A 6-year-old unvaccinated child from rural India presents with fever, sore throat, and a characteristic gray-white adherent pseudomembrane over the tonsils and pharynx that bleeds on removal. Throat swab culture on Loeffler medium confirms Corynebacterium diphtheriae. The structure marked **B** in the diagram is the component of diphtheria toxin responsible for the pathogenic effect. Which of the following best describes the molecular mechanism by which this structure causes cell death?

Explanation

## Why ADP-ribosylation of elongation factor 2, leading to inhibition of protein synthesis and cell death is right The A-subunit (marked **B**) of diphtheria toxin catalyzes ADP-ribosylation of elongation factor 2 (EF-2) in eukaryotic cells. This covalent modification inactivates EF-2, which is essential for translocation of peptides during protein synthesis. The result is immediate arrest of translation and cell death. This is the hallmark mechanism of diphtheria toxin and is explicitly documented in Murray 9e and Park 26e Ch 5. The clinical presentation of pseudomembranous pharyngitis with systemic complications (myocarditis, neuropathy) follows from widespread toxin-mediated cell death. ## Why each distractor is wrong - **Inhibition of bacterial cell wall synthesis by blocking peptidoglycan cross-linking**: This describes the mechanism of β-lactam antibiotics (penicillin, cephalosporins), not diphtheria toxin. Diphtheria toxin is an exotoxin that acts on host eukaryotic cells, not bacterial cell walls. - **Direct binding to the host cell membrane receptor and membrane disruption**: While the B-subunit (marked **A**) binds to HB-EGF receptor on host cells, it does not directly disrupt the membrane. The B-subunit serves only as a delivery vehicle; the A-subunit (**B**) is the catalytic component that enters the cytoplasm and acts on EF-2. - **Phosphorylation of ribosomal RNA, preventing ribosome assembly and translation initiation**: This is not the mechanism of diphtheria toxin. Diphtheria toxin does not phosphorylate rRNA; it ADP-ribosylates EF-2, which is a soluble translation factor, not a ribosomal component. **High-Yield:** Diphtheria toxin A-subunit = ADP-ribosylase of EF-2 → translation arrest → cell death; only antitoxin given early neutralizes circulating toxin; toxoid (formaldehyde-inactivated toxin) is the vaccine. [cite: Murray 9e; Park 26e Ch 5]