Clostridioides difficile Toxin B glucosyltransferase (TcdB-GTD)

The Clostridioides difficile Toxin B (TcdB) glucosyltransferase is the N-terminal enzymatic domain of the TcdB toxin, a primary virulence factor in C. difficile infections (CDI) (UniProt P18177). This domain is released into the host cell cytosol following toxin endocytosis and autoproteolytic cleavage (PubMed 22460965). Once in the cytoplasm, the glucosyltransferase catalyzes the transfer of a glucose moiety from UDP-glucose to conserved threonine residues of Rho family GTPases, such as RhoA, Rac1, and Cdc42 (PubMed 22460965). This covalent modification prevents the GTPases from interacting with their downstream effectors, leading to the collapse of the actin cytoskeleton, loss of intestinal epithelial barrier integrity, and the induction of apoptosis and pro-inflammatory responses (PubMed 29358618). Clinically, this process manifests as severe diarrhea and pseudomembranous colitis. While the FDA-approved monoclonal antibody bezlotoxumab neutralizes TcdB by binding its receptor-binding domains, the glucosyltransferase domain itself is a major target for novel therapeutics (PubMed 27732830). Small-molecule inhibitors like ebselen are under investigation to directly block the toxin's enzymatic activity within the host cell (PubMed 29358618). Targeting this domain offers a way to prevent the cellular damage that drives the symptoms and complications of CDI.

Other names

TcdB glucosyltransferase domainToxin B effector domainGlucosyltransferase domain of TcdBC. difficile Toxin B GTD

Inhibition of toxin-mediated Rho GTPase glucosylation and neutralization of cytotoxic activity