Diphtheria toxin's primary lethal action is to inhibit protein synthesis. What is the direct molecular target and effect that causes cell death?

Introduction / Context:
Corynebacterium diphtheriae secretes diphtheria toxin, a classic AB exotoxin. Understanding its precise molecular target illuminates how a single enzymatic event can globally shut down cellular protein synthesis and kill the host cell.

Given Data / Assumptions:

• Toxin has catalytic A subunit and binding/translocation B subunit.
• ADP-ribosyltransferase activity uses NAD+ as a donor.
• Target is a eukaryotic elongation factor.

Concept / Approach:
The A fragment of diphtheria toxin catalyzes ADP-ribosylation of elongation factor 2 (eEF-2) at a diphthamide residue, an essential post-translationally modified histidine. Modification inactivates eEF-2, halting translocation during elongation at the ribosome, thereby arresting protein synthesis and leading to rapid cell death.

Step-by-Step Solution:
Recognize toxin class: AB ADP-ribosylating enzyme.Identify eEF-2 as the critical target modified at diphthamide.Link loss of eEF-2 function to cessation of polypeptide elongation and cytotoxicity.

Verification / Alternative check:
Mutations that alter diphthamide formation reduce toxin sensitivity, confirming the required enzymatic modification site on eEF-2.

Why Other Options Are Wrong:

• Ion channel formation: describes pore-forming toxins (for example, streptolysin O), not diphtheria toxin.
• Apoptosis induction: may occur secondarily, but not the primary biochemical mechanism.
• DNA alkylation/actin crosslinking: unrelated mechanisms.

Common Pitfalls:
Confusing diphtheria toxin with other ADP-ribosylating toxins (for example, cholera toxin targets Gs alpha) or pore-forming toxins; the hallmark here is eEF-2 inactivation.

Final Answer:
ADP-ribosylation and inactivation of a translational elongation factor