Sirtuin enzymes are not only found throughout nature but are present in various intracellular compartments in eukaryotic cells as well. Of the seven human sirtuins, SIRT6 and 7 are located in the nucleus, and SIRT3, 4, and 5 in the mitochondrial matrix. SIRT1, while in the nucleus, interacts with core histone tails, but it can also be present in the cytoplasm and interact with many non-histone proteins. SIRT2 is normally found in the cytoplasm associated with the microtubule network and can deacetylate α-tubulin but is also associated with the condensed chromatin during mitosis.

Deacetylation of acetyl-lysine residues of proteins is the most widely characterized function of the mammalian sirtuin enzymes, with SIRT1, SIRT2, SIRT3, SIRT5, and SIRT6 exhibiting this activity. SIRT7 has been reported to deacetylate K382 a p53 based peptide; however, an independent was unable to deacetylate AcK382 of the full-length p53 protein, homologous to the peptide sequence used in the prior study. To date, the only reported enzymatic activityof mitochondrial SIRT4 is ADP-ribosyl transfer to glutamate dehydrogenase (GDH). In addition to deacetylase activity, nuclear SIRT6 has been shown to catalyze auto ADP-ribosylation.

Sirtuins are Class III to produce AADPR, leading many to hypothesize that the latter molecule acts as a second messenger responsible for downstream signaling in response to changes in cellular energy states. Consistent with this hypothesis, AADPR hydrolysis enzyme activity has been identified in yeast and humans. A suggested role for AADPR in chromatin silencing has been elucidated from studies in yeast. AADPR produced from sirtuin-catalyzed deacetylation of H4-K16 chromatin mark was found to enhance the formation of silent chromatin, by inducing Sir3 polymerization to form a silencing complex. To date, the signaling roles of AADPR produced from sirtuin-catalyzed deacetylation are poorly understood.

Since human sirtuin proteins are involved in a myriad of biological functions directly related to human aging and disease, and because several details of the catalytic mechanism of sirtuin proteins remain to be determined, this class of proteins is an active target for pharmacological small molecule effector design. In the case of human (HTS). Among the compounds identified in this way have been surfactin suramin and the most potent known sirtuin inhibitors, indole EX527 analogs. Surfactin is a large cyclic lipopeptide that is thought to be competitive with NAD+ binding and may be an effective anti-malarial agent through its ability to inhibit Plasmodium falciparum Sir2. Suramin is very large, and although smaller analogs of this compound have not been potent sirtuin inhibitors, binding of the compound to SIRT5 aided in crystallization of this sirtuin protein. The indoles are noncompetitive with both substrates, are postulated to bind after the release of nicotinamide, and have good ADME characteristics. Structure-activity relationship (SAR) studies of several of the identified inhibitor scaffolds have been performed in an attempt to identify compounds with increased potency, increased selectivity or more optimal drug-like characteristics with only modest success.


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