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N(EPSILON)-THIOACETYL-LYSINE AS A MULTIFACETED TOOL FOR ENZYMATIC PROTEIN LYSINE N(EPSILON)-DEACETYLATION
| Title: | N(EPSILON)-THIOACETYL-LYSINE AS A MULTIFACETED TOOL FOR ENZYMATIC PROTEIN LYSINE N(EPSILON)-DEACETYLATION |
| Author: | Fatkins, David G. |
| Description: | The histone deacetylase (HDAC) family of enzymes catalyze the specific lysine N(epsilon)-deacetylation of proteins such as the core histone proteins, various transcription factors, alpha-tubulin, and acetyl-coenzyme A synthetase that are respectively involved in transcriptional, cytoskeletal, and metabolic control. HDAC-catalyzed reactions represent an integral component for an emerging intracellular signaling mechanism defined by the protein posttranslational reversible lysine N(epsilon)-acetylation and deacetylation, and the enzymes involved have been targeted for developing novel therapies for metabolic and age-related diseases and cancer. In this study, we disclose the synthesis and characterization of N(epsilon)-thioacetyl-lysine as a multi-faceted tool for enzymatic protein lysine N(epsilon)-deacetylation. In specific, by evaluating multiple peptides containing N(epsilon)-thioacetyl-lysine, i) we developed the first spectrophotometric assay selective for HDAC8 that holds potential for rapid inhibitor screening and selective determination of HDAC8 activity; ii) we identified potent and selective peptide-based inhibitors for SIRT1, SIRT2, and SIRT3 that are the only bona fide human class III protein deacetylase enzymes with known physiological substrates. All these results have far-reaching impact on promoting our fundamental understanding and pharmacological exploitation of HDAC-catalyzed reactions. |
| Permanent Link: |
http://rave.ohiolink.edu/etdc/view?acc_num=akron1185377018
http://hdl.handle.net/2374.OX/3497 |
| Date: | 2007 |
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