Possible Role of the Transglutaminase-Catalyzed Reactions in the Pathogenesis of Neurodegenerative Diseases View PDF

^*Vittorio Gentile
Department Of Biochemistry, Biophysics And General Pathology, Second University Of Naples, Italy

^*Corresponding Author:

Vittorio Gentile
Department Of Biochemistry, Biophysics And General Pathology, Second University Of Naples, Italy
Email:vittorio.gentile@unina2.it

Published on: 2015-03-15

Abstract

Transglutaminases are ubiquitous enzymes which catalyze posttranslational 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 cosubstrates 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 and 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.

Keywords

Transglutaminases; Post-translational modifications of proteins; Protein aggregation; Neurodegenerative diseases; Transglutaminase inhibitors; Cystamine

Introduction

Transglutaminases (TGs, E.C. 2.3.2.13) are ubiquitous enzymes which catalyze irreversible post-translational modifications of proteins. Examples of TG-catalyzed reactions include: I) acyl transfer between the γ-carboxamide group of a protein/polypeptide glutaminyl residue and the e-amino group of a protein/polypeptide lysyl residue; II) attachment of a polyamine to the γ-carboxamide of a glutaminyl residue; III) deamidation of the γ-carboxamide group of a protein/polypeptide glutaminyl residue.