Sirtuin Signaling Pathway

Sirtuins are class III histone deacetylase enzymes that use NAD+ as a co-substrate for their enzymatic activities. In mammals seven yeast Sir2p homologue enzymes were identified, which are called sirtuins (SIRT1-7) and these play important roles in aging, metabolism, cancer, inflammation, DNA repair and cellular responses to stress. All mammalian sirtuins contain a conserved catalytic domain including a large and structurally homologous Rossmann-fold domain for NAD+ binding, and a more structurally diverse, smaller, zinc-binding domain. Biochemically, mammalian sirtuins are primarily NAD+-dependent lysine deacetylases, but some of them (SIRT4 and SIRT6) also possess ADP-ribosyltransferase activity.SIRT1, SIRT6 and SIRT7 are primarily nuclear enzymes which regulate transcription factors and with histone modifications coordinate gene expression programs that can direct the cellular metabolic state. In addition SIRT7 plays important role in rRNA transcription and cell cycle regulation. Cytosolic functions of SIRT1 have also been identified. SIRT2 is largely cytosolic and coordinates microtubule dynamics as well as the activity of transcription factors outside the nucleus. SIRT3, SIRT4 and SIRT5 are located in the mitochondrial matrix and directly alter the activity of many metabolic enzymes. SIRT3 has been found to be a tumor suppressor, mainly by inhibiting mitochondrial ROS production through deacetylation and activation of SOD2, IDH2 and FoxO3a. SIRT4 has important roles in cell metabolism and carcinogenesis as well. SIRT5 functions primarily as a malonyl, succinyl and glutaryl deacylase and controls ammonia detoxification by regulating CPS1, the first enzyme of the urea cycle. Indeed, nearly every sirtuin plays a role in regulating metabolism and energy homeostasis by controlling multiple metabolic pathways, such as lipid and glucose metabolism, ketone bodies synthesis, urea cycle and insulin secretion.Out of the seven sirtuins, SIRT3, SIRT4 and SIRT6 have been recently shown to directly regulate metabolic reprogramming in cancer cells. Moreover, SIRT1, SIRT2 and SIRT7 could potentially afffect cancer metabolism by modulating the activity of important metabolic processes.Calorie restriction (CR) and fasting induce sirtuin expression, because reduction in energy intake leads to increased carbon oxidation in mitochondria, which produces NAD+, the key activator of sirtuins, from NADH. The polyphenol resveratrol (RSV) was the first compound described able to mimic CR by stimulating sirtuins. Due to its poor bioavailability, reformulated versions of RSV with improved bioavailability have been developed. Treatment with RSV (resVida, Longevinex, SRT501) showed a marked reduction in signs of aging, tumorigenesis, and also enhanced mitochondrial biogenesis, improved metabolic signaling pathways, and blunted pro-inflammatory pathways. Molecules that are structurally unrelated to resveratrol (SRT1720, SRT2104, SRT2379) have been also developed to stimulate sirtuin activities more potently than resveratrol.Sirtuin inhibitors with a wide range of core structures have been identified for SIRT1, SIRT2, SIRT3 and SIRT5 (splitomicin, sirtinol, AGK2, cambinol, suramin, tenovin, salermide). SIRT1 inhibition has been proposed in the treatment of cancer, immunodeficiency virus infections, Fragile X mental retardation syndrome and for preventing or treating parasitic diseases, whereas SIRT2 inhibitors might be useful for the treatment of cancer and neurodegenerative diseases.