page_title: Tissue transglutaminase
section_title: Mechanism
hierarchical_section_title: Tissue transglutaminase / Mechanism
caption_attribution_description: English: Chemical reaction mechanism for two reactions catalized by tissue transglutaminase.
context_page_description: Tissue transglutaminase is a 78-kDa, calcium-dependent enzyme of the protein-glutamine γ-glutamyltransferases family. Like other transglutaminases, it crosslinks proteins between an ε-amino group of a lysine residue and a γ-carboxamide group of glutamine residue, creating an inter- or intramolecular bond that is highly resistant to proteolysis. Aside from its crosslinking function, tTG catalyzes other types of reactions including deamidation, GTP-binding/hydrolyzing, and isopeptidase activities. Unlike other members of the transglutaminase family, tTG can be found both in the intracellular and the extracellular spaces of various types of tissues and is found in many different organs including the heart, the liver, and the small intestine. Intracellular tTG is abundant in the cytosol but smaller amounts can also be found in the nucleus and the mitochondria. Intracellular tTG is thought to play an important role in apoptosis. In the extracellular space, tTG binds to proteins of the extracellular matrix, binding particularly tightly to fibronectin.
context_section_description: The catalytic mechanism for crosslinking in human tTG involves the thiol group from a Cys residue in the active site of tTG.  The thiol group attacks the carboxamide of a glutamine residue on the surface of a protein or peptide substrate, releasing ammonia, and producing a thioester intermediate.  The thioester intermediate can then be attacked by the surface amine of a second substrate (typically from a lysine residue). The end product of the reaction is a stable isopeptide bond between the two substrates (i.e. crosslinking).  Alternatively, the thioester intermediate can be hydrolyzed, resulting in the net conversion of the glutamine residue to glutamic acid (i.e. deamidation). The deamidation of glutamine residues catalyzed by tTG is thought to be linked to the pathological immune response to gluten in celiac disease.  A schematic for the crosslinking and the deamidation reactions is provided in Figure 1.
caption: Figure 1: Transamidation (crosslinking) and deamidation mechanisms of tissue transglutaminase
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