Diphtheria pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Overview
Pathophysiology
Diphtheria toxin catalyzes the ADP-ribosylation of, and inactivates, the elongation factor eEF-2. In this way, it acts to inhibit translation during eukaryotic protein synthesis. Diphtheria toxin is produced by C. diphtheriae only when infected with a bacteriophage that integrates the toxin-encoding genetic elements into the bacteria.[1][2]
Diphtheria toxin is a single, 60,000 molecular weight protein composed of two peptide chains, fragment A and fragment B, held together by a disulfide bond. Fragment B is a recognition subunit that gains the toxin entry into the host cell by binding to the EGF-like domain of heparin-binding EGF-like growth factor (HB-EGF) on the cell surface. This signals the cell to internalize the toxin within an endosome via receptor-mediated endocytosis. Inside the endosome, the toxin is split by a trypsin-like protease into its individual A and B fragments. The acidity of the endosome causes fragment B to create pores in the endosome membrane, thereby catalyzing the release of fragment A into the cell's cytoplasm.
Fragment A inhibits the synthesis of new proteins in the affected cell. It does this by catalyzing ADP-ribosylation of elongation factor EF-2—a protein that is essential to the translation step of protein synthesis. This ADP-ribosylation involves the transfer of an ADP-ribose from NAD+ to a diphthamide (a modified histidine) residue within the EF-2 protein. Since EF-2 is needed for the moving of tRNA from the A-site to the P-site of the ribosome during protein translation, ADP-ribosylation of EF-2 prevents protein synthesis.
ADP-ribosylation of EF-2 is reversed by giving high doses of nicotinamide (a form of vitamin B3), since this is one of the reaction's end-products, and high amounts will drive the reaction in the opposite direction.[citation needed]
References
- ↑ Victor J Freeman (1951). "STUDIES ON THE VIRULENCE OF BACTERIOPHAGE-INFECTED STRAINS OF CORYNEBACTERIUM DIPHTHERIAE". Journal of Bacteriology. 61 (6): 675–688. PMC 386063. PMID 14850426.
- ↑ Freeman VJ, Morse IU (1953). "FURTHER OBSERVATIONS ON THE CHANGE TO VIRULENCE OF BACTERIOPHAGE-INFECTED AVIRULENT STRAINS OF CORYNEBACTERIUM DIPHTHERIAE". Journal of Bacteriology. 63 (3): 407–414. PMC 169283. PMID 14927573.