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Role of the Transglutaminase Enzymes in the Nervous System and their Possible Involvement in Neurodegenerative Diseases

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Abstract:

Transglutaminases are a large family of related and ubiquitous enzymes which catalyze the cross linking of a glutaminyl residue of a protein/peptide substrate to a lysyl residue 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 bisubstituted /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. These enzymes are also capable of catalyzing other reactions important for cell viability. The distribution and the physiological roles of human transglutaminases have been widely studied in numerous cell types and tissues and their roles in several diseases have begun to be identified. Recently, “tissue” transglutaminase (TG2) has been shown to be involved in the molecular mechanisms responsible for a very widespread human pathology, celiac disease (CD). Transglutaminase activity has also been hypothesized to be directly involved in the pathogenetic mechanisms responsible for several human neurodegenerative diseases, which are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains, such as Alzheimer's disease (AD), Parkinson's disease (PD), supranuclear palsy, Huntington's disease (HD) and the other recently identified polyglutamine diseases, and others. In this review we discuss the biological role of the transglutaminases in the nervous system, with particular interest in the molecular mechanisms, which could involve these enzymes in the pathophysiological processes responsible for human neurodegenerative diseases.

Keywords: Neurodegenerative diseases; Post-translational modifications of proteins; Transglutaminase inhibitors; Transglutaminases

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986709789909594

Affiliations: Department of Biochemistry and Biophysics, Second University of Naples, via Costantinopoli 16, 80138, Naples, Italy.

Publication date: December 1, 2009

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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