WordNet

acute contagious infection caused by the bacterium Corynebacterium diphtheriae; marked by the formation of a false membrane in the throat and other air passages causing difficulty in breathing
a poisonous substance produced during the metabolism and growth of certain microorganisms and some higher plant and animal species

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ジフテリア(呼吸困難を起こすのどの病気)
(特にバクテリアの)毒素

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/01/14 02:00:42」(JST)

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Diphtheria toxin, R domain

complex of diphtheria toxin and heparin-binding epidermal growth factor

Identifiers

Symbol

Diphtheria_R

Pfam

PF01324

InterPro

IPR022404

SCOP

1ddt

SUPERFAMILY

1ddt

TCDB

1.C.7

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

tox diphtheria toxin precursor
Identifiers
Organism	Corynebacterium diphtheriae
Symbol	tox
Entrez	2650491
RefSeq (Prot)	NP_938615
UniProt	Q6NK15
Other data
EC number	2.4.2.36
Chromosome	genome: 0.19 - 0.19 Mb

Diphtheria toxin is an exotoxin secreted by Corynebacterium diphtheriae, the pathogen bacterium that causes diphtheria. Unusually, the toxin gene is encoded by a bacteriophage (a virus that infects bacteria).^[1] The toxin causes the disease diphtheria in humans by gaining entry into the cell cytoplasm and inhibiting protein synthesis.^[2]

Structure[edit]

Diphtheria toxin is a single polypeptide chain of 535 amino acids consisting of two subunits linked by disulfide bridges, 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 cell.^[3]

The crystal structure of the diphtheria toxin homodimer has been determined to 2.5A resolution. The structure reveals a Y-shaped molecule consisting of 3 domains. Fragment A contains the catalytic C domain, and fragment B consists of the T and R domains^[4]^[4]

The N-terminal catalytic domain, known as the C domain, has an unusual beta+alpha fold.^[5] The C domain blocks protein synthesis by transfer of ADP-ribose from NAD to a diphthamide residue of EF-2.^[6]^[7]
A central translocation domain, known as the T domain or TM domain. The T domain has a multi-helical globin-like fold with two additional helices at N-termini, but which has no counterpart to the first globin helix. This domain is thought to unfold in the membrane.^[8] 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.^[6]^[7]
A C-terminal receptor-binding domain, known as the R domain. This domain has a beta-sandwich fold consisting of nine strands in two sheets with Greek-key topology; it is a subclass of immunoglobin-like fold.^[5] The R domain binds to cell surface receptor, permitting the toxin to enter the cell by receptor mediated endocytosis.^[6]^[7]

Mechanism[edit]

Diphthamide

The diphtheria toxin has the same mechanism of action as the enzyme NAD(+)—diphthamide ADP-ribosyltransferase (EC 2.4.2.36). It catalyzes the transfer of NAD⁺ to a diphthamide residue in eukaryotic elongation factor-2 (eEF2), inactivating this protein. It does so by ADP-ribosylating the unusual amino acid diphthamide. In this way, it acts as a RNA translational inhibitor. The catalysed reaction is as follows:

NAD⁺ + peptide diphthamide nicotinamide + peptide N-(ADP-D-ribosyl)diphthamide

The cholera toxin and exotoxin A of Pseudomonas aeruginosa uses a similar mechanism of action.

Lethal dose[edit]

Diphtheria toxin is extraordinarily potent.^[3] 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.^[9]

History[edit]

Diphtheria toxin was discovered in 1890 by Emil Adolf von Behring. In 1951, Freeman found that the toxin gene was not encoded on the bacterial chromosome, but by a lysogenic phage infecting all toxigenic strains.^[10]^[11]^[12]

Clinical use[edit]

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).

