Sirtuin-1

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Sirtuin-1

Available structural data : 4I5I , 4IF6 , 4IG9 , 4KXQ

Properties of human protein
Mass / length primary structure 747 amino acids
Cofactor NAD +, zinc
Identifier
Gene names SIRT1  ; SIR2
External IDs
Enzyme classification
EC, category 3.5.1.- ,  hydrolase
Response type Deacetylation of acetyl lysine in acetyl peptides, ADP ribosylation
Substrate Acetyl peptide + NAD + (peptides are p53 , ku70 , TAF1B , PCAF , MYOD1 , histones , HIV-Tat), peptide + NAD +
Products Peptide + acetyl-NAD +, nicotinamide + ADP-ribosylated peptide
Orthologue
human House mouse
Entrez 23411 93759
Ensemble ENSG00000096717 ENSMUSG00000020063
UniProt Q96EB6 Q923E4
Refseq (mRNA) NM_001142498 NM_001159589
Refseq (protein) NP_001135970 NP_001153061
Gene locus Chr 10: 67.88 - 67.92 Mb Chr 10: 63.32 - 63.38 Mb
PubMed search 23411 93759

Sirtuin-1 (Sir2, Sirt1) (Gen: SIRT1 ) is an enzyme that modifies several regulatory proteins through deacetylation or complex formation and is thus part of signal transduction in humans and other multicellular animals . Sirtuin-1 slows down the initiation of cell death , the differentiation of muscle cells, and switches the metabolism to fat burning . The previously suspected ability to stimulate the formation of heterochromatin is less pronounced. Sirtuin-1 is activated by resveratrol , an ingredient found especially in blue grapes , and other flavonoids such as butein , piceatannol and quercetin . An experimental active ingredient, SRT1720 , activated sirtuin-1 in mice in such a way that they remained slim and powerful despite a high-fat diet. SIRT1 shows direct interactions with 136 proteins in the protein interaction network.

function

SRT1720, a powerful activator for sirtuin-1

Sirtuin-1 is one of seven sirtuins in humans, all of which have the ability to deacetylate (preferably the amino acid lysine in the target peptide), but have different attack peptides.

  • p53 , whose activity as a transcription factor is reduced by deacetylation, as a result of which cell apoptosis , which occurs, for example, in response to DNA damage or oxidative stress, is delayed. Sirtuin-1 is able to counteract the acetylation of p53 by the tumor suppressor PML
  • Forkhead box proteins whose deacetylation, parallel to that of p53, delays apoptosis. In addition, complex formation with FOXO3 strengthens the cell's robustness against oxidative stress
  • the DNA repair protein ku70 , which secretes the apoptosis-inducing factor bax
  • the transcription factor PGC1A , which stimulates gluconeogenesis and the export of glucose from the liver
  • Histones 1, 3 and 4, which have been deacetylated by sirtuin-1 , at least in baker's yeast , in order to initiate the formation of heterochromatin

Sirtuin-1 also acts through direct bonding, among other things

  • PPAR γ , which itself and its cofactors Ncor and Smrt are bound by sirtuin-1 in a state of hunger, as a result of which more fats are mobilized from white adipocytes . At the same time, Sirtuin-1 stops the formation of new fat cells and lyses differentiated cells. The lysis of fat cells alone is sufficient to explain the increase in life in experiments with mice
  • FOXO3 and p53 only in hunger situations, both factors and hunger must be present so that sirtuin-1 can act on PPAR γ . This means that FOXO3, p53 and Sirtuin-1 together form a system that reacts to hunger.

inhibition

The tumor suppressor DBC1 ( deleted in breast cancer ) is a natural inhibitor for sirtuin-1.

pharmacology

Due to the effects of Sirtuin-1 in the body, it seems sensible to increase the level of the protein in existing or threatened diabetes mellitus type 2. Likewise, some pharmacologists promise to increase the longevity of humans in general by activating the sirtuin-1 signaling pathways . So far, there have only been recommendations on nutrition available that specifically concerned the known effects of resveratrol .

Since 2007, substances have been available to the industry that exceed the activating effect of resveratrol. In particular, the SRT1720 substance is said to be effective by a factor of 1000, which would reduce daily intake to the milligram range.

Individual evidence

  1. ↑ UniProt Q96EB6
  2. ↑ JN Feige et al .: Specific SIRT1 Activation Mimics Low Energy Levels and Protects against Diet-Induced Metabolic Disorders by Enhancing Fat Oxidation. Cell Metabolism 8/5 / 2008 : 347-348 doi : 10.1016 / j.cmet.2008.08.017 .
  3. ↑ Sharma et al., 2012: Interactomic and pharmacological insights on human Sirt-1. Front. Pharmacol. 3:40. doi : 10.3389 / fphar.2012.00040 .
  4. ↑ Sirtuin-1.  In: Online Mendelian Inheritance in Man . (English).
  5. ↑ JC Milne et al .: Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450/7170/ 2007 : 712-716. PMID 18046409 .

literature