The sirtuin (silent information regulator 2) proteins are NAD + -dependent deacetylases that are implicated in diverse biological processes including DNA regulation, metabolism and longevity. Homologues of the prototypic yeast Sir2p have been identified in all three kingdoms of life, and while bacteria and archaea typically contain one to two sirtuins, eukaryotic organisms contain multiple members. Sirtuins are regulated in part by the cellular concentrations of the noncompetitive inhibitor, nicotinamide, and several synthetic modulators of these enzymes have been identified. The x-ray crystal structures of several sirtuin proteins in various liganded forms have been determined. This wealth of structural information, together with related biochemical studies, have provided important insights into the catalytic mechanism, substrate specificity, and inhibitory mechanism of sirtuin proteins. Implications for future structural studies to address outstanding questions in the field are also discussed.

The sirtuin proteins are broadly conserved NAD + -dependant deacetylases that are implicated in diverse biological processes including DNA recombination and repair, transcriptional silencing, longevity, apoptosis, axonal protection, insulin signaling and fat mobilization. Because of these associations, the identification of small molecule sirtuin modulators has been of significant interest. Here we report on high throughput screening against the yeast sirtuin, Hst2, leading to the identification of four unique inhibitor scaffolds that also inhibit the human sirtuins, SIRT1, SIRT2 and SIRT3. The identified inhibitor scaffolds range in potency from IC 50 values of 6.5-130 μ M against Hst2. Each of the inhibitor scaffolds binds reversibly to the enzyme, and kinetic analysis reveals that each of the inhibitors is non-competitive with respect to both acetyl-lysine and NAD + binding. Limited SAR analysis of the scaffolds also identifies which functional groups may be important for inhibition. These sirtuin inhibitors are low molecular weight and well-suited for lead molecule optimization, making them useful chemical probes to study the mechanism and biological roles of sirtuins and potential starting points for optimization into therapeutics.

Background: In neonatal chylothorax, thoracic lymphatic drainage is ineffective. The resultant effusions often require drainage, leading to a loss of immune components. Affected infants can be managed with formula or defatted human milk feedings low in long chain triglycerides to decrease lymph production. We hypothesized that there is no significant difference in the immunological profile or antibacterial effect of full fat and defatted human milk. Methods: Milk from lactating mothers was divided into one aliquot that was defatted via centrifugation with the full fat aliquot as control. Macronutrient content was analyzed with mid-infrared spectroscopy. Flow cytometry was used to measure immune cell populations. Lactoferrin, lysozyme, IgA and IgG values were determined using ELISA. The antibacterial properties were determined by inoculating paired full fat and defatted milk samples with Escherichia coli or Streptococcus pneumoniae bacteria and performing colony counts. Results: Compared to full fat milk, defatted milk demonstrated decreased total energy and fat and increased carbohydrate concentrations. Defatted milk demonstrated a significant decrease in all immune cell populations. There was no difference in IgA, IgG, lysozyme or lactoferrin concentrations. Both aliquots demonstrated equivalent