What is the mechanism of action of the exotoxin produced by Corynebacterium diphtheriae (C. diphtheriae)?

From the Guidelines

The exotoxin produced by Corynebacterium diphtheriae acts by inhibiting protein synthesis in host cells. This toxin, known as diphtheria toxin, is encoded by a bacteriophage that infects the bacterium, meaning only C. diphtheriae strains carrying this phage can produce the toxin. The toxin consists of two fragments: fragment A and fragment B. Fragment B binds to specific receptors on susceptible host cells, allowing the toxin to enter through endocytosis. Once inside the cell, fragment A is released and catalyzes the transfer of ADP-ribose from NAD+ to elongation factor 2 (EF-2), a protein essential for protein synthesis. This ADP-ribosylation inactivates EF-2, halting protein synthesis and ultimately causing cell death. The toxin primarily affects the heart, kidneys, and nervous system, explaining the clinical manifestations of diphtheria such as myocarditis, nephritis, and nerve palsies. The potency of diphtheria toxin is remarkable - a single molecule can kill a cell by inactivating over 2,000 EF-2 molecules per minute, making it one of the most potent bacterial toxins known.

Key points to note for USMLE Step 1 purposes include:

• The mechanism of action of the diphtheria toxin
• The role of the bacteriophage in encoding the toxin
• The structure of the toxin, including fragments A and B
• The impact of the toxin on protein synthesis and cell death
• The clinical manifestations of diphtheria, including myocarditis, nephritis, and nerve palsies.

It's worth noting that while the provided evidence does not directly describe the mechanism of action of the diphtheria toxin, the information is well-established in the field of microbiology and immunology 1.

From the Research

Mechanism of Action of Diphtheria Toxin

• The exotoxin produced by Corynebacterium diphtheriae inhibits protein synthesis in eukaryotic cells by ADP-ribosylating elongation factor 2 (EF-2) 2, 3.
• This ADP-ribosylation reaction is catalyzed by the A-fragment of the toxin, which is released after the toxin binds to the cell surface receptor and is internalized by receptor-mediated endocytosis 3, 4.
• The toxin first binds to a receptor on the cell surface, and then the A-fragment is translocated into the cytosol, where it catalyzes the ADP-ribosylation of EF-2 3, 4.
• The ADP-ribosylation of EF-2 prevents it from participating in protein synthesis, thereby inhibiting cell growth and ultimately leading to cell death 5, 3.
• The mechanism of action of diphtheria toxin is similar to that of Pseudomonas exotoxin A, which also ADP-ribosylates EF-2 and inhibits protein synthesis 2, 3.

Key Points for USMLE Step 1

• Diphtheria toxin inhibits protein synthesis by ADP-ribosylating EF-2.
• The A-fragment of the toxin is responsible for catalyzing the ADP-ribosylation reaction.
• The toxin binds to a receptor on the cell surface and is internalized by receptor-mediated endocytosis.
• The ADP-ribosylation of EF-2 prevents it from participating in protein synthesis, leading to cell death.