Human tissue transglutaminase is inhibited by pharmacologic and chemical acetylation |
| |
Authors: | Thung S. Lai Christopher Davies Charles S. Greenberg |
| |
Affiliation: | 1. Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425;2. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425 |
| |
Abstract: | Human tissue transglutaminase (TGM2) is implicated in the pathogenesis of several neurodegenerative disorders including Alzheimer's, Parkinson's and expanded polyglutamine (polyQ) diseases. TGM2 promotes formation of soluble and insoluble high molecular weight aggregates by catalyzing a covalent linkage between peptide‐bound Q residues in polyQ proteins and a peptide‐bound Lys residue. Therapeutic approaches to modulate the activity of TGM2 are needed to proceed with studies to test the efficacy of TGM2 inhibition in disease processes. We investigated whether acetylation of Lys‐residues by sulfosuccinimidyl acetate (SNA) or aspirin (ASA) would alter the crosslinking activity of TGM2. Acetylation by either SNA and/or ASA resulted in a loss of >90% of crosslinking activity. The Lys residues that were critical for inhibition were identified by mass spectrometry as Lys444, Lys468, and Lys663. Hence, acetylation of Lys‐residues may modulate the enzymatic function of TGM2 in vivo and offer a novel approach to treatment of TGM2 mediated disorders. |
| |
Keywords: | transglutaminase neurodegenerative diseases acetylation deacetylation Huntington's disease polyglutamine repeats Parkinson's disease Alzheimer's disease |
|
|