Abstract
Sir2 enzymes are broadly conserved from bacteria to humans, and eukaryotic organisms typically contain multiple Sir2 enzymes that target different protein substrates to mediate diverse biological processes including gene silencing, DNA repair, genome stability, longevity, metabolism, adipogenesis, and cell physiology. These enzymes use a conserved catalytic core domain to bind NAD+ and acetyl-lysine-bearing protein targets. They generate lysine, 2′-0-acetyl-ADP-ribose, and nicotinamide products and contain more variable N- and C-terminal domains that may contribute protein-specific functions. Structural and related biochemical studies on the Sir2 enzymes from several laboratories have provided important insights into their conserved mode of NAD+ and acetyl-lysine binding, recognition, and catalysis, as well as the distinguishing features that allow different members of the family to target their respective cognate substrates. This chapter summarizes the results of the structural analysis of the Sir2 enzymes as well as the implications of these studies for structure-based design of Sir2-specific small-molecule compounds that might modulate Sir2 functions for therapeutic application.
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© 2006 Humana Press Inc., Totowa, NJ
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Zhao, K., Marmorstein, R. (2006). Structure of the Sir2 Family of NAD+-Dependent Histone/Protein Deacetylases. In: Verdin, E. (eds) Histone Deacetylases. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1385/1-59745-024-3:203
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DOI: https://doi.org/10.1385/1-59745-024-3:203
Publisher Name: Humana Press
Print ISBN: 978-1-58829-499-9
Online ISBN: 978-1-59745-024-9
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