Snakebites claim approximately 100,000 lives annually across the globe, posing a significant threat to public health. In a pioneering study, scientists from the Technical University of Munich (TUM) have delved into the evolutionary origins of snake toxins, shedding light on the development of these lethal substances over a period spanning 50 to 120 million years. Their findings have the potential to not only advance the treatment of snakebites but also deepen our understanding of treating conditions like type 2 diabetes and hypertension.
When a snake delivers venom into its prey or an unfortunate victim through a bite, the toxins within the venom interact with receptors on nerve and muscle cells, disrupting crucial communication pathways. This initial disruption results in paralysis and, in the absence of an antidote, can lead to death within minutes or hours. To decipher the intricate evolutionary history of these venomous proteins, a research team focused on a class of snake venoms known as three-finger toxins (3FTxs).
The Emergence of Three-Finger Toxins
Working alongside Burkhard Rost, a professor of bioinformatics, the researchers unraveled the origins of three-finger toxins, demonstrating their development from the Ly6 gene. Remarkably, this gene is not exclusive to snakes but is also found in mammals and other reptiles. It plays diverse roles in metabolic functions, encompassing cell immune responses and neural regulation.
Dr. Ivan Koludarov, a researcher at the Chair for Bioinformatics and one of the study's lead authors, remarks, "Previous research indicates that snakes diverged from other lizards around 120 million years ago. The split between present-day venomous snakes and other snake species occurred approximately 50 million years ago, and both groups already possessed functional 3FTx genes. This implies that the Ly6 gene underwent substantial modifications between 50 and 120 million years ago, leading to its current potent toxic effects."
Throughout evolution, the Ly6 gene, responsible for coding the toxin, underwent numerous duplications. Consequently, venomous snakes now carry multiple copies of this gene, each marked by various segments that have undergone mutations. These mutations have so profoundly altered the function of the encoded protein that it has transitioned into a lethal toxin.
Diverse Forms of Venom
Tobias Senoner, a doctoral candidate at the Chair for Bioinformatics, elaborates, "The gene underwent diverse mutations across different snake species. By examining the resulting protein structures, we can discern four distinct forms of the 3FTx toxin, each exhibiting unique structures and thereby exerting varying effects on the snake's prey."
Prof. Burkhard Rost elucidates, "For our research, we meticulously collated data from the UniProt database, which encompasses information on proteins from all living organisms and viruses. Furthermore, we accessed biomedical and genetic data from the National Center for Biotechnology Information. These datasets were meticulously analyzed through the lens of artificial intelligence."
Enhancements in Treatment and Drug Development
The insights gleaned from this groundbreaking study hold the promise of enhancing the treatment of snakebite victims and advancing drug development. The newfound understanding of these toxins could potentially catalyze the development of innovative treatments for conditions such as type 2 diabetes, hypertension, and more effective pain medications.
Koludarov, I., Senoner, T., Jackson, T.N.W. et al. Domain loss enabled evolution of novel functions in the snake three-finger toxin gene superfamily. Nat Commun 14, 4861 (2023). doi.org/10.1038/s41467-023-40550-0
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