The intersubunit disulfide bridge of ricin is essential for cytotoxicity
Abstract
Alkylation of the cysteine residues which link the A and B chains of ricin through a disulfide bridge produces a molecule which still binds to HeLa cells and is toxic toward in vitro ribosome-directed translation, but which has little or no cytotoxicity toward cells in culture. This and similar observations on diphtheria toxin implicate the intersubunit disulfide bridge in the transport of the toxic subunits of these toxins into the Cytoplasm.
Reference (8)
- OlsnesS. et al.
- WrightH.T. et al.
J. Biol. Chem.
(1984) - LappiD.A. et al.
- NicholsonG.L. et al.
Biochim. Biophys. Acta
(1972)
Cited by (32)
Ricin
2020, Handbook of Toxicology of Chemical Warfare AgentsBiological toxins are produced by a vast number of organisms ranging from the simplest to the most complex, with each having a distinctive mode of action in conjunction with a characteristic molecular structure and biochemistry. The isolation and purification of these toxins provide an easily obtainable source of chemical weapons. Ricin is the most available of the toxins because it is easily recovered from the mash remaining after the extraction of oil from the castor bean. The inhalation LD50 for mice is 3–5 µg/kg and for monkeys is 21–42 µg/kg. Unlike modern acetylcholinesterase inhibitors, the onset of symptoms of ricin exposure is, depending on the exposure route, approximately 12–24 h, resulting in considerably delayed warning signs of exposure. The lack of any warning signs points to the need for a rapid and sensitive analysis that could provide adequate warning. Two basic techniques are utilized to detect ricin: immunoassay and DNA-based assay utilizing the polymerase chain reaction. These technologies have the potential to quickly determine whether an unknown sample possesses ricin activity and could greatly aid in the triage of victims after suspected exposure to ricin.
Ricin
2018, Comprehensive Toxicology: Third EditionRicin is a protein toxin produced by the castor bean plant, Ricinus communis. While all parts of the plant contain ricin, the castor bean seed contains the highest concentration, ranging from ∼ 1–5% by weight. Attempts to exploit the poisonous attributes of ricin for use as a chemical/biological warfare agent have prompted enhanced surveillance of the toxin by international government agencies. Thus, ricin is classified as a Schedule 1 toxic chemical under the Chemical Weapons Convention Regulations (U.S. Department of Commerce, Bureau of Industry and Security, 2006) and as a Centers for Disease Control and Prevention Category B select agent. Depending on the dose and route of exposure, ricin toxicity can be a result of its direct cytotoxic effect by causing protein synthesis inhibition, apoptosis, or upregulation of inflammatory signaling cascades such as mitogen-activated protein kinases and transcription factors. As a result, tissue damage can occur in several organ systems including the lungs, kidneys, liver, and spleen. However, the toxicity of ricin is highest in mucosal regions directly exposed to the toxin. Due to the direct effects of ricin on mucosal cell membranes, the gastrointestinal tract is the most vulnerable site for toxic insult.
Ricin
2015, Handbook of Toxicology of Chemical Warfare Agents: Second EditionBiological toxins are produced by a vast number of organisms ranging from the simplest to the most complex, with each having a distinctive mode of action in conjunction with a characteristic molecular structure and biochemistry. The isolation and purification of these toxins provide an easily obtainable source of chemical weapons. Ricin is the most available of the toxins because it is easily recovered from the mash remaining after the extraction of oil from the castor bean. The inhalation LD50 for mice is 3–5 µg/kg and for monkeys is 21–42 µg/kg. Unlike modern acetylcholinesterase inhibitors, the onset of symptoms of ricin exposure is, depending on exposure route, approximately 12–24 h, resulting in considerably delayed warning signs of exposure. The lack of any warning signs points to the need for a rapid and sensitive analysis that could provide adequate warning. Two basic techniques are being utilized to detect ricin, immunoassay and DNA-based assay utilizing the polymerase chain reaction. These technologies have the potential to quickly determine whether an unknown sample possesses ricin activity and could greatly aid in triage of victims after suspected exposure to ricin.
Eukaryotic expression vectors containing genes encoding plant proteins for killing of cancer cells
2013, Cancer EpidemiologyCitation Excerpt :RIPs cause apoptotic and necrotic lesions and induce production of cytokines, causing inflammation [31]. Ricin, which comes from the seeds of the castor oil plant Ricinus communis, is a highly toxic protein classified as a type 2 RIP [51–55]. It has been used in cancer gene therapy constructs.
Background: Gene therapy has attracted attention for its potential to specifically and efficiently target cancer cells with minimal toxicity to normal cells. At present, it offers a promising direction for the treatment of cancer patients. Numerous vectors have been engineered for the sole purpose of killing cancer cells, and some have successfully suppressed malignant tumours. Many plant proteins have anticancer properties; consequently, genes encoding some of these proteins are being used to design constructs for the inhibition of multiplying cancer cells. Results: Data addressing the function of vectors harbouring genes specifically encoding ricin, saporin, lunasin, linamarase, and tomato thymidine kinase 1 under the control of different promoters are summarised here. Constructs employing genes to encode cytotoxic proteins as well as constructs employing genes of enzymes that convert a nontoxic prodrug into a toxic drug are considered here. Conclusion: Generation of eukaryotic expression vectors containing genes encoding plant proteins for killing of cancer cells may permit the broadening of cancer gene therapy strategy, particularly because of the specific mode of action of anticancer plant proteins.
Ricin
2010, Comprehensive Toxicology, Second EditionRicin is a protein toxin produced by the castor bean plant, Ricinus communis. Since its discovery in the late 1800s, it has been recognized as one of the most potent plant toxins in existence. While all parts of the plant contain ricin, the castor bean seed contains the highest concentration ranging from approximately 1 to 5% by weight. Due to its inherent toxicity, ricin has been implicated in several animal and human poisonings, be it accidental or malicious. Attempts to exploit the poisonous attributes of ricin for use as a chemical/biological warfare agent have prompted enhanced surveillance of the toxin by international government agencies. Thus, ricin is classified as a Schedule 1 toxic chemical under the Chemical Weapons Convention Regulations (U.S. Department of Commerce, Bureau of Industry and Security 2006) and as a CDC Category B select agent. Depending on the dose and route of exposure, ricin toxicity can be a result of its direct cytotoxic effect by causing protein synthesis inhibition, apoptosis, or upregulation of inflammatory signaling cascades such as mitogen-activated protein kinases and transcription factors. As a result, tissue damage can occur in several organ systems including the lungs, kidneys, liver, and spleen. However, the toxicity of ricin is highest in mucosal regions directly exposed to the toxin. Due to the direct effects of ricin on mucosal cell membranes, the gastrointestinal tract is the most vulnerable site for toxic insult.
Toxin entry and trafficking in mammalian cells
2006, Advanced Drug Delivery ReviewsThere is a vast number of bacterial and plant toxins that affect cytosolic targets in mammalian cells, and whether the purpose of the toxin is to act as a defence mechanism against predators, or to cause deliberate cell death in order to form an environment more suitable for bacterial growth, each of these toxins must cross a lipid membrane barrier in order to exert their effect. This review looks at the methods employed by bacterial and plant toxins in order to reach their target. We examine the trafficking methods involved in toxin transport throughout the cell, highlighting the proteins necessary for the toxins movement, and noting how many of the toxins hijack the cells own trafficking and protein processing machinery in order to reach their goals. Studying the trafficking of toxins has led to a greater understanding of retrograde transport, a process which has key relevance to the correct intracellular delivery of pharmacological agents.