Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.
SIRT1 stands for sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae), referring to the fact that its sirtuin homolog (biological equivalent across species) in yeast (Saccharomyces cerevisiae) is Sir2. SIRT1 is an enzyme located primarily in the cell nucleus that deacetylates transcription factors that contribute to cellular regulation (reaction to stressors, longevity).
Function
Sirtuin 1 is a member of the sirtuin family of proteins, homologs of the Sir2 gene in S. cerevisiae. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. The protein encoded by this gene is included in class I of the sirtuin family.
Sirtuin 1 is downregulated in cells that have high insulin resistance. Furthermore, SIRT1 was shown to de-acetylate and affect the activity of both members of the PGC1-alpha/ERR-alpha complex, which are essential metabolic regulatory transcription factors.
In vitro, SIRT1 has been shown to deacetylate and thereby deactivate the p53 protein, and may have a role in activating T helper 17 cells.
Selective ligands
Activators
Lamin A is a protein that had been identified as a direct activator of Sirtuin 1 during a study on progeria. Resveratrol has been claimed to be an activator of Sirtuin 1, but this effect has been disputed based on the fact that the initially used activity assay, using a non-physiological substrate peptide, can produce artificial results. Resveratrol increases the expression of SIRT1, meaning that it does increase the activity of SIRT1, though not necessarily by direct activation. However, resveratrol was later shown to directly activate Sirtuin 1 against non-modified peptide substrates. Resveratrol also enhances the binding between Sirtuin 1 and Lamin A. In addition to resveratrol, a range of other plant-derived polyphenols have also been shown to interact with SIRT1. SRT-1720 was also claimed to be an activator, but this now has been questioned. Methylene blue by increasing NAD+/NADH ratio. Metformin activates both PRKA and SIRT1.
Although neither resveratrol or SRT1720 directly activate SIRT1, resveratrol, and probably SRT1720, indirectly activate SIRT1 by activation of AMP-activated protein kinase (AMPK), which increases NAD+ levels (which is the cofactor required for SIRT1 activity). Elevating NAD+ is a more direct and reliable way to activate SIRT1.
Interactions
Sirtuin 1 has been shown in vitro to interact with ERR-alpha and AIRE.
Human Sirt1 has been reported having 136 direct interactions in interactomic studies involved in numerous processes.
Sir2
Sir2 (whose homolog in mammals is known as SIRT1) was the first gene of the sirtuin genes to be found. It was found in budding yeast, and, since then, members of this highly conserved family have been found in nearly all organisms studied. Sirtuins are hypothesized to play a key role in an organism's response to stresses (such as heat or starvation) and to be responsible for the lifespan-extending effects of calorie restriction.
The three letter yeast gene symbol Sir stands for Silent Information Regulator while the number 2 is representative of the fact that it was the second SIR gene discovered and characterized.
In the roundworm, Caenorhabditis elegans, Sir-2.1 is used to denote the gene product most similar to yeast Sir2 in structure and activity.
Method of action and observed effects
Sirtuins act primarily by removing acetyl groups from lysine residues within proteins in the presence of NAD+; thus, they are classified as "NAD+-dependent deacetylases" and have EC number 3.5.1. They add the acetyl group from the protein to the ADP-ribose component of NAD+ to form O-acetyl-ADP-ribose. The HDAC activity of Sir2 results in tighter packaging of chromatin and a reduction in transcription at the targeted gene locus. The silencing activity of Sir2 is most prominent at telomeric sequences, the hidden MAT loci (HM loci), and the ribosomal DNA (rDNA) locus (RDN1) from which ribosomal RNA is transcribed.