Uptake and function of diphtheria toxin (Homo sapiens)

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3, 9, 10101, 2, 6-8, 1210, 114, 9, 13, 145, 10clathrin-coated endocytic vesiclecytosolendocytic vesicleCD9DT(33-225) disulfide bonded HSP90AA1DT:HBEGF:CD9DT(226-567) disulfide bonded HBEGF(20-208) DT A:BDT(33-225)NAD+CD9 DT(226-567) disulfide bonded DT(226-567) disulfide bonded H+DT(33-225) disulfide bonded DT:HBEGF:CD9ADP-ribo-EEF2CD9EEF2HBEGF(20-208)HBEGF(20-208)CD9 TXNRD1DT(33-225) disulfide bonded DT(33-225) disulfide bonded DT(226-567)HBEGF(20-208) HSP90AB1CD9 NAMDT:HBEGF:CD9DT(226-567) disulfide bonded HBEGF(20-208) 61, 766, 81021, 710661, 74, 1324, 13221, 721, 712


Diphtheria is a serious, often fatal human disease associated with damage to many tissues. Bacteria in infected individuals, however, are typically confined to the lining of the throat or to a skin lesion; systemic effects are due to the secretion of an exotoxin encoded by a lysogenic bacteriophage. The toxin is encoded as a single polypeptide but is cleaved by host furin-like proteases to yield an aminoterminal fragment A and a carboxyterminal fragment B, linked by a disulfide bond. Toxin cleavage can occur when it first contacts the target cell surface, as annotated here, or as late as the point at which fragment A is released into the cytosol. Fragment B mediates toxin uptake into target cell endocytic vesicles, where acidification promotes a conformational change enabling fragment B to form a channel in the vesicle membrane through which fragment A is extruded into the target cell cytosol. Cleavage of the inter-fragment disulfide bond frees DT fragment A, which catalyzes ADP ribosylation of the translation elongation factor 2 (EEF2) in a target cell, thereby blocking protein synthesis. Neither fragment is toxic to human cells by itself (Collier 1975; Pappenheim 1977; Murphy 2011). View original pathway at:Reactome.


Pathway is converted from Reactome ID: 5336415
Reactome version: 66
Reactome Author 
Reactome Author: D'Eustachio, Peter

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Ontology Terms



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  1. DeLange RJ, Williams LC, Drazin RE, Collier RJ.; ''The amino acid sequence of fragment A, an enzymically active fragment of diphtheria toxin. III. The chymotryptic peptides, the peptides derived by cleavage at tryptophan residues, and the complete sequence of the protein.''; PubMed Europe PMC
  2. Lambotte P, Falmagne P, Capiau C, Zanen J, Ruysschaert JM, Dirkx J.; ''Primary structure of diphtheria toxin fragment B: structural similarities with lipid-binding domains.''; PubMed Europe PMC
  3. Pappenheimer AM.; ''Diphtheria toxin.''; PubMed Europe PMC
  4. Van Ness BG, Howard JB, Bodley JW.; ''ADP-ribosylation of elongation factor 2 by diphtheria toxin. NMR spectra and proposed structures of ribosyl-diphthamide and its hydrolysis products.''; PubMed Europe PMC
  5. Moya M, Dautry-Varsat A, Goud B, Louvard D, Boquet P.; ''Inhibition of coated pit formation in Hep2 cells blocks the cytotoxicity of diphtheria toxin but not that of ricin toxin.''; PubMed Europe PMC
  6. Iwamoto R, Higashiyama S, Mitamura T, Taniguchi N, Klagsbrun M, Mekada E.; ''Heparin-binding EGF-like growth factor, which acts as the diphtheria toxin receptor, forms a complex with membrane protein DRAP27/CD9, which up-regulates functional receptors and diphtheria toxin sensitivity.''; PubMed Europe PMC
  7. Michel A, Zanen J, Monier C, Crispeels C, Dirkx J.; ''Partial characterization of diphtheria toxin and its subunits.''; PubMed Europe PMC
  8. Brown JG, Almond BD, Naglich JG, Eidels L.; ''Hypersensitivity to diphtheria toxin by mouse cells expressing both diphtheria toxin receptor and CD9 antigen.''; PubMed Europe PMC
  9. Collier RJ.; ''Diphtheria toxin: mode of action and structure.''; PubMed Europe PMC
  10. Murphy JR.; ''Mechanism of diphtheria toxin catalytic domain delivery to the eukaryotic cell cytosol and the cellular factors that directly participate in the process.''; PubMed Europe PMC
  11. Ratts R, Zeng H, Berg EA, Blue C, McComb ME, Costello CE, vanderSpek JC, Murphy JR.; ''The cytosolic entry of diphtheria toxin catalytic domain requires a host cell cytosolic translocation factor complex.''; PubMed Europe PMC
  12. Collier RJ, Kandel J.; ''Structure and activity of diphtheria toxin. I. Thiol-dependent dissociation of a fraction of toxin into enzymically active and inactive fragments.''; PubMed Europe PMC
  13. Van Ness BG, Howard JB, Bodley JW.; ''ADP-ribosylation of elongation factor 2 by diphtheria toxin. Isolation and properties of the novel ribosyl-amino acid and its hydrolysis products.''; PubMed Europe PMC
  14. Honjo T, Nishizuka Y, Kato I, Hayaishi O.; ''Adenosine diphosphate ribosylation of aminoacyl transferase II and inhibition of protein synthesis by diphtheria toxin.''; PubMed Europe PMC


