Transglutaminases as Possible Therapeutic Targets in Neurodegenerative Diseases

Martin, Antonio; De Vivo, Giulia; Ricotta, Mariangela; Iannuzzi, Maura; Gentile, Vittorio
November 2010
Recent Patents on CNS Drug Discovery;Nov2010, Vol. 5 Issue 3, p195
Academic Journal
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 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, a member of the transglutaminase family of enzymes, has been shown to be involved in the molecular mechanisms responsible for a very widespread human pathology, celiac disease. Transglutaminase activity has also been hypothesized to be involved in the pathogenetic mechanisms responsible for several other 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 transglutaminase inhibitors and their recent patents for the cure of patients with diseases characterized by aberrant transglutaminase activity and on the strategies to design such transglutaminase inhibitors.


Related Articles

  • Characterization of distinct sub-cellular location of transglutaminase type II: changes in intracellular distribution in physiological and pathological states. Piacentini, Mauro; D'Eletto, Manuela; Farrace, Maria; Rodolfo, Carlo; Nonno, Franca; Ippolito, Giuseppe; Falasca, Laura // Cell & Tissue Research;Dec2014, Vol. 358 Issue 3, p793 

    Transglutaminase type II (TG2) is a pleiotropic enzyme that exhibits various activities unrelated to its originally identified functions. Apart from post-translational modifications of proteins (peculiar to the transglutaminase family enzymes), TG2 is involved in diverse biological functions,...

  • A Neurotoxic Phosphoform of Elk-1 Associates with Inclusions from Multiple Neurodegenerative Diseases. Sharma, Anup; Callahan, Linda M.; Jai-Yoon Sul; Kim, Tae Kyung; Barrett, Lindy; Minsun Kim; Powers, James M.; Federoff, Howard; Eberwine, James // PLoS ONE;2010, Vol. 5 Issue 2, p1 

    Neurodegenerative diseases are characterized by a number of features including the formation of inclusions, early synaptic degeneration and the selective loss of neurons. Molecules serving as links between these shared features have yet to be identified. Identifying candidates within the...

  • Transglutaminase-dependent Modulation of Transcription Factor Sp1 Activity. Han, Jeong A; Park, Sang Chul // Molecules & Cells (Springer Science & Business Media B.V.);2000, Vol. 10 Issue 6, p612 

    Modification of transcription factors would result in significant changes in the expression of related genes. Recently, the presence of transglutaminase (TGase) has been reported in nuclei, the biological significances of which have attracted a great concern. In this study, we tested the...

  • Protein O-GlcNAcylation: A Critical Regulator of the Cellular Response to Stress. Chatham, John C.; Marchase, Richard B. // Current Signal Transduction Therapy;Jan2010, Vol. 5 Issue 1, p49 

    The post-translational modification of serine and threonine residues of nuclear and cytoplasmic proteins by the O-linked attachment of the monosaccharide �-N-acetyl-glucosamine (O-GlcNAc) is a highly dynamic and ubiquitous protein modification that plays a critical role in regulating...

  • Motifs tree: a new method for predicting post-translational modifications. Charpilloz, Christophe; Veuthey, Anne-Lise; Chopard, Bastien; Falcone, Jean-Luc // Bioinformatics;Jul2014, Vol. 30 Issue 14, p1974 

    Motivation: Post-translational modifications (PTMs) are important steps in the maturation of proteins. Several models exist to predict specific PTMs, from manually detected patterns to machine learning methods. On one hand, the manual detection of patterns does not provide the most efficient...

  • A smooth handover. Pickett, James // Nature Reviews Molecular Cell Biology;Mar2007, Vol. 8 Issue 3, p178 

    The article presents insights into the mechanisms that ensure a smooth exchange of ubiquitin between enzymes. Ubiquitin and ubiquitin-like molecules (UBL) are tagged to a target protein following sequential conjugation. Three-dimensional structure of an intermediate complex that includes E1...

  • New insights into the post-translational modification of Toll-like receptor signaling molecules. Dunne, Aisling; O'Neill, Luke // Journal of Endotoxin Research;2005, Vol. 11 Issue 6, p325 

    Deregulation of Toll-like receptor (TLR) mediated responses can have devastating effects on the host if left unchecked. It is, therefore, critical that control is exerted at several levels. In this review, we discuss post-translational modification of TLRs and their associated signaling...

  • Disturbed Cooperation of Hepatocytes in the Rhythm of Protein Synthesis by Chelating Agent of Cytoplasmic Calcium BAPTA-AM. Zvezdina, N. D.; Nechaeva, N. V.; Gracheva, E. V.; Novikova, T. E.; Gvazava, I. G.; Fateeva, V. I.; Mal'chenko, L. A.; Brodsky, V. Ya. // Biology Bulletin;Jan2003, Vol. 30 Issue 1, p9 

    Previously we demonstrated synchronized oscillations of protein synthesis rate in hepatocyte cultures upon accumulation of monosialoganglioside GM1 in the medium or after introduction of exogenous GM1 to the medium. The synchronized oscillations of the protein synthesis rate in dense hepatocyte...

  • Integrating Bioinformatics Tools to Handle Glycosylation. Mazola, Yuliet; Chinea, Glay; Musacchio, Alexis // PLoS Computational Biology;Dec2011, Vol. 7 Issue 12, Special section p1 

    The article describes the use of bioinformatics tools to assist the rational design and insertion of N-glycosylation sites in proteins. It offers a background on glycosylation which refers to a co- and post-translational modification that involves the selective attachment of carbohydrates to...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics