TGM2

Transglutaminase 2 (TGM2), also termed tissue transglutaminase or TGase C, is a calcium-dependent enzyme catalyzing post-translational protein modifications through cross-linking, deamidation, and transamidation reactions. It regulates diverse cellular processes, including apoptosis, extracellular matrix (ECM) stabilization, and stress responses by interacting with substrates such as HIF-1α and NF-κB. TGM2 modulates signaling pathways like PI3K/AKT and TGF-β, contributing to fibrosis, inflammation, and cancer progression. Its dysregulation is implicated in celiac disease (autoantibody targeting), neurodegenerative disorders (e.g., Huntington’s), and fibrotic pathologies (e.g., liver cirrhosis).
TGM2’s role in celiac disease involves deamidating gliadin peptides, triggering immune responses via HLA-DQ2/8 presentation. In fibrosis, it cross-links ECM proteins, promoting tissue stiffness. Drug development targets TGM2 inhibition using small molecules (e.g., cystamine derivatives, ZED1227) and monoclonal antibodies. ZED1227, a selective inhibitor, showed efficacy in Phase II trials for celiac disease. Challenges persist in balancing isoform specificity and minimizing off-target effects. Emerging strategies explore RNA interference and allosteric inhibitors to overcome limitations of conventional active-site blockers. Preclinical studies also highlight TGM2’s therapeutic potential in chemoresistance modulation.