Sirtuin

Last updated

Sir2 family
1SZD.png
Crystallographic structure of yeast sir2 (rainbow colored cartoon, N-terminus = blue, C-terminus = red) complexed with ADP (space-filling model, carbon = white, oxygen = red, nitrogen = blue, phosphorus = orange) and a histone H4 peptide (magenta) containing an acylated lysine residue (displayed as spheres) [1]
Identifiers
SymbolSIR2
Pfam PF02146
Pfam clan CL0085
InterPro IPR003000
PROSITE PS50305
SCOP2 1j8f / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 1ici ​, 1j8f ​, 1m2g ​, 1m2h ​, 1m2j ​, 1m2k ​, 1m2n ​, 1ma3 ​, 1q14 ​, 1q17 ​, 1q1a ​, 1s5p ​, 1s7g ​, 1szc ​, 1szd ​, 1yc2 ​, 1yc5 ​

Sirtuins are a family of signaling proteins involved in metabolic regulation. [2] [3] They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life. [2] Chemically, sirtuins are a class of proteins that possess either mono-ADP-ribosyltransferase or deacylase activity, including deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity. [4] [5] [6] The name Sir2 comes from the yeast gene 'silent mating-type information regulation 2', [7] the gene responsible for cellular regulation in yeast.

Contents

From in vitro studies, sirtuins were thought to be implicated in influencing cellular processes like aging, transcription, apoptosis, inflammation [8] and stress resistance, as well as energy efficiency and alertness during low-calorie situations. [9] As of 2018, there was no clinical evidence that sirtuins affect human aging, [10] and a 2022 review criticized researchers who propagate this claim. [11]

Yeast Sir2 and some, but not all, sirtuins are protein deacetylases. Unlike other known protein deacetylases, which simply hydrolyze acetyl-lysine residues, the sirtuin-mediated deacetylation reaction couples lysine deacetylation to NAD+ hydrolysis. [12] This hydrolysis yields O-acetyl-ADP-ribose, the deacetylated substrate and nicotinamide, which is an inhibitor of sirtuin activity itself. These proteins utilize NAD+ to maintain cellular health and turn NAD+ to nicotinamide (NAM). [13] The dependence of sirtuins on NAD+ links their enzymatic activity directly to the energy status of the cell via the cellular NAD+:NADH ratio, the absolute levels of NAD+, NADH or NAM or a combination of these variables.

Sirtuins that deacetylate histones are structurally and mechanistically distinct from other classes of histone deacetylases (classes I, IIA, IIB and IV), which have a different protein fold and use Zn2+ as a cofactor. [14] [15]

Actions and species distribution

Sirtuins are a family of signaling proteins involved in metabolic regulation. [2] [3] They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life. [2] Whereas bacteria and archaea encode either one or two sirtuins, eukaryotes encode several sirtuins in their genomes. In yeast, roundworms, and fruitflies, sir2 is the name of one of the sirtuin-type proteins (see table below). [16] Mammals possess seven sirtuins (SIRT1–7) that occupy different subcellular compartments: SIRT1, SIRT6 and SIRT7 are predominantly in the nucleus, SIRT2 in the cytoplasm, and SIRT3, SIRT4 and SIRT5 in the mitochondria. [2]

History

Research on sirtuin protein was started in 1991 by Leonard Guarente of MIT. [17] [18] Interest in the metabolism of NAD+ heightened after the year 2000 discovery by Shin-ichiro Imai and coworkers in the Guarente laboratory that sirtuins are NAD+-dependent protein deacetylases . [19]

Types

The first sirtuin was identified in yeast (a lower eukaryote) and named sir2. In more complex mammals, there are seven known enzymes that act in cellular regulation, as sir2 does in yeast. These genes are designated as belonging to different classes (I-IV), depending on their amino acid sequence structure. [20] Several gram positive prokaryotes as well as the gram negative hyperthermophilic bacterium Thermotoga maritima possess sirtuins that are intermediate in sequence between classes, and these are placed in the "undifferentiated" or "U" class. In addition, several Gram positive bacteria, including Staphylococcus aureus and Streptococcus pyogenes , as well as several fungi carry macrodomain-linked sirtuins (termed "class M" sirtuins). [6]

