Transglutaminases are 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 the 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. For example, 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.