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Eukaryotic Cell, November 2007, p. 2081-2091, Vol. 6, No. 11
1535-9778/07/$08.00+0     doi:10.1128/EC.00114-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Plasmodium falciparum Sir2: an Unusual Sirtuin with Dual Histone Deacetylase and ADP-Ribosyltransferase Activity{triangledown} ,{dagger}

Catherine J. Merrick and Manoj T. Duraisingh*

Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115

Received 9 April 2007/ Accepted 29 August 2007

In the human malaria parasite Plasmodium falciparum, a member of the sirtuin family has been implicated in the epigenetic regulation of virulence genes that are vital to malaria pathogenesis and persistence. This eukaryotic sirtuin, PfSir2, is divergent in sequence from those characterized thus far and belongs to the phylogenetic class that contains primarily eubacterial and archaeal sirtuins. PfSir2 cofractionates with histones in blood-stage parasites, and the recombinant enzyme efficiently deacetylates the N-terminal tails of histones H3 and H4. In addition, PfSir2 can ADP-ribosylate both histones and itself, an activity that is minimal or absent in most sirtuins with significant deacetylase activity. Strikingly, the deacetylase activity of PfSir2 is dependent on its ADP-ribosylation. Finally, although PfSir2 is not affected by established sirtuin inhibitors, it can be completely inhibited by nicotinamide, a natural product of the sirtuin reaction. This study shows that PfSir2 has the appropriate characteristics to be a direct regulator of chromatin structure in P. falciparum. It also raises the significant possibility that both ADP-ribosylation and deacetylation of histones could be sirtuin-regulated modulators of chromatin structure in this species.

* Corresponding author. Mailing address: Department of Immunology and Infectious Diseases, Harvard School of Public Health, 665 Huntington Avenue, Building 1, Rm. 706, Boston, MA 02115. Phone: (617) 432-2675. Fax: (617) 432-4766. E-mail: mduraisi{at}hsph.harvard.edu

{triangledown} Published ahead of print on 7 September 2007.

{dagger} Supplemental material for this article may be found at http://ec.asm.org/.

Eukaryotic Cell, November 2007, p. 2081-2091, Vol. 6, No. 11
1535-9778/07/$08.00+0     doi:10.1128/EC.00114-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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