Transglutaminase diseases: from biochemistry to the bedside

Abstract

In humans, 9 members of the transglutaminase (TG) family have been identified, of which 8 [factor XIII (FXIII)A and TG1–TG7] catalyze post‐translational protein‐modifying reactions, and 1 does not (protein 4.2). The TG enzymatic activities considered in our discussion of human disease include deamidation of glutamine (Gln) residues, amine incorporation into Gln residues, and protein crosslinking. Except for TG7, which remains poorly studied, all individual TG members have been correlated with disparate human diseases that arise from either TG function or lack of function. Loss of TG function is associated with numerous orphan diseases that affect a relatively small number of individuals: loss of FXIIIa (transamidase‐activated form) crosslinking leads to defects in blood coagulation in FXIII deficiency; loss of TG1 and TG5 cross linking leads to defects in epidermal cornification in lamellar ichthyosis and acral peeling skin syndrome, respectively; loss of TG3 crosslinking in hair‐cuticle formation leads to uncombable hair syndrome; the predicted loss of TG6 crosslinking leads to spinocerebellar ataxia‐35; and loss of the structural erythrocyte membrane protein, protein 4.2, leads to hereditary spherocytosis type 5. The enzymatic activity of TG2 is involved in the exacerbation of celiac disease and in at least 1 case of hemoglobinopathy, characterized by shortened erythrocyte lifespan. TGs are also autoantigens in a number of immune diseases, resulting in the production of autoantibodies against FXIIIa in acquired FXIII deficiency, TG2 in celiac disease, TG3 in dermatitis herpetiformis, TG4 in autoimmume polyglandular syndrome type 1, and TG6 in gluten axonal neuropathy and gluten ataxia. Much still remains to be learned and confirmed with respect to disease mechanisms, particularly with respect to TG‐related immune diseases, in which development of isozyme‐specific inhibitors may be useful for treatment.—Lorand, L., Iismaa, S. E. Transglutaminase diseases: from biochemistry to the bedside. FASEB J. 33, 3–12 (2019). http://www.fasebj.org

Zinc as a modulator of transglutaminase activity – Laboratory and pathophysiological aspects

“…The human TG family comprises eight thiol enzymes including coagulation factor XIII (FXIII) and a protein called band 4.2 [ 17 ]. The enzymes are present both intracellularly and extracellularly in the body.…”

“…TG2 are considered to be associated with a number of physiological functions, including apoptosis and receptor-mediated endocytosis, but has been particularly noted for its role in pathological contexts such as celiac disease and neurodegenerative diseases [ 17 , 19 ].…”

Mechanism of semen liquefaction and its potential for a novel non-hormonal contraception†

“…In humans, SEMGs are important substrates for TGM [ 72 ]. TGM catalyze protein crosslinking by formation of N-ε-(γ-glutamyl)lysine cross-bridges between lysine and glutamine residues of donor and acceptor proteins respectively (reviewed in [ 73 ]). TGM4 is a prostate-specific autoantigen and plays a critical role in male reproduction.…”

Factor XIII: What does it look like?

“…The transformation of FXIII‐A does not induce drastic conformational changes within a particular domain. However, the changes in the position of individual domains indicate considerable structural transitions, usually termed as transition from closed/compact to open/extended structure (reviewed in references ). The resolution of single‐molecule AFM does not seem sufficient to capture such a difference.…”