Mechanism of sirtuin nhibition by nicotinamide: Altering the NAD + cosubstrate specificity of a Sir2 enzyme

José L. Avalos, Katherine M. Bever, Cynthia Wolberger

Research output: Contribution to journalArticlepeer-review

303 Scopus citations

Abstract

Sir2 enzymes form a unique class of NAD+-dependent deacetylases required for diverse biological processes, including transcriptional silencing, regulation of apoptosis, fat mobilization, and lifespan regulation. Sir2 activity is regulated by nicotinamide, a noncompetitive inhibitor that promotes a base-exchange reaction at the expense of deacetylation. To elucidate the mechanism of nicotinamide inhibition, we determined ternary complex structures of Sir2 enzymes containing nicotinamide. The structures show that free nicotinamide binds in a conserved pocket that participates in NAD+ binding and catalysis. Based on our structures, we engineered a mutant that deacetylates peptides by using nicotinic acid adenine dinucleotide (NAAD) as a cosubstrate and is inhibited by nicotinic acid. The characteristics of the altered specificity enzyme establish that Sir2 enzymes contain a single site that participates in catalysis and nicotinamide regulation and provides additional insights into the Sir2 catalytic mechanism.

Original languageEnglish (US)
Pages (from-to)855-868
Number of pages14
JournalMolecular Cell
Volume17
Issue number6
DOIs
StatePublished - Mar 18 2005
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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