Applied Venom Proteomics / Venomics
Zusammenfassung der Projektergebnisse
Proteome research, as the major component in the field of Systems Biology, is employed in the biological and pharmacological research as well as in the biotechnological research. Snake venom is the richest natural source of pharmacologically active compounds influencing important physiological processes, as hemostasis, blood coagulation, cardio-vascular and nervous systems. The complementary scientific and technical potentials of the German group from the University of Hamburg and the Brazilian research group from the Center for Structural Genomics of the University of Sao Jose do Rio Preto and Center for Applied Toxinology, Institute Butantan were combined to work most efficient on the research topics of the project entitled “Applied Venom Proteomics / Venomics”. The results of the joint investigations are of pharmacological, scientific and medical importance. The entire proteomes of four selected snake venoms were determined and published. All snakes, namely Crotalus durissus terrificus, Bothrops alternatus, Pseudechis australis and Daboia russelli siamensis, are of public health significance, the venom of the last one has been chosen from the World Health Organization as an International Reference Venom from the World Health Organization. Structural, functional, biotechnological and pharmacological properties of novel proteins from snake and insect venoms from the biodiversity of Europe, South America, Asia and Australia were determined and published. We isolated and characterized novel proteins affecting the hemostatic and nervous systems, breathing and intravascular hemolysis, and causing renal failure and increased capillary permeability. From each venom between 72 and 102 individual biologically active proteins were analyzed. We also demonstrated for the first time recruitment of (body) transferrin into the venomous system of a snake, which strongly supports the contemporary hypothesis that the venom toxins evolve from the recruitment of body proteins. We also analyzed comparativelly the venom peptidomic compositions of Vipera ammodytes ammodytes, the most toxic snake in Europe and the South American snake Bothrops jararacussu. Structures of a large number of bradykinin-potentiating peptides with a putative hypotensive action were identified and determined. The data published on this topic can be used for future drug discovery and design investigations to obtain a new generation of anti-hypertensive compounds. The high target specificity, small size, structural stability and the relative ease of chemical synthesis make venom peptides highly suitable for pharmaceutical applications and drug discovery investigations to treat diseases, which do not respond to currently available therapies. Moreover, it is possible to optimize their specificity towards target molecules and to improve the drug efficacy by chemical modifications. The crystal structures of pharmacologically important venom toxins, an L-amino acid oxidase with a cytolytic and apoptotic activity, and a myotoxin destroying body tissues were determined. The first structure explained the mechanism of the catalytic oxidative transformation of amino acids and the apoptotic effect of the toxin. The second one revealed determinants of myotoxicity and membrane damaging activity. Antigenic and allergenic epitopes were determined in the three-dimensional structural models of four honeybee venom allergens. The data can be used for the preparation of mutants with reduced IgE-binding capacity, suitable for immunotherapy. The venom proteomics and peptidomics we determined explained the clinical manifestation of the respective snakebites. Detailed summaries of the pharmacologically important components were prepared and published using the experimental data obtained about the venom compositions. These new data are useful for the prediction and adequate treatment of snake bite consequences and for the preparation of new generation of specific anti-venoms. The characterized snake venom proteins and peptides can be used as clinical biomarkers and for drug design and elucidation of mechanisms of health and diseases.
Projektbezogene Publikationen (Auswahl)
- “Proteome analysis of snake venom toxins: pharmacological insights”. Expert Rev. Proteomics 5, 787-797 (2008)
D. Georgieva, R. K. Arni, C. Betzel
(Siehe online unter https://doi.org/10.1586/14789450.5.6.787) - Snake venomics of the Siamese Russell’s viper (Daboia russelli siamensis) – relation to pharmacological activities. J. Proteomics 72, 256-269 (2009)
M. Risch, D. Georgieva, M. Von Bergen, N. Jehmlich, N. Genov, R. K. Arni, C. Betzel
(Siehe online unter https://doi.org/10.1016/j.jprot.2009.01.006) - Snake venomic of Crotalus durissus terrificus – correlation with pharmacological activities. J. Proteome Res. 9, 2302-2316 (2010)
D. Georgieva, M. Öhler, J. Seifert, M. von Bergen, R. K. Arni, N. Genov and Ch. Betzel
(Siehe online unter https://doi.org/10.1021/pr901042p) - The venomic of Bothrops alternatus is a pool of acidic proteins with predominant hemorrhagic and coagulopathic activities. J. Proteome Res. 9, 2422-2437 (2010)
M. Öhler, D. Georgieva, J. Seifert, M. von Bergen, R. K. Arni, N. Genov, C. Betzel
(Siehe online unter https://doi.org/10.1021/pr901128x) - Three-dimensional model of the honeybee venom allergen Api m 7: structural and functional insights. Mol. BioSystems 6, 1056-1060 (2010)
D. Georgieva, K. Greunke, C. Betzel
(Siehe online unter https://doi.org/10.1039/B923127G) - Enzymatic toxins from snake venom: Structural characterization and mechanism of catalysis. FEBS J. 278, 4544-4576 (2011)
T. S. Kang, D. Georgieva, N. Genov, M. T. Murakami, M. Sinha, R. P. Kumar, P. Kaur, S. Kumar, S. Dey, S. Sharma, A. Vrielink, C. Betzel, S. Takeda, R. K. Arni, T. P. Singh, R. M. Kini
(Siehe online unter https://doi.org/10.1111/j.1742-4658.2011.08115.x) - Pseudechis Australis venomics: adaptation for a defence against microbial pathogens and recruitment of body transferrin. J. Proteome Res. 10, 2440-2464 (2011)
D. Georgieva, J. Seifert, M. Öhler, M. von Bergen, P. Spencer, R. K. Arni, N. Genov , C. Betzel
(Siehe online unter https://doi.org/10.1021/pr101248e) - The structure of a native L-amino acid oxidase, the major component of the Vipera ammodytes ammodytes venomic, reveals dynamic active site and quaternary structure stabilization by divalent ions. Molec. BioSystems 7, 379-384 (2011)
D. Georgieva, M. Murakami, M. Perbandt, R. K. Arni, C. Betzel
(Siehe online unter https://doi.org/10.1039/C0MB00101E) - Venom peptide analysis of Vipera ammodytes meridionalis (Viperinae) and Bothrops jararacussu (Crotalinae) demonstrates subfamily-specificity of the peptidome in the family Viperidae. Mol. Biosystems 7, 3298-3307 (2011)
A. Munawar, M. Trusch, D. Georgieva, P. Spencer, V. Frochaux, S. Harder, R. K. Arni, D. Duhalov, N. Genov, H. Schlüter, C. Betzel
(Siehe online unter https://doi.org/10.1039/C1MB05309D)
