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SIR2: The Biochemical Mechanism of NAD+-Dependent Protein Deacetylation and ADP-Ribosyl Enzyme Intermediates

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Abstract:

The Sir2 family of enzymes is a recently described class of NAD+-dependent protein deacetylases that use NAD+ as a reactant to deacetylate acetyllysine residues of protein substrates to form the aminolysine sidechain and a novel product 2’-O-acetyl-ADP-ribose. The founding member of the Sir2 proteins, the yeast Sir2p, has been identified as a key member of SIR complexes responsible for the long-term silencing of genes in the yeast Saccharomyces cerevisiae. Increase of Sir2 activity by caloric restriction or osmotic stress increases genome stability and lifespan in this organism. The Sir2 reaction mechanism couples ADPribosyltransfer and hydrolysis reactions via the formation of a stabilized ADPR-peptidyl intermediate. Principles of the chemistry of stabilized ADPR intermediates are examined for Sir2 and the mechanistically related ADP-ribosylcyclase CD38. An examination of the crystal structures of Sir2 family members is presented with a view to the chemical requirements of the Sir2 reaction. The present review describes the current knowledge of the Sir2 reaction, the reaction mechanism and the regulation of Sir2.

Keywords: adp-ribose intermediates; cd38; protein deacetylation; sir2

Document Type: Review Article

DOI: http://dx.doi.org/10.2174/0929867043455675

Affiliations: Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave F304 Bronx NY 10461, USA.

Publication date: April 1, 2004

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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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