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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

A rendering of the 3D structure of crotoxin from Crotalus durissus terrificusA ribbon diagram of the dimeric crystal structure of crotoxin (PDB #3R0L) is illustrated to highlight the acidic subunit (left side) and to show the basic subunit (right side). 3D molecular rendering and annotations of crotoxin were performed by using the Swiss PDB Viewer software.
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Figure 6: A rendering of the 3D structure of crotoxin from Crotalus durissus terrificusA ribbon diagram of the dimeric crystal structure of crotoxin (PDB #3R0L) is illustrated to highlight the acidic subunit (left side) and to show the basic subunit (right side). 3D molecular rendering and annotations of crotoxin were performed by using the Swiss PDB Viewer software.

Mentions: The precise molecular mechanisms by which presynaptically-acting venom PLA2s (β-neurotoxins) cause neurotoxicity in snakebite victims has been the subject of high interest for several decades. Presynaptically-acting venom PLA2s can cause degeneration of the motor nerve terminals [106]. Structurally, neurotoxic PLA2s such as crotoxin from Crotalus durissus terrificus consists of an acidic subunit which targets the enzyme complex to the synaptic cleft, and a basic subunit which catalyzes the hydrolysis of phospholipids upon binding to specific synaptic proteins (Figure 6). However, the question of how these PLA2s are targeted to the synaptic cleft remains to be elucidated. A recent study partially addressed this question by characterizing the presynaptic effects of an ultrastructurally traceable modified version of ammodytoxin A (a β-neurotoxin), a neurotoxic protein of Vipera ammodytes [107]. In brief, this toxin-nanogold conjugate was intramuscularly injected in mice and their soleus muscles were isolated at different time points for ultrastructural analyses. The electron micrographs showed that this β-neurotoxin was internalized into the motor nerve terminal, followed by its translocation to mitochondria and into vesicular structures [107]. This work suggests that the β-neurotoxins are selectively targeted to synapses of motor neurons, where they are internalized at the synaptic boutons to block neurotransmission at the neuromuscular junction through poorly characterized molecular mechanisms. Other studies that utilized mass spectrometry techniques suggest an alternate toxic mechanism for β-neurotoxins. This model involves the hydrolysis of phospholipids at the plasma membrane after its association with specific protein target(s) in neurons [8]. Additionally, β-neurotoxins can induce the swelling of the axons and dendrites in neurons and this pathological event was associated with a robust Ca2+ influx and mitochondrial pathology induced by phospholipid hydrolysis of mitochondrial membranes [9]. Furthermore, β-neurotoxins bind specifically to mitochondria and induce the opening of the permeability transition pores in mitochondria which stimulate downstream apoptosis [9].


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)

A rendering of the 3D structure of crotoxin from Crotalus durissus terrificusA ribbon diagram of the dimeric crystal structure of crotoxin (PDB #3R0L) is illustrated to highlight the acidic subunit (left side) and to show the basic subunit (right side). 3D molecular rendering and annotations of crotoxin were performed by using the Swiss PDB Viewer software.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: A rendering of the 3D structure of crotoxin from Crotalus durissus terrificusA ribbon diagram of the dimeric crystal structure of crotoxin (PDB #3R0L) is illustrated to highlight the acidic subunit (left side) and to show the basic subunit (right side). 3D molecular rendering and annotations of crotoxin were performed by using the Swiss PDB Viewer software.
Mentions: The precise molecular mechanisms by which presynaptically-acting venom PLA2s (β-neurotoxins) cause neurotoxicity in snakebite victims has been the subject of high interest for several decades. Presynaptically-acting venom PLA2s can cause degeneration of the motor nerve terminals [106]. Structurally, neurotoxic PLA2s such as crotoxin from Crotalus durissus terrificus consists of an acidic subunit which targets the enzyme complex to the synaptic cleft, and a basic subunit which catalyzes the hydrolysis of phospholipids upon binding to specific synaptic proteins (Figure 6). However, the question of how these PLA2s are targeted to the synaptic cleft remains to be elucidated. A recent study partially addressed this question by characterizing the presynaptic effects of an ultrastructurally traceable modified version of ammodytoxin A (a β-neurotoxin), a neurotoxic protein of Vipera ammodytes [107]. In brief, this toxin-nanogold conjugate was intramuscularly injected in mice and their soleus muscles were isolated at different time points for ultrastructural analyses. The electron micrographs showed that this β-neurotoxin was internalized into the motor nerve terminal, followed by its translocation to mitochondria and into vesicular structures [107]. This work suggests that the β-neurotoxins are selectively targeted to synapses of motor neurons, where they are internalized at the synaptic boutons to block neurotransmission at the neuromuscular junction through poorly characterized molecular mechanisms. Other studies that utilized mass spectrometry techniques suggest an alternate toxic mechanism for β-neurotoxins. This model involves the hydrolysis of phospholipids at the plasma membrane after its association with specific protein target(s) in neurons [8]. Additionally, β-neurotoxins can induce the swelling of the axons and dendrites in neurons and this pathological event was associated with a robust Ca2+ influx and mitochondrial pathology induced by phospholipid hydrolysis of mitochondrial membranes [9]. Furthermore, β-neurotoxins bind specifically to mitochondria and induce the opening of the permeability transition pores in mitochondria which stimulate downstream apoptosis [9].

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