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| {{Infobox protein family
| | Emilia Shryock is my title but you can call me anything you like. In her professional lifestyle she is a payroll clerk but she's always wanted her personal company. Years in the past we moved to North Dakota. To perform baseball is [http://essexsinglesnights.co.uk/groups/cures-for-any-candida-tips-to-use-now/ over the counter std test] pastime he will never stop performing. |
| | Symbol = Diphtheria_C
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| | Name = Diphtheria toxin, C domain
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| | image = PDB 1xdt EBI.jpg
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| | width =
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| | caption = complex of diphtheria toxin and heparin-binding epidermal growth factor
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| | Pfam = PF02763
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| | Pfam_clan = CL0084
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| | InterPro = IPR022406
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| | SMART =
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| | PROSITE =
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| | MEROPS =
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| | SCOP = 1ddt
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| | TCDB = 1.C.7
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| | OPM family =
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| | OPM protein =
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| | CAZy =
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| | CDD =
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| }}
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| {{Infobox protein family
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| | Symbol = Diphtheria_T
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| | Name = Diphtheria toxin, T domain
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| | image = PDB 1xdt EBI.jpg
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| | width =
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| | caption = complex of diphtheria toxin and heparin-binding epidermal growth factor
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| | Pfam = PF02764
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| | Pfam_clan =
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| | InterPro = IPR022405
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| | SMART =
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| | PROSITE =
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| | MEROPS =
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| | SCOP = 1ddt
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| | TCDB = 1.C.7
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| | OPM family =
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| | OPM protein =
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| | CAZy =
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| | CDD =
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| }}
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| {{Infobox protein family
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| | Symbol = Diphtheria_R
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| | Name = Diphtheria toxin, R domain
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| | image = PDB 1xdt EBI.jpg
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| | width =
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| | caption = complex of diphtheria toxin and heparin-binding epidermal growth factor
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| | Pfam = PF01324
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| | Pfam_clan =
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| | InterPro = IPR022404
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| | SMART =
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| | PROSITE =
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| | MEROPS =
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| | SCOP = 1ddt
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| | TCDB = 1.C.7
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| | OPM family =
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| | OPM protein =
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| | CAZy =
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| | CDD =
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| }}
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| {{Infobox nonhuman protein
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| | Name = tox diphtheria toxin precursor
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| | image =
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| | width =
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| | caption =
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| | Organism = ''Corynebacterium diphtheriae''
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| | TaxID = 257309
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| | Symbol = tox
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| | AltSymbols =
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| | IUPHAR_id =
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| | ATC_prefix =
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| | ATC_suffix =
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| | ATC_supplemental =
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| | CAS_number =
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| | CAS_supplemental =
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| | DrugBank =
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| | EntrezGene = 2650491
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| | PDB =
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| | RefSeqmRNA =
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| | RefSeqProtein = NP_938615
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| | UniProt = Q6NK15
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| | ECnumber = 2.4.2.36
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| | Chromosome = genome
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| | EntrezChromosome = NC_002935
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| | GenLoc_start = 188726
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| | GenLoc_end = 190912
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| }}
