Sirtuin deacetylation mechanism and catalytic role of the dynamic cofactor binding loop

Yawei Shi, Yanzi Zhou, Shenglong Wang, Yingkai Zhang

Research output: Contribution to journalArticle

Abstract

Sirtuins constitute a novel family of protein deacetylases and play critical roles in epigenetics, cell death, and metabolism. In spite of numerous experimental studies, the key and most complicated stage of its NAD +-dependent catalytic mechanism remains to be elusive. Herein, by employing Born-Oppenheimer ab initio quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations, a state-of-the-art computational approach to study enzyme reactions, we have characterized the complete deacetylation mechanism for a sirtuin enzyme, determined its multistep free-energy reaction profile, and elucidated essential catalytic roles of the conserved dynamic cofactor binding loop. These new detailed mechanistic insights could facilitate the design of novel mechanism-based sirtuin modulators.

Original languageEnglish (US)
Pages (from-to)491-495
Number of pages5
JournalJournal of Physical Chemistry Letters
Volume4
Issue number3
DOIs
StatePublished - Feb 7 2013

Fingerprint

Enzymes
Sirtuins
Molecular mechanics
enzymes
Quantum theory
Cell death
Metabolism
NAD
Modulators
Free energy
Molecular dynamics
metabolism
Proteins
death
quantum mechanics
modulators
Computer simulation
free energy
molecular dynamics
proteins

Keywords

  • ab initio QM/MM molecular dynamics simulation
  • enzyme catalysis
  • free energy and umbrella sampling
  • protein deacetylation
  • reaction mechanisms

ASJC Scopus subject areas

  • Materials Science(all)

Cite this

Sirtuin deacetylation mechanism and catalytic role of the dynamic cofactor binding loop. / Shi, Yawei; Zhou, Yanzi; Wang, Shenglong; Zhang, Yingkai.

In: Journal of Physical Chemistry Letters, Vol. 4, No. 3, 07.02.2013, p. 491-495.

Research output: Contribution to journalArticle

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