References[edit]

^ TABLE 1. Bacterial virulence properties altered by bacteriophages from Patrick L. Wagner, Matthew K. Waldor (August 2002). "Bacteriophage Control of Bacterial Virulence". Infection and Immunity 70 (8): 3985–3993. doi:10.1128/IAI.70.8.3985-3993.2002. PMC 128183. PMID 12117903.
^ Bell CE, Eisenberg D (1996). "Crystal structure of diphtheria toxin bound to nicotinamide adenine dinucleotide". Biochemistry 35 (4): 1137–1149. doi:10.1021/bi9520848. PMID 8573568.
^ ^a ^b Murphy JR (1996). "Corynebacterium Diphtheriae: Diphtheria Toxin Production". In Baron S et al.. Medical microbiology (4 ed.). Galveston, Texas: Univ. of Texas Medical Branch. ISBN 0-9631172-1-1.
^ ^a ^b Choe S, Bennett MJ, Fujii G, Curmi PM, Kantardjieff KA, Collier RJ, Eisenberg D (May 1992). "The crystal structure of diphtheria toxin". Nature 357 (6375): 216–22. doi:10.1038/357216a0. PMID 1589020. Cite uses deprecated parameters (help)
^ ^a ^b Bell CE, Eisenberg D (January 1997). "Crystal structure of nucleotide-free diphtheria toxin". Biochemistry 36 (3): 481–8. doi:10.1021/bi962214s. PMID 9012663. Cite uses deprecated parameters (help)
^ ^a ^b ^c Bennett MJ, Eisenberg D (September 1994). "Refined structure of monomeric diphtheria toxin at 2.3 A resolution". Protein Sci. 3 (9): 1464–75. doi:10.1002/pro.5560030912. PMC 2142954. PMID 7833808. Cite uses deprecated parameters (help)
^ ^a ^b ^c Bell CE, Eisenberg D (January 1996). "Crystal structure of diphtheria toxin bound to nicotinamide adenine dinucleotide". Biochemistry 35 (4): 1137–49. doi:10.1021/bi9520848. PMID 8573568. Cite uses deprecated parameters (help)
^ Bennett MJ, Choe S, Eisenberg D (September 1994). "Refined structure of dimeric diphtheria toxin at 2.0 A resolution". Protein Sci. 3 (9): 1444–63. doi:10.1002/pro.5560030911. PMC 2142933. PMID 7833807. Cite uses deprecated parameters (help)
^ Pappenheimer A (1977). "Diphtheria toxin.". Annu Rev Biochem 46 (1): 69–94. doi:10.1146/annurev.bi.46.070177.000441. PMID 20040.
^ Freeman VJ (June 1951). "Studies on the virulence of bacteriophage-infected strains of Corynebacterium diphtheriae". J. Bacteriol. 61 (6): 675–88. PMC 386063. PMID 14850426. Cite uses deprecated parameters (help)
^ Freeman VJ, Morse IU (March 1952). "Further observations on the change to virulence of bacteriophage-infected a virulent strains of Corynebacterium diphtheria". J. Bacteriol. 63 (3): 407–14. PMC 169283. PMID 14927573. Cite uses deprecated parameters (help)
^ Diphtheria from Todar's Online Textbook of Bacteriology, Kenneth Todar 2009. Accessed 08 September 2010.

External links[edit]

Diphtheria Toxin at the US National Library of Medicine Medical Subject Headings (MeSH)
How Diphtheria Toxin Works - Animation

This article incorporates text from the public domain Pfam and InterPro IPR022406

This article incorporates text from the public domain Pfam and InterPro IPR022405

This article incorporates text from the public domain Pfam and InterPro IPR022404

UpToDate Contents

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1. ジフテリアの臨床的特徴、診断、および治療 clinical manifestations diagnosis and treatment of diphtheria
2. ジフテリアの疫学および病態生理 epidemiology and pathophysiology of diphtheria
3. 髄膜炎菌ワクチン meningococcal vaccines
4. リウマチ性疾患におけるサイトカインネットワーク：治療の意味 cytokine networks in rheumatic diseases implications for therapy
5. 7～18歳の小児におけるジフテリア、破傷風、および百日咳ワクチン diphtheria tetanus and pertussis immunization in children 7 through 18 years of age

English Journal

A model of liver carcinogenesis originating from hepatic progenitor cells with accumulation of genetic alterations.

