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Protein toxin inhibitors of protein synthesis
J P Perentesis1, S P Miller, J W Bodley
1Department of Biochemistry, University of Minnesota, Minneapolis 55455.
Abstract:
Two classes of extremely toxic proteins kill eukaryotic cells by covalently modifying unique structural features of components that are essential for protein synthesis. Intoxication by these proteins results from the entry of a catalytic fragment into the cytoplasm. One class is typified by diphtheria toxin and Pseudomonas exotoxin A. The catalytic component of these toxins ADP-ribosylates and inactivates elongation factor 2 which is an essential participant in protein synthesis. This modification occurs at a unique post-translational histidine derivative, diphthamide, that is present in the ribosomal binding site of the elongation factor. The two toxins differ in their molecular organization but appear to possess identical reaction mechanisms and very similar active sites. The other class contains two types of toxins typified, respectively, by alpha-sarcin, a member of a family of fungal toxins, and ricin, a member of a group of closely related plant proteins collectively termed ribosome-inactivating proteins. The catalytic components of the two types of toxins in this second class inactivate the large ribosomal subunit through two different hydrolytic alterations of 23-28S RNA. alpha-Sarcin and its congeners act as a specific endonuclease whereas ricin and its congeners act as a specific N-glycosidase. These hydrolytic cleavages occur at a pair of adjacent nucleotides within a highly conserved sequence near the 3' terminus of 23-28S RNA. The covalent integrity of this region of RNA is essential to elongation factor-dependent ribosomal functions and is located within the ribosomal binding domain of these factors. Both of these classes of toxins are being employed as 'magic bullets' to eliminate pathological cells. By combining the catalytic component of these toxins with various cell targeting components, useful and specific anticancer and immunomodulatory agents have been created.
Insights
Two classes of toxic proteins target protein synthesis by modifying essential components. These toxins, used in cancer therapy, inactivate elongation factor 2 or ribosomal RNA.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Two classes of highly toxic proteins target eukaryotic protein synthesis.
- These toxins function by entering the cytoplasm and modifying essential protein synthesis machinery.
Purpose of the Study:
- To elucidate the mechanisms of action of two distinct classes of protein synthesis-inhibiting toxins.
- To highlight their potential applications in targeted therapies.
Main Methods:
- Analysis of toxin mechanisms involving ADP-ribosylation of elongation factor 2.
- Investigation of ribosomal RNA inactivation by endonucleolytic or N-glycosidase activity.
Main Results:
- Diphtheria toxin and Pseudomonas exotoxin A ADP-ribosylate elongation factor 2 at the diphthamide residue.
- Alpha-sarcin and ricin family toxins inactivate the large ribosomal subunit by hydrolyzing specific 23-28S RNA sequences.
Conclusions:
- These toxins represent powerful tools for cell targeting due to their specific mechanisms.
- Their catalytic components are being developed into targeted anticancer and immunomodulatory agents.