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101381view11:27, 1 November 2018ReactomeTeamreactome version 66
100919view21:02, 31 October 2018ReactomeTeamreactome version 65
100460view19:37, 31 October 2018ReactomeTeamreactome version 64
100007view16:20, 31 October 2018ReactomeTeamreactome version 63
99560view14:54, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99188view12:42, 31 October 2018ReactomeTeamreactome version 62
93858view13:41, 16 August 2017ReactomeTeamreactome version 61
93423view11:23, 9 August 2017ReactomeTeamreactome version 61
88347view16:15, 1 August 2016FehrhartOntology Term : 'toxin and toxicant response pathway' added !
86509view09:19, 11 July 2016ReactomeTeamreactome version 56
83154view10:11, 18 November 2015ReactomeTeamVersion54
81508view13:02, 21 August 2015ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
ADP-ribo-EEF2ProteinP13639 (Uniprot-TrEMBL)
CD9 ProteinP21926 (Uniprot-TrEMBL)
CD9ProteinP21926 (Uniprot-TrEMBL)
DT A:BComplexR-CPH-5334760 (Reactome)
DT(226-567) disulfide bonded ProteinP00588 (Uniprot-TrEMBL)
DT(226-567)ProteinP00588 (Uniprot-TrEMBL)
DT(33-225) disulfide bonded ProteinP00588 (Uniprot-TrEMBL)
DT(33-225)ProteinP00588 (Uniprot-TrEMBL)
DT:HBEGF:CD9ComplexR-HSA-5334770 (Reactome)
DT:HBEGF:CD9ComplexR-HSA-5334772 (Reactome)
DT:HBEGF:CD9ComplexR-HSA-5334780 (Reactome)
EEF2ProteinP13639 (Uniprot-TrEMBL)
H+MetaboliteCHEBI:15378 (ChEBI)
HBEGF(20-208) ProteinQ99075 (Uniprot-TrEMBL)
HBEGF(20-208)ProteinQ99075 (Uniprot-TrEMBL)
HSP90AA1ProteinP07900 (Uniprot-TrEMBL)
HSP90AB1ProteinP08238 (Uniprot-TrEMBL)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NAMMetaboliteCHEBI:17154 (ChEBI)
TXNRD1ProteinQ16881 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADP-ribo-EEF2ArrowR-HSA-5336421 (Reactome)
CD9ArrowR-HSA-5336420 (Reactome)
CD9R-HSA-5336417 (Reactome)
DT A:BR-HSA-5336417 (Reactome)
DT(226-567)ArrowR-HSA-5336420 (Reactome)
DT(33-225)ArrowR-HSA-5336420 (Reactome)
DT(33-225)mim-catalysisR-HSA-5336421 (Reactome)
DT:HBEGF:CD9ArrowR-HSA-5336413 (Reactome)
DT:HBEGF:CD9ArrowR-HSA-5336417 (Reactome)
DT:HBEGF:CD9ArrowR-HSA-5336422 (Reactome)
DT:HBEGF:CD9R-HSA-5336413 (Reactome)
DT:HBEGF:CD9R-HSA-5336420 (Reactome)
DT:HBEGF:CD9R-HSA-5336422 (Reactome)
DT:HBEGF:CD9mim-catalysisR-HSA-5336420 (Reactome)
EEF2R-HSA-5336421 (Reactome)
H+ArrowR-HSA-5336420 (Reactome)
HBEGF(20-208)ArrowR-HSA-5336420 (Reactome)
HBEGF(20-208)R-HSA-5336417 (Reactome)