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| '''Diphtheria toxin''' is an [[exotoxin]] secreted by ''[[Corynebacterium diphtheriae]]'', the [[pathogen]] [[bacteria|bacterium]] that causes [[diphtheria]]. Unusually, the toxin [[gene]] is encoded by a [[bacteriophage]] (a [[virus]] that infects bacteria).<ref>[http://iai.asm.org/cgi/content/full/70/8/3985/T1 TABLE 1. Bacterial virulence properties altered by bacteriophages] from {{cite journal | author = Patrick L. Wagner, Matthew K. Waldor | title = Bacteriophage Control of Bacterial Virulence | journal = Infection and Immunity | date = August 2002 | pages = 3985–3993 | pmid = 12117903 | volume = 70 | issue = 8 | pmc = 128183 | doi = 10.1128/IAI.70.8.3985-3993.2002}}</ref> The toxin causes the disease diphtheria in humans by gaining entry into the cell cytoplasm and inhibiting protein synthesis.<ref name="PUB00000429">{{cite journal |doi=10.1021/bi9520848 |author=Bell CE, Eisenberg D |title=Crystal structure of diphtheria toxin bound to nicotinamide adenine dinucleotide |journal=Biochemistry |volume=35 |issue=4 |pages=1137–1149 |year=1996 |pmid=8573568}}</ref>
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| ==Structure==
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| Diphtheria toxin is a single [[polypeptide]] chain of 535 amino acids consisting of two [[Protein subunit|subunits]] linked by [[disulfide bridge]]s, known as an A-B toxin. Binding to the cell surface of the B subunit (the less stable of the two subunits) allows the A subunit (the more stable part of the protein) to penetrate the [[Host (biology)|host cell]].<ref name=Baron>{{cite book | author = Murphy JR | editor = Baron S ''et al.'' | title = Medical microbiology | year = 1996 | publisher = Univ. of Texas Medical Branch | location = Galveston, Texas | isbn = 0-9631172-1-1 | edition = 4 | chapter = ''Corynebacterium Diphtheriae'': Diphtheria Toxin Production | url = http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed.section.1752 }}</ref>
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| The [[crystal structure]] of the diphtheria toxin [[homodimer]] has been determined to 2.5[[Angstrom|A]] resolution. The [[secondary structure|structure]] reveals a Y-shaped [[molecule]] consisting of 3 [[protein domains|domains]]. Fragment A contains the [[catalytic]] C domain, and fragment B consists of the T and R domains<ref name="pmid1589020">{{cite journal | author = Choe S, Bennett MJ, Fujii G, Curmi PM, Kantardjieff KA, Collier RJ, Eisenberg D | title = The crystal structure of diphtheria toxin | journal = Nature | volume = 357 | issue = 6375 | pages = 216–22 |date=May 1992 | pmid = 1589020 | doi = 10.1038/357216a0 | url = }}</ref><ref name="pmid1589020"/>
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| *The [[N-terminal]] catalytic domain, known as the C domain, has an unusual beta+alpha [[protein folding|fold]].<ref name="pmid9012663">{{cite journal | author = Bell CE, Eisenberg D | title = Crystal structure of nucleotide-free diphtheria toxin | journal = Biochemistry | volume = 36 | issue = 3 | pages = 481–8 |date=January 1997 | pmid = 9012663 | doi = 10.1021/bi962214s | url = }}</ref> The C domain blocks [[protein biosynthesis|protein synthesis]] by transfer of [[ADP-ribose]] from [[Nicotinamide adenine dinucleotide|NAD]] to a [[diphthamide]] residue of EF-2.<ref name="pmid7833808">{{cite journal | author = Bennett MJ, Eisenberg D | title = Refined structure of monomeric diphtheria toxin at 2.3 A resolution | journal = Protein Sci. | volume = 3 | issue = 9 | pages = 1464–75 |date=September 1994 | pmid = 7833808 | pmc = 2142954 | doi = 10.1002/pro.5560030912 | url = }}</ref><ref name="pmid8573568">{{cite journal | author = Bell CE, Eisenberg D | title = Crystal structure of diphtheria toxin bound to nicotinamide adenine dinucleotide | journal = Biochemistry | volume = 35 | issue = 4 | pages = 1137–49 |date=January 1996 | pmid = 8573568 | doi = 10.1021/bi9520848 | url = }}</ref>
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| *A central translocation domain, known as the T domain or TM domain. The T domain has a multi-helical [[globin]]-like [[protein folding|fold]] with two additional [[Alpha helix|helices]] at N-termini, but which has no counterpart to the first [[globin]] [[helix]]. This domain is thought to unfold in the [[Cell membrane|membrane]].<ref name="pmid7833807">{{cite journal | author = Bennett MJ, Choe S, Eisenberg D | title = Refined structure of dimeric diphtheria toxin at 2.0 A resolution | journal = Protein Sci. | volume = 3 | issue = 9 | pages = 1444–63 |date=September 1994 | pmid = 7833807 | pmc = 2142933 | doi = 10.1002/pro.5560030911 | url = }}</ref> [[pH]]-induced [[conformational change]] in the T domain triggers insertion into the [[endosomal membrane]] and facilitates the transfer of the C domain into the [[cytoplasm]].<ref name="pmid7833808"/><ref name="pmid8573568"/>
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| *A [[C-terminal]] receptor-binding domain, known as the R domain. This domain has a [[beta-sandwich]] [[protein folding|fold]] consisting of nine strands in two sheets with Greek-key topology; it is a subclass of [[immunoglobin]]-like fold.<ref name="pmid9012663"/> The R domain binds to [[cell surface receptors|cell surface receptor]], permitting the [[toxin]] to enter the [[cell (biology)|cell]] by [[receptor (biochemistry)|receptor]] mediated [[endocytosis]].<ref name="pmid7833808"/><ref name="pmid8573568"/>
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| ==Mechanism==
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| [[Image:Diphthamide.png|thumb|[[Diphthamide]]]]
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| The diphtheria toxin has the same mechanism of action as the enzyme [[NAD(+)—diphthamide ADP-ribosyltransferase]] ({{EC number|2.4.2.36}}). It catalyzes the transfer of NAD<sup>+</sup> to a diphthamide residue in eukaryotic [[EEF2|elongation factor-2]] (eEF2), inactivating this protein. It does so by [[ADP ribosylation|ADP-ribosylating]] the unusual [[amino acid]] [[diphthamide]]. In this way, it acts as a [[Translation (genetics)|RNA translational]] inhibitor. The catalysed reaction is as follows:
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| : NAD<sup>+</sup> + peptide diphthamide <math>\rightleftharpoons</math> nicotinamide + peptide N-(ADP-D-ribosyl)diphthamide
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| The [[cholera toxin]] and [[pseudomonas exotoxin|exotoxin A]] of [[Pseudomonas aeruginosa]] uses a similar mechanism of action.
