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Snake Venom Cytotoxins, Phospholipase A2s, and Zn(2+)-dependent Metalloproteinases: Mechanisms of Action and Pharmacological Relevance.

Gasanov SE, Dagda RK, Rael ED - J Clin Toxicol (2014)

Bottom Line: We also propose biomedical applications whereby snake venom toxins can be employed for treating human diseases.Additionally, increasing our understanding of the molecular mechanism(s) by which snake venom PLA2s promote hydrolysis of cell membrane phospholipids can give insight into the underlying biomedical implications for treating autoimmune disorders that are caused by dysregulated endogenous PLA2 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.

View Article: PubMed Central - PubMed

Affiliation: Applied Mathematics and Informatics Department, Moscow State University Branch, 22 A. Timur Avenue, Tashkent 100060, Uzbekistan ; Science Department, Tashkent Ulugbek International School, 5-A J. Shoshiy Street, Tashkent 100100, Uzbekistan.

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 A2s (PLA2s), 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 PLA2s promote hydrolysis of cell membrane phospholipids can give insight into the underlying biomedical implications for treating autoimmune disorders that are caused by dysregulated endogenous PLA2 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.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram of a model by which cardiotoxins can form inverted micelles and translocate inside lipid bilayers. Cardiotoxin can imbed inside an inverted micelle (left panel) when trapped between two liposomes or two lipid bilayers (Figure 2). Cardiotoxins can also imbed inside cell membranes to form a transient inverted micelle from which the cytotoxin translocates to either the outer or the inner leaflet of the lipid bilayer with the hydrophilic portion (shaded) exposed to the bulk solvent while the hydrophobic region (non-shaded) of cardiotoxin interacts with phospholipid tails.
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Figure 3: Schematic diagram of a model by which cardiotoxins can form inverted micelles and translocate inside lipid bilayers. Cardiotoxin can imbed inside an inverted micelle (left panel) when trapped between two liposomes or two lipid bilayers (Figure 2). Cardiotoxins can also imbed inside cell membranes to form a transient inverted micelle from which the cytotoxin translocates to either the outer or the inner leaflet of the lipid bilayer with the hydrophilic portion (shaded) exposed to the bulk solvent while the hydrophobic region (non-shaded) of cardiotoxin interacts with phospholipid tails.

Mentions: In addition to binding to PS, some cytotoxins have the ability to interact with cardiolipin (CL) in vitro. For instance, N. oxiana cytotoxins interact with liposomes enriched with CL to form non-bilayer structures which results in the externalization of CL to the outer leaflet of liposomal membranes [14,46–48]. By using EPR, 1H-, 2H- and 31P-NMR spectroscopic techniques, we showed that Naja cytotoxins form intermembrane toxin-lipid complexes that resemble inverted micelles that are characterized by an isotropic orientation of the alkyl tails of phospholipids [16,47,48]. Such atypical lipid-based complexes with the cytotoxin positioned in the center of the micelle are produced when cell membranes of two cells interact prior to membrane fusion [16] (Figure 2). These unique lipid-protein complexes (also reported in a recent study by Forouhar et al. [49]) mediate not only cell membrane fusion, but also stimulate the transient formation of pores [49]. Following membrane fusion, an inverted micelle containing cytotoxins can insert into a bilayer of the fused cell (Figure 3) with the ensuing internalization of cytotoxin into the cytosol [47] and the translocation of cytotoxin to mitochondria [30,86,87] (Figure 5). Once bound to mitochondria, a cytotoxin internalizes into the mitochondrial intermembrane space and sequesters anionic phospholipids (CL and PS) located on the inner leaflet of the outer mitochondrial membrane (OMM) and promotes the formation of transient inverted micelles (Figure 4), which trigger the fusion of the OMM with the inner mitochondrial membrane (IMM) and the externalization of CL to the outer leaflet of the OMM. Furthermore, cytotoxin induces the permeabilization of the OMM and causes the subsequent release of cytochrome C [47]. In addition, cytotoxin promotes the formation of inverted micelles between adjacent membranes of the cristae (Figure 4) (our unpublished observations). This pathological event triggers the formation of transient pores [49] which should destabilize oxidative phosphorylation. Hence, given that externalization of CL of damaged mitochondria signals for mitochondrial autophagy (mitophagy) [88], it is possible to synthesize anti-cancer recombinant versions of cytotoxin that can selectively target mitochondria, overactivate mitophagy by inducing the externalization of CL leading to a decrease in oxidative phosphorylation, and induce a loss of ATP with detrimental consequences to cancer cells (Figure 5).


