In Plasmodium falciparum, the causative agent of cerebral malaria, silent 
information regulator 2 (Sir2) has been implicated in pathogenesis through its 
role in var gene silencing. P. falciparum Sir2 (PfSir2) in addition to the 
catalytic core, has a 13 residue N-terminal and 4 residue C-terminal extension 
over the shorter Archaeoglobus fulgidus Sir2. In this paper, we highlight our 
studies aimed at understanding the kinetic mechanism of PfSir2 and the role of 
N- and C-terminal extensions in protein function and oligomerization. 
Bisubstrate kinetic analysis showed that PfSir2 exhibits a rapid equilibrium 
ordered sequential mechanism, with peptide binding preceding NAD(+). This study 
also reports on surfactin as a novel Sir2 inhibitor exhibiting competitive 
inhibition with respect to NAD(+) and uncompetitive inhibition with acetylated 
peptide. This inhibition pattern with surfactin provides further support for 
ordered binding of substrates. Surfactin was also found to be a potent inhibitor 
of intra-erythrocytic growth of P. falciparum with 50% inhibitory concentration 
in the low micromolar range. PfSir2, like the yeast homologs (yHst2 and Sir2p), 
is a trimer in solution. However, dissociation of trimer to monomers in the 
presence of NAD(+) is characteristic of the parasite enzyme. Oligomerization 
studies on N- and/or C-terminal deletion constructs of PfSir2 highlight the role 
of C-terminus of the protein in mediating homotrimerization. N-terminal deletion 
resulted in reduced catalytic efficiency although substrate affinity was not 
altered in the constructs. Interestingly, deletion of both the ends relaxed 
NAD(+) specificity.