Transglutaminase and the Liver

Introduction

Transglutaminases (TGs) are enzymes that covalently cross-link one protein chain through a glutamine residue to a lysine residue in another protein chain in a process known as transamidation. These enzymes are found in almost all mammalian tissues and cells. They play significant roles in the pathogenesis of various human disorders, such as neurodegenerative and autoimmune diseases, inflammatory enteropathies, liver and pulmonary fibrosis, and cancer. Tissue TG or Transglutaminase 2 (TG2) has sparked the most interest because it is noticed in almost all tissues and has been linked to the pathogenesis of celiac disease, ulcerative colitis, Crohn's disease, inflammation of the liver, and fibrosis.

What Are Transglutaminases?

• Proteinases and enzymes that enhance aggregation and crosslinking of proteins, stabilize tissues and cells against mechanical ‘wear-and-tear,’ and protect tissues from toxic material leakage from dying cells are all found in mammalian tissues.

• The TGs are essential enzymes that catalyze the transamidation of specific glutamine residues from one protein chain to the amino group of the side chain of a lysine residue in a second protein chain (leading to the formation of a covalent N-glutaminyl-lysyl-isopeptide bond) or to the free amino group of a soluble amine such as a polyamine.

• This cross-linking reaction is irreversible because the isopeptide bond is prone to cleavage by proteinases. As a result, TG-cross-linked proteins can efficiently stabilize tissues and can only be eliminated through their complete degradation.

What Is the Action Of Ttransglutaminases?

• The presence of calcium affects the activity of mammalian TGs. TGs create a covalent thioester intermediate with the distal free amide group of protein-bound glutamine residues through their active side thiol group at elevated calcium levels (above 0.5 mM), which are only present in extracellular fluids or in severely damaged or apoptotic (self dying) cells.

• The release of one ammonia molecule follows this first step. Next, the enzyme's free thiol is regenerated by reacting with a second nucleophilic acceptor substrate (such as lysine), which then interacts with the peptidylglutamyl-thioester intermediate to establish the isopeptide bond.

• Without complete amines, H2O can act as an alternative acceptor through its oxygen atom. However, it is negatively polarised and tends to result in the donor glutamine being deamidated to a glutamic acid residue.

• All of these changes alter the properties of the substrate proteins, influencing their solubility (in the case of cross-linking) or charge because an electrically neutral glutamine residue in the substrate protein is converted to a negatively charged residue or positively charged in the particular instance of transamidation by the polyamines spermidine or spermine.

• Substrate specificity and the characteristics of these reactions are determined by the biochemical properties of the TGs, specifically, their structure and regulation, which have been analyzed recently.

How Many Transglutaminases Are There?

• TGs are a group of enzymes with at least eight isoforms that are products of various genes (TG1 to TG7 and plasma Factor XIII), as well as potential splicing variations being described more frequently and often containing altered catalytic properties.

• Plasma factor XIII is engaged in blood clotting and wound healing, TG1 and TG3 in epidermal terminal differentiation, and TG4 in reproduction, but the roles of TG5, TG6, and TG7 are unknown.

What Is the Role of Transglutaminase 2 in Liver Diseases?

• When the liver is repeatedly damaged by viral, toxic, metabolic products, it generally responds with a chronic wound-healing reaction that results in fibrosis, an excess accumulation of Extracellular matrix.

• Cirrhosis, or advanced fibrosis with severe distortion of architecture of the liver vascularity, results when fibrogenesis ( the new synthesis and deposition of the Extracellular matrix) proceeds to outbalance fibrinolysis (removal of the Extracellular matrix).

• Cirrhosis is the most critical indicator of morbidity and mortality in patients with chronic liver disease. Significant attempts are being made to develop antifibrotic agents that can halt or reverse fibrosis progression.

• The extracellular matrix (ECM) is a highly complicated structure made up of collagens, proteoglycans, glycosaminoglycans, noncollagenous (glyco) proteins, ECM-bound growth factors, proteases, and enzymes that provide anchoring, structure, and signals to the cells that are embedded in it conversely the cells condition their ECM.

• In the normal liver, a low-density ECM exists between hepatocytes and the sinusoidal endothelium, whereas a high-density ECM is found in the portal area. Liver fibrogenesis is primarily driven by activated hepatic stellate cells and perivascular or portal fibroblasts that differentiate into excess ECM-producing myofibroblasts (MFs), cells that closely mimic, for example, dermal or intestinal myofibroblasts in scar or stricture formation.

• Because a variety of ECM molecules (such as procollagens, fibronectin, or laminins) are TG2 substrates, and because significant wound healing and fibrogenesis regulators (Transforming growth factor, Tumor necrosis factor, interleukin-6) enhance expression of TG2 and has been linked to liver fibrogenesis.

• As a result, TG2 is thought to be profibrogenic because its cross-linking activity stabilizes the ECM network, conferring resistance to proteolytic breakdown.

• This was shown in fibrotic liver specimens from patients suffering from chronic hepatitis B or C, as well as alcoholic hepatitis, where elevated levels of TG2 are identified extracellularly and in connection with the formation of N-glutaminyl-lysyl cross-links, which is an indicator of TG2 activation.

• TG2 may also promote hepatic fibrogenesis by activating transforming growth factor-1, the most effective profibrogenic cytokine, on the cell surface. However, the impact of the TG2-mediated rise in Nuclear factor-kB signaling, for example, in response to Tumor necrosis factor (TNF), is considerably less clear because TNF has both fibrinolytic and fibrogenic properties.

Conclusion

The distinct bi-functional properties of tissue TG elicit. There is a lot of curiosity about its roles in various processes. Hepatic injury, fibrosis, and regeneration are all symptoms of liver disease. The part of tissue TG in hepatic fibrogenesis has become more established. It is currently thought that increased tTGase activity causes activation. Transforming growth factor -Beta, the most potent fibrogenic cytokine, and many ECM components are stabilized. The tissue TG's Guanosine triphosphate (GTP) binding and Guanosine triphosphatase activity is a factor in 1-adrenergic signaling and may thus play a role function in hepatocyte proliferation.