2 subtypes, i.e., the Asp49-PLA2s with N6, E6 or R6 substitution and the Lys49-PLA2. However, not all subtypes were expressed in each of the species. Venom N6-PLA2s from P. mangshanensis and P. tokarensis venom were weakly neurotoxic toward chick biventer cervicis tissue preparations. The venoms of P. tokarensis and P. flavoviridis contained identical PLA2 isoforms. In most Protobothrop disintegrins, sequences flanking the RGD-motif are conserved. Phylogenetic analyses based on amino acid sequences of both families of the acidic PLA2s and the disintegrins clarify that these species could belong to a monophyletic group.


Assuntos
Venenos de Crotalídeos/química , Desintegrinas/química , Fosfolipases A/química , Sequência de Aminoácidos , Animais , Venenos de Crotalídeos/classificação , Venenos de Crotalídeos/genética , Desintegrinas/classificação , Desintegrinas/genética , Dados de Sequência Molecular , Fosfolipases A/classificação , Fosfolipases A/genética , Fosfolipases A2 , Filogenia , Proteômica , Homologia de Sequência de Aminoácidos , Viperidae/genética , Viperidae/metabolismo
5.
Int J Biochem Cell Biol ; 36(6): 981-5, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15094112

RESUMO

ADAMTS proteases are complex secreted enzymes containing a prometalloprotease domain of the reprolysin type attached to an ancillary domain with a highly conserved structure that includes at least one thrombospondin type 1 repeat. Known functions of ADAMTS proteases include processing of procollagens and von Willebrand factor as well as catabolism of aggrecan, versican and brevican. They have been demonstrated to have important roles in connective tissue organization, coagulation, inflammation, arthritis, angiogenesis and cell migration. ADAMTS can be grouped into distinct clades within which there is conservation of modular organization, protein sequence, gene structure and possibly, of substrate preference. ADAMTS proteases are synthesized as zymogens, with constitutive proprotein convertase removal of the propeptide occurring prior to secretion. Their enzymatic specificity is heavily influenced by their ancillary domain, which plays a critical role in directing these enzymes to their substrates, the cell surface and the extracellular matrix.


Assuntos
Desintegrinas/química , Desintegrinas/metabolismo , Metaloendopeptidases/química , Metaloendopeptidases/metabolismo , Motivos de Aminoácidos/genética , Desintegrinas/classificação , Humanos , Metaloendopeptidases/classificação , Estrutura Terciária de Proteína/genética , Trombospondina 1/genética
6.
Development ; 130(19): 4665-72, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12925592

RESUMO

Several features of the pigment defect in belted (bt) mutant mice suggest that it occurs as a result of a defect in melanocyte development that is unique from those described for other classical white-spotting mutations. We report here that bt mice carry mutations in Adamts20, a novel member of the ADAMTS family of secreted metalloproteases. Adamts20 shows a highly dynamic pattern of expression in the developing embryo that generally precedes the appearance of melanoblasts in the same region, and is not expressed in the migrating cells themselves. Adamts20 shows remarkable homology with GON-1, an ADAMTS family protease required for distal tip cell migration in C. elegans. Our results suggest that the role of ADAMTS proteases in the regulation of cell migration has been conserved in mammalian development.


Assuntos
Desintegrinas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Melanócitos/fisiologia , Metaloendopeptidases/metabolismo , Mutação , Proteínas ADAM , Proteínas ADAMTS , Animais , Movimento Celular/fisiologia , Desintegrinas/química , Desintegrinas/classificação , Desintegrinas/genética , Embrião de Mamíferos/fisiologia , Humanos , Hibridização In Situ , Metaloendopeptidases/química , Metaloendopeptidases/classificação , Metaloendopeptidases/genética , Camundongos , Camundongos Endogâmicos C57BL , Filogenia , Pigmentação/genética , Pele/citologia , Pele/crescimento & desenvolvimento , Pele/metabolismo
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