Sirtuins and Pyridine Nucleotides

Abstract

The silencer information regulator (Sir) family of proteins has attracted much attention during the past decade due to their prominent role in metabolic homeostasis in mammals. The Sir1-4 proteins were first discovered in yeast as nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, which through a gene silencing effect promoted longevity. The subsequent discovery of a homologous sirtuin (Sirt) family of proteins in the mammalian systems soon led to the realization that these molecules have beneficial effects in metabolism- and aging-related diseases. Through their concerted functions in the central nervous system, liver, pancreas, skeletal muscle, and adipose tissue, they regulate the body’s metabolism. Sirt1, -6, and -7 exert their functions, predominantly, through a direct effect on nuclear transcription of genes involved in metabolism, whereas Sirt3-5 reside in the mitochondrial matrix and regulate various enzymes involved in the tricarboxylic acid and urea cycles, oxidative phosphorylation, as well as reactive oxygen species production. An interesting aspect of sirtuin’s functionality involves their regulation by the circadian rhythm, which impacts their function via cyclically regulating systemic NAD+ availability, further establishing the link of these proteins to metabolism. In this review we will discuss the relation of sirtuins to NAD+ metabolism, their mechanism of function, and their role in metabolism and mitochondrial functions. In addition, we will describe their effects in the cardiovascular and central nervous systems.

Hypertrophic and Inflammatory Markers in Isoproterenol-Induced CardiacHypertrophy and its Pharmacological Correction

“…Rapid glycolysis during neuronal activation increases the conversion of pyruvate to lactate and an increased NADH/NAD + ratio, which in turn increases cerebral blood flow [8]. Loss of NAD can make a cell unable to carry out its energy-dependent functions and defend itself against oxidative stress because of loss of activity of certain cell-survival factors that are NAD-dependent, such as sirtuins [9]. Treatment with exogenous NAD blocked the induction of atrial natriuretic factor release from nuclei, thus suggesting the antihypertrophic activity of NAD [6].…”

“…The intracellular NAD + /NADH ratio controls flux through various dehydrogenase enzymes involved in both anaerobic and aerobic metabolism and also regulates posttranslational protein modification. The intracellular NADP + /NADPH ratio controls flux through the pentose phosphate and the polyol pathways, while also regulating ion channel function and oxidative stress progression [9,10]. Not only does the NAD + /NADH ratio regulate the rates of ATP production, it can also modify energy substrate preference and depletion of cellular NAD levels and deterioration in NAD-mediated activation of Silent Information regulator (SIRT)3, but not SIRT1 cascade mechanism [9,11,12].…”

“…The intracellular NADP + /NADPH ratio controls flux through the pentose phosphate and the polyol pathways, while also regulating ion channel function and oxidative stress progression [9,10]. Not only does the NAD + /NADH ratio regulate the rates of ATP production, it can also modify energy substrate preference and depletion of cellular NAD levels and deterioration in NAD-mediated activation of Silent Information regulator (SIRT)3, but not SIRT1 cascade mechanism [9,11,12]. The exogenous NAD restored the activity of endogenous anti-hypertrophic signaling via activation of the SIRT3-liver kinase B (LKB) 1-AMP kinase (AMPK) pathway [6].…”

Nicotinamide Riboside Delivery Generates Nad+ Reserves to Protect Vascular Cells Against Oxidative Damage

“…NMN is degraded outside of the cell and brought in as either NA, or NR, creating an additional step for up-take (201). Finally, Nam is a known SIRT inhibitor (256).…”

The Biology of Immortality

“…For example, a group of 7 "sirtuin" genes help protect against cellular stress [50][51][52][53][54]. Overexpression of the Sir2 gene in yeast and C. elegans has been reported to increase their lifespans in some [3,27,53] but not all studies [55].…”