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.

Membrane-active toxins from snake venom have been used previously to study protein-lipid interactions and to probe the physical and biochemical states of biomembranes. To extend these studies, we have isolated from Naja naja kaowthia (cobra) venom a cytotoxin free of detectable phospholipase A2 (PLA2). The amino acid composition, pI (10.2), and net charge of the cytotoxin compares well with membrane-active toxins isolated from venoms of other cobras. The cytotoxin, shown by a spin label method, associates with PLA2 in buffers at pH values between 7.0 and 5.0, but not at pH 4.0. It is suggested that cytotoxin and PLA2 (pI close to 4.8) associate electrostatically in the native venom. The effect of the cytotoxin on model phospholipid membranes was studied by EPR of spin probes in oriented lipid multilayers and 1H-NMR of sonicated liposomes. The cytotoxin did not significantly affect the packing of lipids in pure phosphatidylcholine (PC) membranes and in PC membranes containing 10 mol% phosphatidic acid (PA) or cardiolipin (CL). However, the cytotoxin induced an increase in membrane permeability and formation of nonbilayer structures in PC membranes containing 40 mol% of PA or CL. The purified cytotoxin was cytocidal to Jurkat cells, but had little effect on normal human lymphocytes. However, both Jurkat cells and normal lymphocytes were killed equivalently when treated with 10(-9) m PLA2 and 10(-5) m cytotoxin in combination. From its effect on model membranes and Jurkat cells, it is suggested that purified cytotoxin preferentially targets and disrupts membranes that are rich in acidic phospholipids on the extracellular side of the plasma membrane.

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The metalloproteinase composition and biochemical profiles of rattlesnake venom can be highly variable among rattlesnakes of the same species. We have previously shown that the neurotoxic properties of the Mojave rattlesnake (Crotalus scutulatus scutulatus) are associated with the presence of the Mojave toxin A subunit suggesting the existence of a genetic basis for rattlesnake venom composition. In this report, we hypothesized the existence of a genetic basis for intraspecies variation in metalloproteinase-associated biochemical properties of rattlesnake venom of the Mojave rattlesnake. To address this question, we PCR-amplified and compared the genomic DNA nucleotide sequences that code for the mature metalloproteinase domain of fourteen Mojave rattlesnakes captured from different geographical locations across the southwest region of the United States. In addition, the venoms from the same rattlesnakes were tested for their ability to hydrolyze fibrinogen, fibrin, casein, and hide powder azure and for induction of hemorrhage in mice. Overall, based on genomic sequencing and biochemical data, we classified Mojave rattlesnake venom into four distinct groups of metalloproteinases. These findings indicate that differences in nucleotide sequences encoding the mature proteinase domain and noncoding regions contribute to differences in venom metalloproteinase activities among rattlesnakes of the same species.