Kim SK, Nasu A, Komori J, Shimizu T, Matsumoto Y, Minaki Y, Kohno K, Shimizu K, Uemoto S, Chiba T, Marusawa H.Author information Department of Gastroenterology and Hepatology, Graduate School of MedicineKyoto University, Kyoto, Japan.AbstractActivation-induced cytidine deaminase (AID) contributes to inflammation-associated carcinogenesis through its mutagenic activity. In our study, by taking advantage of the ability of AID to induce genetic aberrations, we investigated whether liver cancer originates from hepatic stem/progenitor cells that accumulate stepwise genetic alterations. For this purpose, hepatic progenitor cells enriched from the fetal liver of AID transgenic (Tg) mice were transplanted into recipient "toxin-receptor mediated conditional cell knockout" (TRECK) mice, which have enhanced liver regeneration activity under the condition of diphtheria toxin treatment. Whole exome sequencing was used to determine the landscape of the accumulated genetic alterations in the transplanted progenitor cells during tumorigenesis. Liver tumors developed in 7 of 11 (63.6%) recipient TRECK mice receiving enriched hepatic progenitor cells from AID Tg mice, while no tumorigenesis was observed in TRECK mice receiving hepatic progenitor cells of wild-type mice. Histologic examination revealed that the tumors showed characteristics of hepatocellular carcinoma and partial features of cholangiocarcinoma with expression of the AID transgene. Whole exome sequencing revealed that several dozen genes acquired single nucleotide variants in tumor tissues originating from the transplanted hepatic progenitor cells of AID Tg mice. Microarray analyses revealed that the majority of the mutations (>80%) were present in actively transcribed genes in the liver-lineage cells. These findings provided the evidence suggesting that accumulation of genetic alterations in fetal hepatic progenitor cells progressed to liver cancers, and the selection of mutagenesis depends on active transcription in the liver-lineage cells.
International journal of cancer. Journal international du cancer.Int J Cancer.2014 Mar 1;134(5):1067-76. doi: 10.1002/ijc.28445. Epub 2013 Sep 16.
Activation-induced cytidine deaminase (AID) contributes to inflammation-associated carcinogenesis through its mutagenic activity. In our study, by taking advantage of the ability of AID to induce genetic aberrations, we investigated whether liver cancer originates from hepatic stem/progenitor cells
PMID 23959426

Impact of macrophage deficiency and depletion on continuous glucose monitoring in vivo.

Klueh U1, Qiao Y2, Frailey JT2, Kreutzer DL2.Author information 1Center for Molecular Tissue Engineering, University of Connecticut, School of Medicine, Farmington, CT 06030, USA; Department of Surgery, University of Connecticut, School of Medicine, Farmington, CT 06030, USA. Electronic address: klueh@nso.uchc.edu.2Center for Molecular Tissue Engineering, University of Connecticut, School of Medicine, Farmington, CT 06030, USA; Department of Surgery, University of Connecticut, School of Medicine, Farmington, CT 06030, USA.AbstractAlthough it is assumed that macrophages (MQ) have a major negative impact on continuous glucose monitoring (CGM), surprisingly there is no data in the literature to directly support or refute the role of MQ or related foreign body giant cells in the bio-fouling of glucose sensors in vivo. As such, we developed the hypothesis that MQ are key in controlling glucose sensor performance and CGM in vivo and MQ deficiencies or depletion would enhance CGM. To test this hypothesis we determined the presence/distribution of MQ at the sensor tissue interface over a 28-day time period using F4/80 antibody and immunohistochemical analysis. We also evaluated the impact of spontaneous MQ deficiency (op/op mice) and induced-transgenic MQ depletions (Diphtheria Toxin Receptor (DTR) mice) on sensor function and CGM utilizing our murine CGM system. The results of these studies demonstrated: 1) a time dependent increase in MQ accumulation (F4/80 positive cells) at the sensor tissue interface; and 2) MQ deficient mice and MQ depleted C57BL/6 mice demonstrated improved sensor performance (MARD) when compared to normal mice (C57BL/6). These studies directly demonstrate the importance of MQ in sensor function and CGM in vivo.
Biomaterials.Biomaterials.2014 Feb;35(6):1789-96. doi: 10.1016/j.biomaterials.2013.11.055. Epub 2013 Dec 9.
Although it is assumed that macrophages (MQ) have a major negative impact on continuous glucose monitoring (CGM), surprisingly there is no data in the literature to directly support or refute the role of MQ or related foreign body giant cells in the bio-fouling of glucose sensors in vivo. As such,
PMID 24331705

Adjuvant effect of diphtheria toxin after mucosal administration in both wild type and diphtheria toxin receptor engineered mouse strains.

