Cellular Mechanisms of Action of Snake Phospholipase A2 Toxins

Abstract

Snake venoms contain a large amount of toxins endowed with phospholipase A2 (PLA2) activity. Despite an overall conserved structure, snake PLA2s display a variety of pharmacological activities that are the result of different cell targets and mode of actions. Here follows an overview of the present knowledge on the mechanism of action of the two main classes of snake PLA2s, myotoxins and neurotoxins, derived from in vivo, ex vivo, and in vitro models, along with a comparison with mammalian secreted PLA2 (sPLA2) homologues. In spite of many qualified efforts, several aspects of snake envenomation are still undefined, including the identification of specific receptors on nerve and muscle membranes. Further studies are required to elucidate the unclear molecular steps of snakebite intoxication that might contribute to shed light also on the mode of action of mammalian PLA2 counterparts. There is a high degree of homology in terms of primary structure between snake and mammalian sPLA2s, suggesting that snake PLA2 receptors might be also candidates for mammalian sPLA2s; this topic is of high relevance, in the light of the emerging involvement of mammalian sPLA2s in many human disorders

Bioassay-guided fractionation, phospholipase A2-inhibitory activity and structure elucidation of compounds from leaves of Schumanniophyton magnificum

“…However, while there are claims on its use traditionally for the treatment of snake bite and relieve of pain, there are no scientific reports on the use of its leaves for this purpose. Since local inflammation and pain are important features of snakebite envenomation due to increase in the activities of PLA 2 present in the venom (Tonello and Rigoni 2017), and S. magnificum has potential in inhibiting PLA 2 (Mohanapriya et al 2017;Sajon et al 2017), this study seeks to investigate and establish a scientific report on the anti-inflammatory effects of S. magnificum leaves via the inhibition of PLA 2 activity. It also seeks to investigate the nature of compounds responsible for the effects.…”

A Snake Venom-Secreted Phospholipase A2Induces Foam Cell Formation Depending on the Activation of Factors Involved in Lipid Homeostasis

“…sPLA 2 s are major protein components of Bothrops snake venoms and are classified into groups I and II, according to their biochemical and structural characteristics. Noteworthy, sPLA 2 s from Bothrops snake venoms share structural and functional features with mammalian inflammatory GIIA sPLA 2 s, which are found in high concentrations in inflammatory exudates [ 3 , 4 ]. Our group has previously demonstrated that an Asp49 sPLA 2 , named myotoxin-III (MT-III), isolated from Bothrops asper snake venom, activates inflammatory functions of macrophages, including formation of lipid droplets (LDs) and upregulation of perilipin 2 (PLIN2), a scaffold protein involved in LD assembly and macrophage differentiation into foam cells [ 5 – 7 ].…”

Nucleolin internalizes Bothrops asper Lys49 phospholipase A2 forming cell surface amyloid-like assemblies

“…Various pharmacological applications have been proposed to exploit the diverse functionalities of snake PLA 2 s, including antiviral and antitumoral activities. However, the basic mechanisms of these activities are not known (6)(7)(8).…”

“…Notwithstanding the many efforts made by several laboratories to identify myotoxic PLA 2 s receptors/acceptors in cell membranes, this search is still ongoing. Moreover, the internalization and possible interaction of these toxins with intracellular targets have not been explored (7).…”

“…A large subfamily of natural variants of snake PLA 2 s have no enzymatic activity, since they have a critical mutation at position 49: the aspartic acid is substituted by another amino acid (lysine in most cases), resulting in the impossibility to coordinate the calcium ion essential for catalysis. Despite the lack of catalytic activity, these PLA 2 homologues show a high myotoxic activity and other toxic effects (7,9).…”