Which bacterial enzyme is the target of diphtheria toxin, leading to inhibition of protein synthesis and cell death?

Explanation

## Diphtheria Toxin Mechanism of Action **Key Point:** Diphtheria toxin is an AB-type exotoxin produced by *Corynebacterium diphtheriae* that catalyzes ADP-ribosylation of elongation factor 2 (EF-2), resulting in complete inhibition of protein synthesis and cell death. ### Molecular Mechanism 1. **Toxin Structure:** Diphtheria toxin consists of: - Fragment A (catalytic domain): ADP-ribosyltransferase activity - Fragment B (binding domain): binds to heparin-binding EGF-like growth factor (HB-EGF) receptor 2. **EF-2 Inactivation:** - Fragment A ADP-ribosylates a unique amino acid called diphthamide on EF-2 - Diphthamide is found exclusively in eukaryotic EF-2 (not in prokaryotes) - Single ADP-ribosylation of one EF-2 molecule is sufficient to block protein synthesis 3. **Consequence:** Complete cessation of protein synthesis → cell death ### Why EF-2 is the Target **High-Yield:** EF-2 is essential for translocation of peptidyl-tRNA from A site to P site during the elongation phase of protein synthesis. Inactivation of even a single EF-2 molecule halts all protein synthesis. **Clinical Pearl:** This explains why diphtheria toxin is so potent — a single toxin molecule can kill a cell because it only takes one inactivated EF-2 to block all protein synthesis. This is in contrast to many other toxins that require multiple hits. **Mnemonic:** **EF-2** = **E**longation **F**actor **2** (the target of diphtheria toxin); **DIP**hthamide = unique amino acid on EF-2 that gets **ADP**-ribosylated ### Comparison: Why Other Enzymes Are Wrong | Enzyme | Role | Why NOT Target | |--------|------|----------------| | **EF-2** | Translocation during elongation | ✓ CORRECT TARGET — ADP-ribosylation blocks all protein synthesis | | **rRNA Polymerase** | Transcription, not translation | Diphtheria toxin does not target transcription machinery | | **Aminoacyl-tRNA Synthetase** | Charging tRNAs | Not the target; EF-2 is the sole target | | **Peptidyl Transferase** | Peptide bond formation | Part of ribosome; not the specific target of diphtheria toxin |