Chapman TJ, Georas SN.Author information Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester Medical Center, 601 Elmwood Ave., Box 692, Rochester, NY 14610, USA.AbstractThe finding that murine and simian cells have differential susceptibility to diphtheria toxin (DTx) led to the development of genetically engineered mouse strains that express the simian or human diphtheria toxin receptor (DTR) under the control of various mouse gene promoters. Injection of DTx into DTR engineered mice allows for rapid and transient depletion of various cell populations. There are several advantages to this approach over global knockout mice, including normal mouse development and temporal control over when cell depletion occurs. As a result, many DTR engineered mouse strains have been developed, resulting in significant insights into the cell biology of various disease states. We used Foxp3(DTR) mice to attempt local depletion of Foxp3+ cells in the lung in a model of tolerance breakdown. Intratracheal administration of DTx resulted in robust depletion of lung Foxp3+ cells. However, DTx administration was accompanied by significant local inflammation, even in control C57Bl/6 mice. These data suggest that DTx administration to non-transgenic mice is not always an immunologically inert event, and proper controls must be used to assess various DTx-mediated depletion regimens.
Journal of immunological methods.J Immunol Methods.2013 Dec 31;400-401:122-6. doi: 10.1016/j.jim.2013.10.010. Epub 2013 Nov 5.
The finding that murine and simian cells have differential susceptibility to diphtheria toxin (DTx) led to the development of genetically engineered mouse strains that express the simian or human diphtheria toxin receptor (DTR) under the control of various mouse gene promoters. Injection of DTx into
PMID 24200744

Japanese Journal

Pathology : Eosinophilic Granuloma with Splendore-Hoeppli Material Caused by Toxigenic Corynebacterium ulcerans in a Heifer

MURAKAMI Kenji,HATA Eiji,HATAMA Shinichi [他]
The journal of veterinary medical science 76(6), 931-935, 2014-06
NAID 40020141305

Eosinophilic Granuloma with Splendore-Hoeppli Material Caused by Toxigenic Corynebacterium ulcerans in a Heifer

MURAKAMI Kenji,HATA Eiji,HATAMA Shinichi,WADA Yoshihiro,ITO Mitsuru,ISHIKAWA Yoshiharu,KADOTA Koichi
Journal of Veterinary Medical Science, 2014
… Rod-shaped Gram-positive organisms were detected with metachromatic granules, producing diphtheria toxin with 5, 30 and 48 amino acid differences to another C. … The toxin is highly cytotoxic, and may be responsible for the formation of abundant Splendore-Hoeppli material. … The lesion was therefore judged to be an allergic reaction to bacterial antigens or diphtheria toxin. …
NAID 130003391301

Behavioural and Anatomical Characterization of Mutant Mice With Targeted Deletion of D₁ Dopamine Receptor–Expressing Cells : Response to Acute Morphine

Daniela Babovic,Jiang Luning,Goto Satoshi [他],Gantois Ilse,Schütz Günter,Lawrence Andrew J.,Waddington John L.,Drago John
Journal of Pharmacological Sciences 121(1), 39-47, 2013
… The present study examines the effects of morphine in adult mutant (MUT) mice expressing the attenuated diphtheria toxin-176 gene in Drd1a-expressing cells, a mutant line shown previously to undergo post-natal striatal atrophy and loss of Drd1a-expression. …
NAID 130003362671

Related Pictures

Diphtheria Toxoid; Diphtheria Vaccine Diphtheria toxin mechanism - YouTube Diphtheria toxin; Corynebacterium Diphtheriae Toxin Diphtheria Pathway Toxin Scientific Names Used Stock Vector (Royalty Free) 627604628 Diphtheria toxin - Wikipedia Diphtheria - microbewiki Corynebacterium diptheriae(Microbiology) Toxins | Special Issue : Diphtheria Toxin

