Snake Venom Cytotoxins, Phospholipase A2s, and Zn2+-dependent Metalloproteinases: Mechanisms of Action and Pharmacological Relevance

Abstract

Snake venom toxins are responsible for causing severe pathology and toxicity following envenomation including necrosis, apoptosis, neurotoxicity, myotoxicity, cardiotoxicity, profuse hemorrhage, and disruption of blood homeostasis. Clinically, snake venom toxins therefore represent a significant hazard to snakebite victims which underscores the need to produce more efficient anti-venom. Some snake venom toxins, however, have great potential as drugs for treating human diseases. In this review, we discuss the biochemistry, structure/function, and pathology induced by snake venom toxins on human tissue. We provide a broad overview of cobra venom cytotoxins, catalytically active and inactive phospholipase A 2 s (PLA 2 s), and Zn 2+ -dependent metalloproteinases. We also propose biomedical applications whereby snake venom toxins can be employed for treating human diseases. Cobra venom cytotoxins, for example, may be utilized as anti-cancer agents since they are efficient at destroying certain types of cancer cells including leukemia. Additionally, increasing our understanding of the molecular mechanism(s) by which snake venom PLA 2 s promote hydrolysis of cell membrane phospholipids can give insight into the underlying biomedical implications for treating autoimmune disorders that are caused by dysregulated endogenous PLA 2 activity. Lastly, we provide an exhaustive overview of snake venom Zn 2+ -dependent metalloproteinases and suggest ways by which these enzymes can be engineered for treating deep vein thrombosis and neurodegenerative disorders.

The possible role of nonbilayer structures in regulating ATP synthase activity in mitochondrial membranes

“…We have previously shown that phospholipids with rapid isotropic mobility on the NMR time scale are responsible for giving rise to the 31 P-NMR signal A, while immobilized phospholipids with an isotropic orientation of phosphate groups are responsible for generating the 31 P-NMR signal B [4, 5]. Signal B was detectable for both mitochondria examined at 15°C or at higher temperatures (Fig.…”

“…It is clear that this drastic change in temperature distorts the barrier properties of the mitochondrial membranes and decreases ATP synthase activity. An interesting finding is that treating mitochondria with CTII, which is an amphiphilic protein that is capable of entering the intermembrane space of mitochondria [4, 5], increased the intensity of nonbilayer signal B; this increase was accompanied by an increase in ATP synthase activity (Fig. 1).…”

“…This finding indicates that DCCD-BP and CTII have similar regions on their molecular surfaces that bind phospholipids, and thereby produce a population of immobilized phospholipids with a nonbilayer packing. As we have demonstrated previously, CTII interacts with the lipid bilayer in such a manner that the long molecular axis is parallel to the alkyl chains of lipids and perpendicular to the membrane surface [4]. By using the Auto-DockVina program, we obtained the hypothetical conformations that result from interactions of acidic phospholipids with CTII.…”

“…The mechanism of how H + protons are transferred from the intermembrane space into the mitochondrial matrix to induce the structural changes that arise in the F 0 subunits to trigger rotation of the rotor of the ATP synthase complex remain to be elucidated [3]. In this work, we analyzed the ATP-synthase activity of mitochondria and the changes in phospholipid packing in mitochondrial membranes in response to changes in temperature and upon treatment with the cobra snake venom membrane-active protein CTII, which interacts with phospholipids in a lipid phase similarly to the dicyclohexylcarbodiimide- binding protein (DCCD-BP) of the F 0 group [4]. In addition, computer modeling was used to study the interaction of the molecular surface of CTII with lipids found in the mitochondrial membrane, including phosphatidylcholine, cardiolipin, phosphatidic acid, and phosphatidylserine.…”

Ultrasound findings in 42 patients with cytotoxic tissue damage following bites by South African snakes

“…Snake cytotoxins create pores in cell membranes by acting on the phospholipid bilayers resulting in cytolysis 1. Phospholipase A 2 is one of the main venom enzymes that cause this effect.…”