Editing Diphtheria (section)

==Mechanism==
[[Diphtheria toxin]] (DT) is produced only by ''C.&nbsp;diphtheriae'' infected with a certain type of [[bacteriophage]].<ref>{{cite journal | author = Freeman, Victor J | title = Studies on the Virulence of Bacteriophage-Infected Strains of Corynebacterium Diphtheriae | journal = Journal of Bacteriology | year = 1951 | pages = 675–688 | pmid = 14850426 | volume = 61 | issue = 6 | pmc=386063| doi = 10.1128/JB.61.6.675-688.1951 }}</ref><ref>{{cite journal | author = Freeman VJ, Morse IU | title = Further Observations on the Change to Virulence of Bacteriophage-Infected Avirulent Strains of Corynebacterium Diphtheriae | journal = Journal of Bacteriology | year = 1953 | pages = 407–414 | pmid = 14927573 | volume = 63 | issue = 3 | pmc=169283| last2 = Morse | doi = 10.1128/JB.63.3.407-414.1952 }}</ref>  [[Toxin|Toxinogenicity]] is determined by phage conversion (also called [[Lysogenic cycle|lysogenic conversion]]); i.e., the ability of the bacterium to make DT changes as a consequence of infection by a particular phage. DT is encoded by the ''tox'' gene. Strains of corynephage are either ''tox''<sup>+</sup> (e.g., corynephage β) or ''tox''<sup>−</sup> (e.g., corynephage γ). The ''tox'' gene becomes integrated into the bacterial genome.<ref name="Holmes">{{cite journal |last1=Holmes |first1=R. K. |title=Biology and molecular epidemiology of diphtheria toxin and the tox gene. |journal=The Journal of Infectious Diseases |date=2000 |volume=181 |issue=Supplement 1 |pages=S156–S167 |doi=10.1086/315554 |pmid=10657208|doi-access=free }}</ref> The chromosome of ''C.&nbsp;diphtheriae'' has two different but functionally equivalent bacterial attachment sites (attB) for integration of β prophage into the chromosome.

The diphtheria toxin precursor is a [[protein]] of [[molecular mass|molecular weight]] 60&nbsp;[[Dalton (unit)|kDa]]. Certain proteases, such as trypsin, selectively cleave DT to generate two [[peptide]] chains, amino-terminal fragment A (DT-A) and carboxyl-terminal fragment B (DT-B), which are held together by a [[disulfide bond]].<ref name="Holmes" /> DT-B is a recognition subunit that gains entry of DT 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, DT is split by a trypsin-like [[protease]] into DT-A and DT-B. The acidity of the endosome causes DT-B to create pores in the endosome membrane, thereby catalysing the release of DT-A into the [[cytoplasm]].<ref name="Holmes" />

Fragment A inhibits the synthesis of new proteins in the affected cell 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.<ref name="entrez">{{cite web | title = Entrez Gene: EEF2 eukaryotic translation elongation factor 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1938}}</ref>

ADP-ribosylation of EF-2 is reversed by giving high doses of [[nicotinamide]] (a form of vitamin B<sub>3</sub>), since this is one of the reaction's end products, and high amounts drive the reaction in the opposite direction.<ref>{{cite journal | author = Collier JR | title = Diphtheria toxin: mode of action and structure. | journal = Bacteriological Reviews | year = 1975 | pages = 54–85 | pmid = 164179 | volume = 39 | issue = 1 | pmc=413884| doi = 10.1128/MMBR.39.1.54-85.1975 }}</ref>