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Identified virulence factors of Corynebacterium: Toxin


DT (diphtheria toxin)  

Related genes: tox;
Keywords: Toxin; Intracellular toxin; ADP-ribosyltransferase; A-B type;
Characteristics:
DT is the first member of the mono-ADP-ribosyltransferase (ART) family to be identitfied and is one of the best-studied and best-understood bacterial toxins.
Encoded on a mobile temperate bacteriophage (corynephage) and is exported via the general secretory pathway.
Structure features:
Glu148 in DT is crucial for catalytic activity. This glutamate forms a hydrogen bond to the 2' hydroxyl group of the nicotinamide ribose of NAD+ and has been suggested to stabilize the oxacarbenium intermediate after dissociation of the nicotinamide moiety.
Tyr54 and Tyr65 in DT form a hydrophobic pocket that binds the nicotinamide moiety.
His21 in DT is an essential histidine residue that can greatly affects ART activity.
PDB code: 1DTP.
Figures:
Structural properties of DT. (From: Deng Q, Barbieri JT., 2008. Molecular mechanisms of the cytotoxicity of ADP-ribosylating toxins. Annu. Rev. Microbiol. 62:271-288.)


Functions:
DT acts on and inhibit translation elongation factor 2 (eEF2), thereby blocking its function on the ribosome and inhibiting protein synthesis in the host cell.
Mechanism:
DT is secreted as a single 58-kDa polypeptide that is cleaved into two fragments before or during the binding of the epidermal growth factor (EGF)-like growth factor precursor (HB-EGF) that functions as the DT receptor. Then DT is taken into the host cell by receptor-mediated endocytosis. It reaches the cytoplasm by penetrating through the membrane in the early endosome. The catalytic fragment of DT is released into the cytoplasm and catalyzes the ADP-ribosylation of eEF2, resulting in inhibition of protein synthesis.
DT toxin catalyzes the transfer of ADP-ribose from NAD+ to the N3 atom of the diphthamide imidazole ring in eEF2 and has evolved a specific mechanism for inactivating the eukaryotic protein synthetic machinery without affecting the couterpart elongation factor G that is present in the bacterial pathogens that produce the offending toxins.
DT has shown intrinsic nuclease activity by degrading double-stranded DNA without apparent specificity for nucleotide sequence.
References:
Collier RJ, 2001. Understanding the mode of action of diphtheria toxin: a perspective on progress during the 20th century. Toxicon 39(11):1793-1803.
Ratts R, et al., 2003. The cytosolic entry of diphtheria toxin catalytic domain requires a host cell cytosolic translocation factor complex. J Cell Biol 160(7):1139-1150.
Lee JW, et al., 2005. Mechanistic aspects of the deoxyribonuclease activity of diphtheria toxin. Biochim Biophys Acta 1747(1):121-131.
Yates SP, et al., 2006. Stealth and mimicry by deadly bacterial toxins. Trends Biochem Sci 31(2):123-133.
Deng Q, Barbieri JT., 2008. Molecular mechanisms of the cytotoxicity of ADP-ribosylating toxins. Annu. Rev. Microbiol. 62:271-288.








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