Potential of transglutaminase 2 as a therapeutic target.
BACKGROUND
Increased expression and activity of transglutaminase 2 - a calcium-dependent enzyme which catalyzes protein cross-linking, polyamination or deamidation at selective glutamine residues - are involved in the etiopathogenesis of several pathological conditions, such as neurodegenerative disorders, autoimmune diseases and inflammatory diseases. Inhibition of enzyme activity has potential for therapeutic management of these diseases.


METHODS
The major results achieved in the last twelve years of research in the field of inhibition of tranglutaminase activity using cell cultures as well as in vivo models of high-social-impact or widespread diseases, such as CNS neurodegenerative disorders, celiac sprue, cancer and fibrotic diseases.


RESULTS
Beneficial effects of enzyme activity inhibition have been observed in neurodegeneration and fibrosis in vivo models by delivery of the competitive inhibitor cystamine and more recently designed inhibitors, such as thiomidaziolium or norleucine derivatives, which irreversibly bind the active site cysteine residue. Transglutaminase 2 targeting with specific antibodies has also been shown to be a promising tool for celiac disease treatment.


CONCLUSIONS
New insights from transglutaminase inhibition studies dealing with side effects of in vivo administration of pan-transglutaminase inhibitors will help in design of novel therapeutic approaches to various diseases.
Caccamo
Daniela
D
University of Messina, Policlinico Universitario, Department of Biochemical, Physiological and Nutritional Sciences, Italy.
Currò
Monica
M
Ientile
Riccardo
R
D000818:Animals; D002118:Calcium / Q000378:metabolism; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D002118:Calcium