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| ==Lethal dose==
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| Diphtheria toxin is extraordinarily potent.<ref name=Baron /> The [[lethal dose]] for humans is about 0.1 μg of toxin per kg of bodyweight. A massive release of toxin into the body will likely cause lethal [[necrosis]] of the [[heart]] and [[liver]].<ref name=Pappenheimer_1977>{{cite journal | author = Pappenheimer A | title = Diphtheria toxin. | journal = Annu Rev Biochem | volume = 46 | issue = 1| pages = 69–94 | year = 1977 | pmid = 20040 | doi = 10.1146/annurev.bi.46.070177.000441}}</ref>
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| ==History==
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| Diphtheria toxin was discovered in 1890 by [[Von Behring|Emil Adolf von Behring]]. In 1951, Freeman found that the toxin gene was not encoded on the bacterial chromosome, but by a [[Lysogenic cycle|lysogenic]] [[phage]] infecting all toxigenic strains.<ref name="pmid14850426">{{cite journal | author = Freeman VJ | title = Studies on the virulence of bacteriophage-infected strains of Corynebacterium diphtheriae | journal = J. Bacteriol. | volume = 61 | issue = 6 | pages = 675–88 |date=June 1951 | pmid = 14850426 | pmc = 386063 | doi= }}</ref><ref name="pmid14927573">{{cite journal | author = Freeman VJ, Morse IU | title = Further observations on the change to virulence of bacteriophage-infected a virulent strains of Corynebacterium diphtheria | journal = J. Bacteriol. | volume = 63 | issue = 3 | pages = 407–14 |date=March 1952 | pmid = 14927573 | pmc = 169283 | doi = }}</ref><ref>[http://www.textbookofbacteriology.net/diphtheria.html Diphtheria] from [http://www.textbookofbacteriology.net/kt_toc.html Todar's Online Textbook of Bacteriology], Kenneth Todar 2009. Accessed 08 September 2010.</ref>
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| ==Clinical use==
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| The drug [[denileukin diftitox]] uses diphtheria toxin as an [[antineoplastic]] agent. [[Resimmune]]™ is an [[immunotoxin]] which is in Clinical Trials in [[Cutaneous T cell lymphoma]] patients. It uses diphtheria toxin (truncated by the cell binding domain) coupled to anti-CD3ε Ab (UCHT1).
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| ==References==
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| {{Reflist|35em}}
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| ==External links==
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| * {{MeshName|Diphtheria+Toxin}}
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| * [http://www.sumanasinc.com/webcontent/animations/content/diphtheria.html How Diphtheria Toxin Works - Animation]
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| {{Glycosyltransferases}}
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| {{Toxins}}
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| {{Pore-forming toxins}}
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| {{InterPro content|IPR022406}}
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| {{InterPro content|IPR022405}}
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| {{InterPro content|IPR022404}}
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| [[Category:Protein domains]]
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| [[Category:Peripheral membrane proteins]]
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| [[Category:Bacterial toxins]]
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| [[Category:Diphtheria]]
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Emilia Shryock is my title but you can call me anything you like. In her professional lifestyle she is a payroll clerk but she's always wanted her personal company. Years in the past we moved to North Dakota. To perform baseball is over the counter std test pastime he will never stop performing.