Transglutaminases in Medical Research

Transglutaminase (TGase) is an enzyme that catalyzes the acyl transfer reaction. It uses the C-carboxamide group of the glutamine residue in the peptide bond as the acyl donor, and the E-amino group of the lysyl residue in the polypeptide chain as the acyl acceptor, forming intramolecular and intermolecular E-C-(Glutamyl)-lysine isopeptide bonds, which allow protein molecules to cross-link. TGase is widely distributed in nature. TGase was first isolated and purified from mammals, and then proteins with TGase activity were found from microorganisms, plants, vertebrates, amphibians, fish and birds. In mammals, TGase is widely distributed in various tissues, such as blood, liver, hair follicle, epidermis, prostate and so on. It participates in various physiological functions, such as cell adhesion, cell differentiation, cell death and maintenance of extracellular matrix stability. It has attracted increasing attention that TGase is closely related to some human diseases, such as neurodegeneration, autoimmune states (such as celiac disease), cancer, inflammation and tissue fibrosis.

Classification of TGase in Mammals

There are many kinds of TGase, which are distributed in various tissues and perform different functions. The discovered TGase can be divided into 8 categories from the gene level (Factor XIII a, TGase 1, TGase 2, TGase 3, TGase 4, TGase 5, TGase 6, TGase 7), 6 of which have been separated, purified and characterized at the protein level.

Relationship Between TGase and Diseases

TGase and Inflammatory Diseases

TGase is closely related to a series of inflammatory diseases, including wound healing, tissue repair, fibrosis and autoimmune status.

TGase and Wound Healing

Several different types of TGase are involved in wound healing, through their synergistic effect, complete wound healing in trauma or pathological process. The most important of these is Factor XIIIa. Factor XIIIa can reduce blood loss after trauma by increasing the stability of fibers during blood coagulation, activating platelets, and participating in the regeneration of granulation tissue. TGase type 1 and type 3 are involved in the repair of epidermal trauma. TGase2 is involved in angiogenesis and stabilizing the extracellular matrix in the process of trauma repair by acting as a cell adhesion protein or an integrin-binding receptor.

TGase and Tissue Fibrosis

TGase is closely related to several chronic inflammatory states in liver diseases (cirrhosis, liver fibrosis, alcoholic liver and hepatitis C) and fibrosis of kidney and lung. In different stages of liver injury and fibrosis, the mRNA level of TGase2 increases. In vitro experiments have proved that under the condition of exogenously induced liver injury, nuclear factor kappaB will bind to the promoter of TGase2, thereby increasing the expression of TGase2. TGase2 is mainly involved in the formation of liver fibrosis by catalyzing the cross-linking of extracellular matrix.

TGase and Autoimmune Diseases

TGase is associated with a series of autoimmune diseases, which are typically characterized by the production of antibodies against TGase. TGase and Chronic Neurodegeneration

TGase plays a very important role in chronic neurodegeneration. They are characterized by the formation of aggregates of highly cross-linked insoluble proteins. Mainly include Alzheimer’s type senile dementia, polyglutamine (polyQ) tail diseases, such as Huntington’s disease, Parkinson’s disease, progressive supranuclear palsy.

TGase and Neoplastic Diseases

Research in this field is quite active at present, and many reports are related to this problem. The general view is that the activity of TGase2 in tumor cells is lower than that in corresponding normal tissues observed in vitro, which contains normal forms of TGase, also contains modified forms of TGase, and sometimes even inactive forms, and subcellular localization may also occur Change. The decline of TGase activity in tumors is often a biological indicator of poor prognosis, and may be related to tumor metastasis, making it easier for cells to sneak into the bloodstream through the basement membrane.

Application of TGase in Diagnosis and Therapy

The diagnosis of celiac disease can use ELISA method to detect the antibody against TGase. Experiments have shown that the activity of TGase in AD cerebrospinal fluid is higher than that in normal brain tissue, so that TGase can be used as a diagnostic indicator for some neurodegenerative diseases. TGase was first used in the treatment of FXIIIa as a replacement therapy for the treatment of rare blood coagulation gene defect diseases. Purified enzymes are used as exogenous bioglue to help repair surgical wounds, fractures and cartilage damage. In addition, some people use retinoids as a specific inducer to induce the expression of TGase2 for the treatment of malignant tumors and acne.