Physiopathological roles of human transglutaminase 2

Transglutaminase 2 (TG2, “tissue” TGase) belongs to the family of the TGase enzymes that catalyze posttranslational modifications of proteins, such as the cross-linking of a glutaminyl residue of a protein/peptide substrate to a lysyl residue of a protein/peptide cosubstrate with the formation of an N-gamma-(epsilon-L-glutamyl)-L-lysine [GGEL] cross-link (isopeptidic bond) and the concomitant release of ammonia. The TGase family includes, to date, at least eight zymogens/enzymes (Table 1), which can also catalyze other important reactions for cell life. Recently, several findings concerning the relationships between the biochemical activities of the TGs and the basic molecular mechanisms responsible for some human diseases have been reported. For example, several neurodegenerative diseases, such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), supranuclear palsy, etc., are characterized in part by aberrant cerebral TGs activity and by increased cross-linked proteins in affected brains. In this review, we describe the biochemistry, the molecular biology, and the physiopathological roles of the TG2 enzyme, with particular reference to human pathologies in which the molecular mechanism of disease can be due to its biochemical activities, such as in a very common human disease, celiac disease (CD), and also in some physiopathological states, including neuropsychiatric disorders.