Abstract
Phospholipases A2 constitute the major components from Bothrops snake venoms and have been extensively investigated not only because they are relatively very abundant in these venoms but mainly because they display a range of many relevant biological effects, including: myotoxic, cytotoxic, edemainducing, artificial membrane disrupting, anticoagulant, neuromuscular, platelet aggregation inhibiting, hypotensive, bactericidal, anti-HIV, anti-tumoural, anti-malarial and anti-parasitic. The primary structures of several PLA2s have been elucidated through direct amino acid sequencing or, inderectly, through the corresponding nucleotide sequencing. Two main subgroups were thus described: (i) Asp49 PLA2s, showing low (basic, highly myotoxic) to relatively high (acidic, less or non myotoxic) Ca++-dependent hydrolytic activity upon artificial substrates; (ii) Lys49 PLA2s (basic, highly myotoxic), showing no detectable hydrolytic activity on artificial substrates. Several crystal structures of Lys49 PLA2s from genus Bothrops have already been solved, revealing very similar fold patterns. Lack of catalytic activity of myotoxic Lys49- PLA2s, first related solely with the fact that Lys49 occupies the position of the calcium ion in the catalyticly active site of Asp49 PLA2s, is now also attributed to Lys122 which interacts with the carbonyl of Cys29 hyperpolarising the peptide bond between Cys29 and Gly30 and trapping the fatty acid product in the active site, thus interrupting the catalytic cycle. This hypothesis, supported for three recent structures, is also discussed here. All Asp49 myotoxins showed to be pharmacologically more potent when compared with the Lys49 variants, but phospholipid hydrolysis is not an indispensable condition for the myotoxic, cytotoxic, bactericidal, anti-HIV, anti-parasitic, liposome disrupting or edema-inducing activities. Recent studies on site directed mutagenesis of the recombinant Lys49 myotoxin from Bothrops jararacussu revealed the participation of important amino acid residues in the membrane damaging and myotoxic activities.
Keywords: inflammatory human diseases, envenomation, prostaglandins, prostacyclins, tromboxanes, leucotrienes, myonecrosis
Call for Papers in Thematic Issues
Catalytic C-H bond activation as a tool for functionalization of heterocycles
The major topic is the functionalization of heterocycles through catalyzed C-H bond activation. The strategies based on C-H activation not only provide straightforward formation of C-C or C-X bonds but, more importantly, allow for the avoidance of pre-functionalization of one or two of the cross-coupling partners. The beneficial impact of ...read more
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