Clostridioides difficile toxin glucosyltransferase domain (GTD) (GTD)

The Clostridioides difficile toxin glucosyltransferase domain (GTD) is the N-terminal enzymatic component of the large clostridial toxins TcdA and TcdB, which are the primary virulence factors responsible for Clostridioides difficile infection (CDI) (Voth & Ballard, 2005, Clin Microbiol Rev). Following the uptake of the holotoxin into host cells via receptor-mediated endocytosis, the GTD is translocated into the cytosol and released through autoproteolytic cleavage by an adjacent cysteine protease domain (Pruitt et al., 2012, J Biol Chem). Once in the cytoplasm, the GTD functions as a glycosyltransferase that catalyzes the transfer of a glucose moiety from UDP-glucose to conserved threonine residues on Rho-family GTPases, such as Rho, Rac, and Cdc42 (UniProt P18177). This covalent modification permanently inactivates the GTPases, leading to the disassembly of the actin cytoskeleton, loss of intestinal epithelial barrier integrity, and the induction of apoptosis and pro-inflammatory responses (Bender et al., 2015, ACS Chem Biol). Because the GTD is the direct mediator of cellular damage, it is a major focus for the development of therapeutic inhibitors and neutralizing agents aimed at mitigating the symptoms of pseudomembranous colitis and antibiotic-associated diarrhea (Gerding et al., 2015, N Engl J Med). Current research efforts are particularly focused on small-molecule inhibitors that can penetrate the host cell membrane to directly block the enzymatic activity of the GTD within the cytosol.

Other names

TcdA glucosyltransferase domainTcdB glucosyltransferase domainN-terminal glucosyltransferase domainRho-glucosylating toxin domain

Inhibition of the enzymatic transfer of glucose from UDP-glucose to host Rho-family GTPases, thereby preventing the inactivation of cellular signaling and maintaining the integrity of the intestinal epithelium (Bender et al., 2015, ACS Chem Biol).