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Human tissue transglutaminase is inhibited by pharmacologic and chemical acetylation
Author(s) -
Lai Thung S.,
Davies Christopher,
Greenberg Charles S.
Publication year - 2010
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1002/pro.301
Subject(s) - acetylation , tissue transglutaminase , peptide , biochemistry , chemistry , in vivo , p300 cbp transcription factors , peptide sequence , lysine , enzyme , biology , amino acid , gene , microbiology and biotechnology , histone acetyltransferases
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 Lys 444 , Lys 468 , and Lys 663 . 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.