Chemistry of Gene Silencing: The Mechanism of NAD+-Dependent Deacetylation Reactions

Citations Over TimeTop 10% of 2001 papers

Abstract

The Sir2 enzyme family is responsible for a newly classified chemical reaction, NAD(+)-dependent protein deacetylation. New peptide substrates, the reaction mechanism, and the products of the acetyl transfer to NAD(+) are described for SIR2. The final products of SIR2 reactions are the deacetylated peptide and the 2' and 3' regioisomers of O-acetyl ADP ribose (AADPR), formed through an alpha-1'-acetyl ADP ribose intermediate and intramolecular transesterification reactions (2' --> 3'). The regioisomers, their anomeric forms, the interconversion rates, and the reaction equilibria were characterized by NMR, HPLC, 18O exchange, and MS methods. The mechanism of acetyl transfer to NAD(+) includes (1) ADP ribosylation of the peptide acyl oxygen to form a high-energy O-alkyl amidate intermediate, (2) attack of the 2'-OH group on the amidate to form a 1',2'-acyloxonium species, (3) hydrolysis to 2'-AADPR by the attack of water on the carbonyl carbon, and (4) an SIR2-independent transesterification equilibrating the 2'- and 3'-AADPRs. This mechanism is unprecedented in ADP-ribosyl transferase enzymology. The 2'- and 3'-AADPR products are candidate molecules for SIR2-initiated signaling pathways.

Related Papers

• → Intramolecular isotope effects in the reactions of CF32+ and CO22+ with HD(2001)28 cited
• → Differential inhibition of hepatic ferrochelatase by regioisomers of N-butyl-, N-pentyl-, N-hexyl-, and N-isobutylprotoporphyrin IX.(1988)15 cited
• → Nature of weak inter-and intramolecular interactions in crystals 8. Influence of intermolecular contacts on the strength of intramolecular O-H...N bonds in crystals of 3-(2-hydroxyphenyl)-1,2,4-triazoles(2006)3 cited
• → Stimulation intramolecular F⋯H hydrogen bond by intramolecular N → Si interaction in Si-fluoro derivatives of 8-mercaptoquinoline: DFT and MP2 calculations(2018)1 cited
• 煙酰型輔酶NAD(P)(上標 +)和NAD(P)H再生的研究進展(2004)