Transglutaminases are a class of ubiquitous enzymes which catalyze post-translational modifications of proteins.
The main activity of these enzymes is the cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl
residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include
monoamines or polyamines (to form mono- or bi-substituted /crosslinked adducts) or –OH groups (to form ester
linkages). In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl
residue. Transglutaminase activity has been suggested to be involved in molecular mechanisms responsible for both
physiological or pathological processes. Recently, transglutaminase activity has been shown to be responsible for a widespread
human autoimmune disease, the Celiac Disease. Interestingly, neurodegenerative diseases, such as Alzheimer’s
disease, Parkinson’s disease, supranuclear palsy, Huntington’s disease and other polyglutamine diseases, are characterized
in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This review
focuses on the possible molecular mechanisms responsible for such diseases and on the possible therapeutic effects
of transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity.