Acyl transfer mechanisms of tissue transglutaminase

•Review of detailed mechanisms of tissue transglutaminase.•Amide hydrolysis and transamidation reactions.•Catalytic machinery resembles cysteine proteases.•Activity regulated through large conformational changes.

Tissue transglutaminase (TG2) is a calcium-dependent enzyme that catalyses several acyl transfer reactions. The most biologically relevant of these involve protein-bound Gln residues as an acyl-donor substrate, and either water or a primary amine as an acyl-acceptor substrate. The former leads to deamidation of Gln to Glu, whereas the latter leads to transamidation, typically resulting in protein cross-linking when the amine substrate is a protein-bound Lys residue. In this review, we present an overview of over fifty years of mechanistic studies that have led to our current understanding of TG2-mediated hydrolysis and transamidation.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide