protein-glutamine gamma-glutamyltransferase activity

Definition

Target type: molecularfunction

Catalysis of the reaction: L-glutaminyl-[protein] + L-lysyl-[protein] = [protein]-L-lysyl-N(6)-5-L-glutamyl-[protein] + NH4+. This reaction is the formation of the N6-(L-isoglutamyl)-L-lysine isopeptide, resulting in cross-linking polypeptide chains; the gamma-carboxamide groups of peptidyl-glutamine residues act as acyl donors, and the 6-amino-groups of peptidyl-lysine residues act as acceptors, to give intra- and intermolecular N6-(5-glutamyl)lysine cross-links. [EC:2.3.2.13]

Protein-glutamine gamma-glutamyltransferase (TGase) activity is a critical molecular function involved in diverse cellular processes. TGases catalyze the formation of isopeptide bonds between the gamma-carboxamide group of glutamine residues in proteins and the epsilon-amino group of lysine residues in proteins or other molecules. This post-translational modification, known as transglutaminase-mediated cross-linking, contributes to a range of biological events. Here's a detailed description of its molecular function:

* **Substrate Recognition and Binding:** TGases bind to specific glutamine residues within target proteins. The specificity for glutamine residues is determined by the enzyme's active site and the surrounding amino acid environment.

* **Catalytic Mechanism:** The enzymatic reaction involves a two-step mechanism:
* **Step 1: Activation of Glutamine:** The enzyme activates the gamma-carboxamide group of glutamine by forming a covalent intermediate, a thioester bond with a cysteine residue in the enzyme's active site.
* **Step 2: Formation of Isopeptide Bond:** The activated glutamine then reacts with the epsilon-amino group of lysine residues in target proteins or other molecules, forming an isopeptide bond. This reaction is irreversible and forms a stable covalent link between the two substrates.

* **Regulation:** The activity of TGases is tightly regulated by a variety of factors, including:
* **Calcium Concentration:** Most TGases are calcium-dependent, requiring the presence of calcium ions for optimal activity.
* **Post-translational Modifications:** Phosphorylation and other modifications can influence the activity of TGases.
* **Protein-Protein Interactions:** TGases can interact with other proteins, modulating their activity and substrate specificity.

* **Biological Roles:** TGases play diverse and important roles in various cellular processes:
* **Cell Signaling:** TGases are involved in signal transduction pathways, mediating interactions between proteins and other molecules.
* **Tissue Remodeling and Wound Healing:** TGases contribute to tissue repair and wound healing by cross-linking extracellular matrix proteins, providing structural integrity and stability.
* **Coagulation:** TGases are involved in blood coagulation by cross-linking fibrinogen, promoting the formation of fibrin clots.
* **Immune Response:** TGases are implicated in immune responses by modulating the activity of immune cells and regulating the expression of immune mediators.
* **Cell Death:** TGases are associated with apoptosis and necrosis, playing a role in the regulation of cell death processes.
* **Protein Structure and Function:** TGases can modify the structure and function of proteins by cross-linking them, leading to changes in their stability, activity, and interactions with other molecules.

* **Disease Implications:** Dysregulation of TGase activity has been linked to various diseases, including:
* **Cancer:** TGases are implicated in tumorigenesis and cancer progression, promoting cell proliferation and angiogenesis.
* **Neurological Disorders:** Aberrant TGase activity has been associated with neurodegenerative diseases such as Alzheimer's and Parkinson's diseases.
* **Cardiovascular Diseases:** TGases are involved in atherosclerosis and heart disease by contributing to the formation of atherosclerotic plaques.

**Conclusion:** Protein-glutamine gamma-glutamyltransferase activity is a versatile molecular function that plays critical roles in a wide array of cellular and physiological processes. Its ability to catalyze the formation of isopeptide bonds contributes to signal transduction, tissue remodeling, immune responses, cell death, protein structure, and function. Dysregulation of TGase activity is implicated in various diseases, highlighting its significance in maintaining cellular and organismal health.'
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Proteins (2)

Compounds (18)