Transglutaminase inhibition as a possible therapeutical approach to protect cells from death in neurodegenerative diseases.
2013
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
absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Recently,
“tissue” transglutaminase (transglutaminase 2), a member of the transglutaminase family of enzymes, has been
shown to be involved in the molecular mechanisms responsible for some human pathologies, including celiac disease, a
very widespread human pathology. Transglutaminase activity has also been hypothesized to be involved in the pathogenetic
mechanisms responsible for other several human diseases, including neurodegenerative diseases, often associated to
celiac disease. 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 therapeutic effects of
selective transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity and on
the strategies to design such transglutaminase inhibitors. In addition, the review also examines available patents that relates
to cysteamine and derivatives.
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