Abstract
Venoms contain active substances with highly specific physiological effects and are increasingly being used as sources of novel diagnostic, research and treatment tools for human disease. Experimental characterisation of individual toxin activities is a severe rate-limiting step in the discovery process, and in-silico tools which allow function to be predicted from sequence information are essential. Toxins are typically members of large multifunctional families of structurally similar proteins that can have different biological activities, and minor sequence divergence can have significant consequences. Thus, existing predictive tools tend to have low accuracy. We investigated a classification model based on physico-chemical attributes that can easily be calculated from amino-acid sequences, using over 250 (mostly novel) viperid phospholipase A2 toxins. We also clustered proteins by sequence profiles, and carried out in-vitro tests for four major activities on a selection of isolated novel toxins, or crude venoms known to contain them. The majority of detected activities were consistent with predictions, in contrast to poor performance of a number of tested existing predictive methods. Our results provide a framework for comparison of active sites among different functional sub-groups of toxins that will allow a more targeted approach for identification of potential drug leads in the future.
Highlights
Animal toxins often form functionally diverse families, being based on a relatively limited number of basicAbbreviations used: PLA2, phospholipase A2; svPLA2, snake venom phospholipase A2; DFA, discriminant function analysis; MW, molecular weight; MALDI–TOF, matrix-assisted laser-desorption ionisation–timeof-flight; LC–ES, liquid chromatography–electrospray ionisation tandem.scaffolds yet achieving a diverse range of physiological effects through interaction with a multitude of molecular targets
We investigated a classification model based on physico-chemical attributes that can be calculated from amino-acid sequences, using over 250 viperid phospholipase A2 toxins
Full-length sequences of PLA2 genes ranging in length between 1832 and 2001 bp were obtained from 24 individuals of 20 nominal species
Summary
Animal toxins often form functionally diverse families, being based on a relatively limited number of basic. Scaffolds yet achieving a diverse range of physiological effects through interaction with a multitude of molecular targets. They offer a virtually unlimited pool of bioactive compounds with therapeutic and pharmacological potential, a fact which is attracting increasing interest in academic, industrial and medical arenas (King, 2011). Prescreening of newly identified compounds with in-silico techniques to identify functional hypotheses for subsequent experimental testing is highly desirable but limited by current levels of accuracy of many existing bioinformatics methods (Clark and Radivojac, 2010; Koonin, 2000).
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