Toxin - Mode of action

The A domain remains in the latent form even after uptake, gets activated only by proteolytic cleavage and reduction of disulfide bond. All form of these toxins have common mode of action - Catalyze transfer of the ADP group from the coenzyme.

Diphtheria toxin

- Its a protein of about 62,000 mol.wt
- The A and B domains are synthesized as single polypeptide chain
- The AB dimeric domain undergoes endocytosis and membrane translocation (out of vesicles with cytoplasm) to release domain A to reach cytoplasm and begin its toxic action.
- Domain A is resistant to denaturizing and is long-lived inside the cell.
- A single molecule can kill a cell
- Killing takes place by catalyzing ADP-ribosylation (addition of ADP-ribose group) to the eukaryotic elongation factor 2(EF2).
- EF2 is a protein that catalyzes the hydrolysis of GTP, which drives the movement of ribosome on eukaryotic mRNA.
- The substance for this reaction is the coenzyme NAD.

NAD+ + EF-2 =======>> ADP-ribosyl-EF2 + Nicotinamide

- The modified EF2 protein cannot participate in the elongation chain of protein synthesis and the cell dies because it can no longer synthesis protein.
- EF2 is the only known substrate for diphtheria toxin, and the specificity is that EF2 contains a rare modification in one of its histidine residues and this site is recognized by diphtheria toxin for ADP-ribosylation.
- Mutant cells cannot modify histidine and become resistant to the toxin.
- This leads to myocarditis, neuritis, necrosis of mucous membrane.