The role of transglutaminase-2 and its substrates in human diseases

The most characteristic enzymatic function of the class of enzymes known as transglutaminases (TG, EC 2.3.2.13) is the formation of covalent bonds between epsilon-amino groups of primary amines (from lysines or others) and the gamma-carboxamine group of glutamine residues of proteins. In the last years, a growing body of evidence indicate that the most interesting member of the TG family, namely the tissue TG (tTG, also called transglutaminase type 2, TG2), possesses more than one catalytic function. In fact, TG2 is able to catalyze a crosslinking reaction, a deamidation reaction and also shows GTP-binding/hydrolyzing and isopeptidase activities. Therefore, it can act on several classes of substrates, ranging from proteins to peptides, small reactive molecules like mono- and polyamines, and nucleotides. Given the broad spectrum of potentially different activities, elucidating the role of TG2 and its substrates in cellular functions and human diseases is a difficult task. In this study we focus our attention on substrates of TG2 and report a number of interesting considerations about their possible interplay in biological processes and involvement in human diseases, including genetic disorders. A significant improvement in understanding this complex scenario may come from a "multi-interfaced" approach, by exploiting different bioinformatic tools. Starting from a database of known TG2 substrates and using bioinformatic cross-search among other databases, we generated relational tables from which an involvement of TG2 in several genetic disorders can be hypothesized. Developing new bioinformatic tools and strategies to investigate the role of TG2 in molecular mechanisms underlying human diseases will add new light to this fascinating field of research.