Transglutaminases

Transglutaminases are a family of calcium-dependent enzymes that catalyze covalent crosslinking between proteins by forming γ-glutamyl-ε-lysine isopeptide bonds between glutamine residues in one protein and lysine residues in another. They can also catalyze deamidation of glutamine to glutamic acid when amine donors are scarce, altering protein charge and properties. The result is stabilization of protein networks and increased resistance to proteolysis, a feature that is important in tissues and in extracellular matrices.

In humans, seven transglutaminases (TGM1–TGM7) have been identified, with distinct tissue distributions and functions. TG2 is the most widely expressed and studied, while TG1 and TG3 are key in epidermal differentiation and formation of the cornified envelope. Other family members have roles in muscle, prostate, skin, brain, and other tissues. Most mammalian transglutaminases require calcium for activity, and their functional roles range from structural crosslinking to participation in signaling pathways. In some contexts, TG2 can also bind guanine nucleotides, shifting its activity toward regulatory functions.

A widely used industrial example is microbial transglutaminase (MTG) from Streptomyces species, which is active without added calcium and is employed to crosslink proteins in food processing. MTG is used to improve texture, water retention, and stability in products such as meat, dairy, and bakery items, and it also finds applications in protein conjugation and biomaterials.

Clinical relevance includes autoantibodies against TG2 as a diagnostic marker for celiac disease; dysregulation of transglutaminases has been linked to autoimmune and neurodegenerative conditions. Regulation of activity occurs through calcium binding and, for some isoforms like TG2, by nucleotide binding, which can influence whether the enzyme crosslinks proteins or participates in signaling.