Plasmodium Falciparum Sir2: An Unusual Sirtuin With Dual Histone Deacetylase and ADP-ribosyltransferase Activity

Eukaryot Cell. 2007 Nov;6(11):2081-91. doi: 10.1128/EC.00114-07. Epub 2007 Sep 7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP Ribose Transferases / metabolism*
  • Amino Acid Sequence
  • Animals
  • Genetic Complementation Test
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / isolation & purification
  • Histone Deacetylases / metabolism*
  • Lysine / metabolism
  • Models, Biological
  • Molecular Sequence Data
  • Mutation / genetics
  • NAD / metabolism
  • Niacinamide / pharmacology
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / enzymology*
  • Protozoan Proteins / chemistry
  • Protozoan Proteins / isolation & purification
  • Protozoan Proteins / metabolism*
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism
  • Schizosaccharomyces pombe Proteins / metabolism
  • Sequence Alignment
  • Sirtuins / chemistry
  • Sirtuins / isolation & purification
  • Sirtuins / metabolism*

Substances

  • Protozoan Proteins
  • Recombinant Proteins
  • Schizosaccharomyces pombe Proteins
  • NAD
  • Niacinamide
  • ADP Ribose Transferases
  • Sirtuins
  • Histone Deacetylases
  • Lysine