MEDCHEM E CHEMBIO Lecture 7 Toxins

• Toxins


  Substances created by plants and animals (living cell and organisms) that are poisonous to humans. Man-made substances are excluded by this definition.
• Toxins can be small molecules, peptides, or proteins that are capable of causing disease on contact with or absorption by body tissues interacting with biological macromolecules such as enzymes or cellular receptors
• Toxins


  • They vary greatly in their severity, ranging from usually minor and acute (as in a bee sting) to almost immediately deadly (as in botulinum toxin)
  • They are produced for predation and defence
• Types of toxins


  • Cyanotoxins (produced by cyanobacteria)
  • Hemotoxins (target and destroy red blood cells)
  • Necrotoxins (cause necrosis in cells)
  • Neurotoxins (affect the nervous systems)
  • Cytotoxins (toxic at the cellular level)
  • Apitoxin (honey bee venom)
  • Mycotoxins (produced by fungi)
• LD50


  The dose required to kill half the members of a tested population after a specified test duration
• Alpha-amanitin has an oral LD50 of 0.1 mg/kg for rats
• Alpha-amanitin targets RNA polymerase II (RNA pol II), an enzyme found in eukaryotic cells which catalyses the transcription of DNA to synthesize precursors of mRNA

  
• Interaction of alpha-amanitin with RNA pol II


  • There is a strong hydrogen bond between hydroxyproline (2) of alpha-amanitin and bridge helix residue Glu-A822
  • There is an indirect interaction involving the backbone carbonyl group of 4,5-dihydroxyisoleucine (3) of alpha-amanitin, hydrogen-bonded to residue Gln-A768, which is, in turn, hydrogen-bonded to bridge helix residue His-A816
  • There are several hydrogen bonds between alpha-amanitin and the region adjacent to the bridge helix

  
• The binding of alpha-amanitin toxin


  Restricts the movement of the helix bridge, causing the rate of translocation to slow down tremendously and resulting in strain placed on the bridge helix
• There is no effective antidote for severe amatoxin poisoning
• 1. acetylcysteine, benzylpenicillin, cimetidine, thioctic acid, and silybin were tested but they were not effective in limiting hepatic injury after alpha-amanitin poisoning
• Batrachotoxin


  A member of a family of steroidal alkaloids called batrachotoxins, first discovered in poison dart frogs of the genus Phyllobates
• Batrachotoxin is one of the most potent natural neurotoxins known because it binds to, and irreversibly opens, voltage-gated sodium channels
• The activity of batrachotoxin depends on temperature, reaching its maximum at 37 degrees Celsius (body temperature)
• Voltage-gated ion channels


  • Underlie the nerve impulse and mediate conduction across the synapses, making them especially prominent components of the nervous system
• Binding of batrachotoxin


  BTX can only bind to a sodium channel when the channel is in its open conformation, and it is stabilized within its receptor by an electrostatic interaction
• Currently no effective antidote exists for the treatment of batrachotoxin poisoning
• Membrane depolarization can be prevented or reversed by either tetrodotoxin (from puffer fish) or saxitoxin, which have effects antagonistic to those of batrachotoxin on sodium flux
• Certain anaesthetics may act as receptor antagonists to the action of batrachotoxin, while other local anesthetics block its action altogether by acting as competitive antagonists