HSP90AA1ArrowR-HSA-5336420 (Reactome)
HSP90AB1ArrowR-HSA-5336420 (Reactome)
NAD+R-HSA-5336421 (Reactome)
NAMArrowR-HSA-5336421 (Reactome)
R-HSA-5336413 (Reactome) The target cell clathrin-coated vesicle containing diphtheria toxin (DT A:B) in a complex with target cell proteins HBEGF and CD9 is transformed into an endocytic vesicle (Murphy 2011).
R-HSA-5336417 (Reactome) Diphtheria toxin fragments A and B, linked by a disulfide bond (DT A:B) (Collier and Kandel 1971; DeLange et al. 1979; Lambotte et al. 1980; Michel et al. 1972) bind to molecules of proheparin-binding EGF-like growth factor (HBEGF) and CD9 antigen on the target cell plasma membrane. While binding to HBEGF is sufficient for DT A:B uptake into a target cell, presence of CD9 on the target cell surface substantially increases its sensitivity to DT and cross-linking and immunopreciptitation studies indicate that DT A:B, HBEGF, and CD9 form a complex on the cell surface (Brown et al. 1993; Iwamoto et al. 1994). The organization and order of assembly of the complex are not known.
R-HSA-5336420 (Reactome) The normal process of acidification of the endocytic vesicle containing diphtheria toxin (DT A:B) associated with target cell proteins HBEGF and CD9 is thought to cause a conformational change in the toxin. Its B fragment forms a channel in the endocytic vesicle membrane through which the A fragment is extruded into the target cell cytosol. There, reduction of the disulfide bond connecting the A and B fragments releases the A fragment to refold. The process requires participation of target cell heat shock proteins (HSP90AA1 and HSP90AB1) and thioredoxin reductase 1 (TXNRD1), which may mediate disulfide bond cleavage (Ratts et al. 2003; Murphy 2011).
R-HSA-5336421 (Reactome) Target cell elongation factor 2 (EEF2) is ADP-ribosylated in a reaction catalyzed by cytosolic diphtheria toxin fragment A (DT A), inactivating it (Honjo et al. 1971; Van Ness et al. 1980a,b). The loss of EEF2 activity blocks target cell protein synthesis, and a small number of DT A molecules are capable of inactivating sufficient EEF2 to cause target cell death (Collier 1975).
R-HSA-5336422 (Reactome) The complex of diphtheria toxin (DT A:B) and target cell surface proteins HBEGF and CD9 is taken up by endocytosis into a clathrin-coated vesicle (Moya et al. 1985; Murphy 2011).
TXNRD1ArrowR-HSA-5336420 (Reactome)
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