Substrate specificity of SIRT1-catalyzed lysine Nepsilon-deacetylation reaction probed with the side chain modified Nepsilon-acetyl-lysine analogs

Bioorganic Chemistry
Nuttara JamonnakWeiping Zheng

Abstract

Peptides containing L-N(epsilon)-acetyl-lysine (L-AcK) or its side chain modified analogs were prepared and assayed using SIRT1, the prototypical human silent information regulator 2 (Sir2) enzyme. While previous studies showed that the side chain acetyl group of L-AcK can be extended to bulkier acyl groups for Sir2 (including SIRT1)-catalyzed lysine N(epsilon)-deacylation reaction, our current study suggested that SIRT1-catalyzed deacetylation reaction had a very stringent requirement for the distance between the alpha-carbon and the side chain acetamido group, with that found in L-AcK being optimal. Moreover, our current study showed that SIRT1 catalyzed the stereospecific deacetylation of L-AcK versus its D-isomer. The results from our current study shall constitute another piece of important information to be considered when designing inhibitors for SIRT1 and Sir2 enzymes in general.

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Jun 26, 2014·Future Medicinal Chemistry·Jing HuHening Lin
Nov 2, 2011·Neuro-degenerative Diseases·Aparna Raghavan, Zahoor A Shah
Feb 23, 2012·Journal of the American Chemical Society·Blair C R DancyPhilip A Cole
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Sep 16, 2010·Molecular BioSystems·Brett M Hirsch, Weiping Zheng

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