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Toxins 2015, 7(8), 2757-2772; doi:10.3390/toxins7082757

The Father, Son and Cholix Toxin: The Third Member of the DT Group Mono-ADP-Ribosyltransferase Toxin Family

Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, Canada
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Academic Editor: Ken Teter
Received: 5 June 2015 / Revised: 17 July 2015 / Accepted: 20 July 2015 / Published: 24 July 2015
(This article belongs to the Special Issue The Cell Biology of Toxins and Effector Proteins from Vibrio cholerae)
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Abstract

The cholix toxin gene (chxA) was first identified in V. cholerae strains in 2007, and the protein was identified by bioinformatics analysis in 2008. It was identified as the third member of the diphtheria toxin group of mono-ADP-ribosyltransferase toxins along with P. aeruginosa exotoxin A and C. diphtheriae diphtheria toxin. Our group determined the structure of the full-length, three-domain cholix toxin at 2.1 Å and its C-terminal catalytic domain (cholixc) at 1.25 Å resolution. We showed that cholix toxin is specific for elongation factor 2 (diphthamide residue), similar to exotoxin A and diphtheria toxin. Cholix toxin possesses molecular features required for infection of eukaryotes by receptor-mediated endocytosis, translocation to the host cytoplasm and inhibition of protein synthesis. More recently, we also solved the structure of full-length cholix toxin in complex with NAD+ and proposed a new kinetic model for cholix enzyme activity. In addition, we have taken a computational approach that revealed some important properties of the NAD+-binding pocket at the residue level, including the role of crystallographic water molecules in the NAD+ substrate interaction. We developed a pharmacophore model of cholix toxin, which revealed a cationic feature in the side chain of cholix toxin active-site inhibitors that may determine the active pose. Notably, several recent reports have been published on the role of cholix toxin as a major virulence factor in V. cholerae (non-O1/O139 strains). Additionally, FitzGerald and coworkers prepared an immunotoxin constructed from domains II and III as a cancer treatment strategy to complement successful immunotoxins derived from P. aeruginosa exotoxin A. View Full-Text
Keywords: cholix toxin; elongation factor 2; ADP-ribosylation; inhibitor development; computational chemistry cholix toxin; elongation factor 2; ADP-ribosylation; inhibitor development; computational chemistry
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Lugo, M.R.; Merrill, A.R. The Father, Son and Cholix Toxin: The Third Member of the DT Group Mono-ADP-Ribosyltransferase Toxin Family. Toxins 2015, 7, 2757-2772.

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