Transglutaminase 2 and Anti Transglutaminase 2 Autoantibodies in Celiac Disease and Beyond: TG2 Double-Edged Sword: Gut and Extraintestinal Involvement

Abstract

Transglutaminase2 is a pleiotropic enzyme expressed ubiquitously and abundantly. It has been implicated in a variety of physiological processes, such as growth, differentiation, migration, signaling, cytoprotection, cell death and survival, wound healing, angiogenesis, inflammation, apoptosis and autophagy. It operates intracellularly in multiple organelles, extracellularly and on cell surface. Apart from catalyzing post-translational modifications of proteins, by deamidation and cross-linking, it exercises G-protein, isomerase and kinase activities and non-enzymatic biological functions. Aberrant activation or deregulation of its functions is involved in numerous human disease. The most known one is celiac disease, but the present review will expand on extraintestinal entities. It plays a role in inflammatory, degenerative-age related, neurodegenerative, malignant, metabolic and hormonal, autoimmune and genetic conditions. Increased knowledge of its structure, functions and regulation in homeostatic phase, open the opportunity to design new therapeutic strategies to inhibit its malfunction in pathological situations. Characteristics of Physiologic Transglutaminase2 (TG2)Transglutaminase (Enzyme Commission [EC] no. 2.3.2.13, OMIN * 190196), i.e., protein-glutamine γ-glutamyltransferase, belongs to the class of transferases. It catalyzes the formation of an isopeptide bond between the group of γ-carboxamides of glutamine residues (donor) and the first-order ε-amine groups of different compounds, for instance, proteins (acceptors of an acyl residue). The human TG2 gene is localized to chromosome 20q11-12, the protein is made up of 687 amino acids and it is called also tissue TG. It is the most abundant and most studied of the nine members of the TG enzyme family [1].Three reactions are catalyzed by transglutaminase: an acyl-transfer reaction, a crosslinking reaction between Gln and Lys residues of proteins or peptides (transamidation), and deamidation. If lysine is the acceptor of an acyl group, then a protein molecule is enriched with this amino acid. The transfer of an acyl group onto a lysine residue bound in the polypeptide chain induces the process of crosslinking. In addition, transglutaminase catalyzes the reaction of deamination if there is an absence of free amine groups. The reactions catalyzed by this enzyme result in significant post translational modification and changes in the physical and chemical properties of proteins, such as modifications in the viscosity, thermal stability, elasticity, and resilience [2]. Beside the primary TG enzymes' activity of catalyzing the calciumdependent post translational modifications, it can also bind and hydrolyze GTP, exhibit protein disulphide isomerase and kinase activities, independently of calcium and mediates trans-membrane signal transduction and interactions between cell surface proteins and the extracellular matrix. It can interact with a number of cell surface proteins, in a non-enzymatic way, taking part in cell adhesion passways and extracellul...

Comparison of the Reliability of 17 Celiac Disease Associated Bio-Markers to Reflect Intestinal Damage

“…The basic idea is that tTg not only able to deamidate gliadin peptides but also to cross-link with a high catalytic rate [22][23][24]. In the latter case, tTg/gliadin complexes are formed, resulting in the formation of new epitopes (neo-epitopes), evidence has been shown in-vitro.…”

Processed Food Additive Microbial Transglutaminase and Its Cross-Linked Gliadin Complexes Are Potential Public Health Concerns in Celiac Disease

“…The autoantigen in CD is the enzyme tissue transglutaminase (tTG), that functionally imitates its family member mTG [12][13][14]. Both transaminases can deamidate or cross-link (transamidate) gliadin peptides, thus potentiating their attachment and presentation by the HLA-DQ2/8 grooves to stimulate committed celiacogenic CD4+ T cells, inducing mucosal inflammation and destruction [40,41]. The epidemiology and phenotype of CD are constantly changing.…”

“…Gliadin peptides are ideal substrates for transglutaminases, be it the tTG or the mTG [7,[12][13][14]24,25,40,41]. Natively, the TGs catalyzes the transamidation of peptidyl bound glutaminyl resides (acting as an acyl donor) with a primary amine, typically the side chain of lysine residue (acting as an acyl acceptor), resulting in protein cross-linking.…”

Are Non-Celiac Autoimmune Diseases Responsive to Gluten-Free Diet?

“…Tissue and microbial transglutaminases are extensively distributed in the human body and intestinal lumen, respectively [39,54,57]. Human transglutaminase plays a role in end organ affected ADs.…”