Understanding the kinetic and structural features of plasmodium falciparum Sir2: a NAD+ dependent deacetylase

Abstract

The silent information regulator (Sir) family of genes was first discovered by Klar et al when a spontaneous mutation at the mating type loci HMR and HML of yeast led to their desilencing and sterility of the strains [1]. At the same time another set of mutations were discovered in yeast with similar phenotype, which led to the identification of 4 genes belonging to the Sir family [2-4]. Gottlieb and colleagues showed that in yeast, Sir2 is the only gene that is required to suppress recombination in the rRNA genes [5]. In 1991, Gottschling et al showed that Sir2 is required for silencing telomeric genes in yeast [6]. Following this set of discoveries, Braunstein et al demonstrated that in yeast, telomeric and mating-type loci genes had hypoacetylated histones upon Sir2 overexpression [7]. This distinguished Sir2 from other Sir proteins as having deacetylase activity. Further, studies in yeast led to the understanding that Sir2 proteins are also required for the maintenance of genomic integrity and cell cycle progression [8]. The finding of Sir2 homologues in yeast and, shortly thereafter, in organisms ranging from bacteria to plants and mammals, demonstrated that Sir2 is a member of a large and ancient family of genes that are now referred to as ‘sirtuins’ (Sir2-like proteins).