★リンクテーブル★

リンク元	「DT」「ジフテリア毒素」

「DT」

Diphtheria toxin, T domain
	; complex of diphtheria toxin and heparin-binding epidermal growth factor
Identifiers
Symbol	Diphtheria_T
Pfam	PF02764
InterPro	IPR022405
SCOP	1ddt
SUPERFAMILY	1ddt
TCDB	1.C.7
Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Diphtheria toxin, C domain
	; complex of diphtheria toxin and heparin-binding epidermal growth factor
Identifiers
Symbol	Diphtheria_C
Pfam	PF02763
Pfam clan	CL0084
InterPro	IPR022406
SCOP	1ddt
SUPERFAMILY	1ddt
TCDB	1.C.7
Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

　　[★]

「ジフテリア毒素」

　　[★]

英: diphtheria toxin
同: ジフテリアトキシン
関: ジフテリア

[1] TABLE 1. Bacterial virulence properties altered by bacteriophages from Patrick L. Wagner, Matthew K. Waldor (August 2002). "Bacteriophage Control of Bacterial Virulence". Infection and Immunity 70 (8): 3985–3993. doi:10.1128/IAI.70.8.3985-3993.2002. PMC 128183. PMID 12117903.

[PUB00000429-2] Bell CE, Eisenberg D (1996). "Crystal structure of diphtheria toxin bound to nicotinamide adenine dinucleotide". Biochemistry 35 (4): 1137–1149. doi:10.1021/bi9520848. PMID 8573568.

[Baron-3] Murphy JR (1996). "Corynebacterium Diphtheriae: Diphtheria Toxin Production". In Baron S et al.. Medical microbiology (4 ed.). Galveston, Texas: Univ. of Texas Medical Branch. ISBN 0-9631172-1-1.

[pmid1589020-4] Choe S, Bennett MJ, Fujii G, Curmi PM, Kantardjieff KA, Collier RJ, Eisenberg D (May 1992). "The crystal structure of diphtheria toxin". Nature 357 (6375): 216–22. doi:10.1038/357216a0. PMID 1589020. Cite uses deprecated parameters (help)

[pmid9012663-5] Bell CE, Eisenberg D (January 1997). "Crystal structure of nucleotide-free diphtheria toxin". Biochemistry 36 (3): 481–8. doi:10.1021/bi962214s. PMID 9012663. Cite uses deprecated parameters (help)

[pmid7833808-6] Bennett MJ, Eisenberg D (September 1994). "Refined structure of monomeric diphtheria toxin at 2.3 A resolution". Protein Sci. 3 (9): 1464–75. doi:10.1002/pro.5560030912. PMC 2142954. PMID 7833808. Cite uses deprecated parameters (help)

[pmid8573568-7] Bell CE, Eisenberg D (January 1996). "Crystal structure of diphtheria toxin bound to nicotinamide adenine dinucleotide". Biochemistry 35 (4): 1137–49. doi:10.1021/bi9520848. PMID 8573568. Cite uses deprecated parameters (help)

[pmid7833807-8] Bennett MJ, Choe S, Eisenberg D (September 1994). "Refined structure of dimeric diphtheria toxin at 2.0 A resolution". Protein Sci. 3 (9): 1444–63. doi:10.1002/pro.5560030911. PMC 2142933. PMID 7833807. Cite uses deprecated parameters (help)

[Pappenheimer_1977-9] Pappenheimer A (1977). "Diphtheria toxin.". Annu Rev Biochem 46 (1): 69–94. doi:10.1146/annurev.bi.46.070177.000441. PMID 20040.

[pmid14850426-10] Freeman VJ (June 1951). "Studies on the virulence of bacteriophage-infected strains of Corynebacterium diphtheriae". J. Bacteriol. 61 (6): 675–88. PMC 386063. PMID 14850426. Cite uses deprecated parameters (help)

[pmid14927573-11] Freeman VJ, Morse IU (March 1952). "Further observations on the change to virulence of bacteriophage-infected a virulent strains of Corynebacterium diphtheria". J. Bacteriol. 63 (3): 407–14. PMC 169283. PMID 14927573. Cite uses deprecated parameters (help)

[12] Diphtheria from Todar's Online Textbook of Bacteriology, Kenneth Todar 2009. Accessed 08 September 2010.

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案内

diphtheria toxin