Plasmodium falciparum Sir2 is an NAD+-dependent deacetylase and an acetyllysine-dependent and acetyllysine-independent NAD+ glycohydrolase

Jarrod B. French, Yana Cen, Anthony A. Sauve

Research output: Contribution to journalArticlepeer-review

43 Scopus citations


Sirtuins are NAD+-dependent enzymes that deacetylate a variety of cellular proteins and in some cases catalyze protein ADP-ribosyl transfer. The catalytic mechanism of deacetylation is proposed to involve an ADPR-peptidylimidate, whereas the mechanism of ADP-ribosyl transfer to proteins is undetermined. Herein we characterize a Plasmodium falciparum sirtuin that catalyzes deacetylation of histone peptide sequences. Interestingly, the enzyme can also hydrolyze NAD+. Two mechanisms of hydrolysis were identified and characterized. One is independent of acetyllysine substrate and produces α-stereochemistry as established by reaction of methanol which forms α-1-O-methyl-ADPR. This reaction is insensitive to nicotinamide inhibition. The second solvolytic mechanism is dependent on acetylated peptide and is proposed to involve the imidate to generate β-stereochemistry. Stereochemistry was established by isolation of β-1-O-methyl-ADPR when methanol was added as a cosolvent. This solvolytic reaction was inhibited by nicotinamide, suggesting that nicotinamide and solvent compete for the imidate. These findings establish new reactions of wildtype sirtuins and suggest possible mechanisms for ADP-ribosylation to proteins. These findings also illustrate the potential utility of nicotinamide as a probe for mechanisms of sirtuin-catalyzed ADP-ribosyl transfer.

Original languageEnglish (US)
Pages (from-to)10227-10239
Number of pages13
Issue number38
StatePublished - Sep 23 2008
Externally publishedYes

Fingerprint Dive into the research topics of 'Plasmodium falciparum Sir2 is an NAD<sup>+</sup>-dependent deacetylase and an acetyllysine-dependent and acetyllysine-independent NAD<sup>+</sup> glycohydrolase'. Together they form a unique fingerprint.

Cite this