Snake Venom Cytotoxins, Phospholipase A2s, and Zn(2+)-dependent Metalloproteinases: Mechanisms of Action and Pharmacological Relevance.

Gasanov SE, Dagda RK, Rael ED - J Clin Toxicol (2014)

Schematic diagram of a model by which cardiotoxins can form inverted micelles and translocate inside lipid bilayers. Cardiotoxin can imbed inside an inverted micelle (left panel) when trapped between two liposomes or two lipid bilayers (Figure 2). Cardiotoxins can also imbed inside cell membranes to form a transient inverted micelle from which the cytotoxin translocates to either the outer or the inner leaflet of the lipid bilayer with the hydrophilic portion (shaded) exposed to the bulk solvent while the hydrophobic region (non-shaded) of cardiotoxin interacts with phospholipid tails.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4060629&req=5

Figure 3: Schematic diagram of a model by which cardiotoxins can form inverted micelles and translocate inside lipid bilayers. Cardiotoxin can imbed inside an inverted micelle (left panel) when trapped between two liposomes or two lipid bilayers (Figure 2). Cardiotoxins can also imbed inside cell membranes to form a transient inverted micelle from which the cytotoxin translocates to either the outer or the inner leaflet of the lipid bilayer with the hydrophilic portion (shaded) exposed to the bulk solvent while the hydrophobic region (non-shaded) of cardiotoxin interacts with phospholipid tails.
Mentions: In addition to binding to PS, some cytotoxins have the ability to interact with cardiolipin (CL) in vitro. For instance, N. oxiana cytotoxins interact with liposomes enriched with CL to form non-bilayer structures which results in the externalization of CL to the outer leaflet of liposomal membranes [14,46–48]. By using EPR, 1H-, 2H- and 31P-NMR spectroscopic techniques, we showed that Naja cytotoxins form intermembrane toxin-lipid complexes that resemble inverted micelles that are characterized by an isotropic orientation of the alkyl tails of phospholipids [16,47,48]. Such atypical lipid-based complexes with the cytotoxin positioned in the center of the micelle are produced when cell membranes of two cells interact prior to membrane fusion [16] (Figure 2). These unique lipid-protein complexes (also reported in a recent study by Forouhar et al. [49]) mediate not only cell membrane fusion, but also stimulate the transient formation of pores [49]. Following membrane fusion, an inverted micelle containing cytotoxins can insert into a bilayer of the fused cell (Figure 3) with the ensuing internalization of cytotoxin into the cytosol [47] and the translocation of cytotoxin to mitochondria [30,86,87] (Figure 5). Once bound to mitochondria, a cytotoxin internalizes into the mitochondrial intermembrane space and sequesters anionic phospholipids (CL and PS) located on the inner leaflet of the outer mitochondrial membrane (OMM) and promotes the formation of transient inverted micelles (Figure 4), which trigger the fusion of the OMM with the inner mitochondrial membrane (IMM) and the externalization of CL to the outer leaflet of the OMM. Furthermore, cytotoxin induces the permeabilization of the OMM and causes the subsequent release of cytochrome C [47]. In addition, cytotoxin promotes the formation of inverted micelles between adjacent membranes of the cristae (Figure 4) (our unpublished observations). This pathological event triggers the formation of transient pores [49] which should destabilize oxidative phosphorylation. Hence, given that externalization of CL of damaged mitochondria signals for mitochondrial autophagy (mitophagy) [88], it is possible to synthesize anti-cancer recombinant versions of cytotoxin that can selectively target mitochondria, overactivate mitophagy by inducing the externalization of CL leading to a decrease in oxidative phosphorylation, and induce a loss of ATP with detrimental consequences to cancer cells (Figure 5).

Bottom Line: We also propose biomedical applications whereby snake venom toxins can be employed for treating human diseases.Additionally, increasing our understanding of the molecular mechanism(s) by which snake venom PLA2s promote hydrolysis of cell membrane phospholipids can give insight into the underlying biomedical implications for treating autoimmune disorders that are caused by dysregulated endogenous PLA2 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.

View Article: PubMed Central - PubMed

Affiliation: Applied Mathematics and Informatics Department, Moscow State University Branch, 22 A. Timur Avenue, Tashkent 100060, Uzbekistan ; Science Department, Tashkent Ulugbek International School, 5-A J. Shoshiy Street, Tashkent 100100, Uzbekistan.

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 A2s (PLA2s), 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 PLA2s promote hydrolysis of cell membrane phospholipids can give insight into the underlying biomedical implications for treating autoimmune disorders that are caused by dysregulated endogenous PLA2 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.

No MeSH data available.


Related in: MedlinePlus