ClassSubclassSpeciesIntracellular
location		ActivityCellular FunctionCatalytic Domains [21] Histone Deacetylation Target [22] Non-Histone Deacetylation Target [22] Pathology [22]
BacteriaYeastMouseHuman
IaSir2,
Hst1		Sirt1 SIRT1 Nucleus, cytoplasmDeacetylaseMetabolism inflammation244-498 (of 766aa) H3K9ac, H1K26ac, H4K16ac Hif-1α, Hif-2α, MYC, P53, BRCA1, FOXO3A, MyoD, Ku70, PPARγ, PCAF, Suv39h1, TGFB1, WRN, NBS1Neurodegenerative diseases, Cancer: acute myeloid leukemia, colon, prostate, ovarian, glioma, breast, melanoma, lung adenocarcinoma
bHst2Sirt2 SIRT2 Nucleus and cytoplasmDeacetylaseCell cycle, tumorigenesis65-340 (of 388aa) H3K56ac, H4K16ac Tubulin, Foxo3a, EIF5A, P53, G6PD, MYCNeurodegenerative diseases, Cancer: brain tissue, glioma
Sirt3 SIRT3 MitochondriaDeacetylaseMetabolism126-382 (of 399aa) H3K56ac, H4K14acSOD2, PDH, IDH2, GOT2, FoxO3aNeurodegenerative diseases, Cancer: B cell chronic lymphocytic leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, breast, gastric
cHst3,
Hst4
IISirt4 SIRT4 MitochondriaADP-ribosyl transferaseInsulin secretion45-314 (of 314aa)UnknownGDH, PDHCancer: breast, colorectal
IIISirt5 SIRT5 MitochondriaDemalonylase, desuccinylase and deacetylaseAmmonia detoxification41-309 (of 310aa)UnknownCPS1Cancer: pancreatic, breast, non-small cell lung carcinoma
IVaSirt6 SIRT6 NucleusDemyristoylase, depalmitoylase, ADP-ribosyl transferase and deacetylaseDNA repair, metabolism, TNF secretion35-274 (of 355aa) H3K9ac, H3K56ac UnknownCancer: breast, colon
bSirt7 SIRT7 NucleolusDeacetylase rRNA transcription 90-331 (of 400aa)H3K18acHif-1α, Hif-2αCancer: liver, testis, spleen, thyroid, breast
U cobB [23] Regulation of acetyl-CoA synthetase [24] metabolism
MSirTM [6] ADP-ribosyl transferaseROS detoxification

SIRT3, a mitochondrial protein deacetylase, plays a role in the regulation of multiple metabolic proteins like isocitrate dehydrogenase of the TCA cycle. It also plays a role in skeletal muscle as a metabolic adaptive response. Since glutamine is a source of a-ketoglutarate used to replenish the TCA cycle, SIRT4 is involved in glutamine metabolism. [25]

Ageing

Although preliminary studies with resveratrol, an activator of deacetylases such as SIRT1, [26] led some scientists to speculate that resveratrol may extend lifespan, no clinical evidence for such an effect has been discovered, as of 2018. [10]

Tissue fibrosis

A 2018 review indicated that SIRT levels are lower in tissues from people with scleroderma, and such reduced SIRT levels may increase risk of fibrosis through modulation of the TGF-β signaling pathway. [27]

DNA repair in laboratory studies

SIRT1, SIRT6 and SIRT7 proteins are employed in DNA repair. [28] SIRT1 protein promotes homologous recombination in human cells and is involved in recombinational repair of DNA breaks. [29]

SIRT6 is a chromatin-associated protein and in mammalian cells is required for base excision repair of DNA damage. [30] SIRT6 deficiency in mice leads to a degenerative aging-like phenotype. [30] In addition, SIRT6 promotes the repair of DNA double-strand breaks. [31] Furthermore, over-expression of SIRT6 can stimulate homologous recombinational repair. [32]

SIRT7 knockout mice display features of premature aging. [33] SIRT7 protein is required for repair of double-strand breaks by non-homologous end joining. [33]

Inhibitors

Certain sirtuin activity is inhibited by nicotinamide, which binds to a specific receptor site. [34] It is an inhibitor in vitro of SIRT1, but can be a stimulator in cells. [35]

Activators

List of known sirtuin activator in vitro
CompoundTarget/SpecificityReferences
Piceatannol SIRT1 [36]
SRT-1720 SIRT1 [36]
SRT-2104 SIRT1 [36]
Beta-Lapachone SIRT1 [36]
Cilostazol SIRT1 [36]
Quercetin and rutin derivativesSIRT6 [37]
Luteolin SIRT6 [37]
Fisetin SIRT6 [37]
Phenolic acid SIRT6 [37]
Fucoidan SIRT6 [38]
Curcumin SIRT1, SIRT6 [39]
Pirfenidone SIRT1 [40]
Myricetin SIRT6 [37]
Cyanidin SIRT6 [37]
Delphinidin SIRT6 [37]
Apigenin SIRT6 [37]
Butein SIRT6 [41]
Isoliquiritigenin SIRT6 [41]
Ferulic acid SIRT1 [41]
Berberine SIRT1 [41]
Catechin SIRT1 [41]
Malvidin SIRT1 [41]
Pterostilbene SIRT1 [41]
Tyrosol SIRT1 [41]


See also

Related Research Articles

<span class="mw-page-title-main">Nicotinamide adenine dinucleotide</span> Chemical compound which is reduced and oxidized

Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other, nicotinamide. NAD exists in two forms: an oxidized and reduced form, abbreviated as NAD+ and NADH (H for hydrogen), respectively.

<span class="mw-page-title-main">Histone deacetylase</span> Class of enzymes important in regulating DNA transcription

Histone deacetylases (EC 3.5.1.98, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on both histone and non-histone proteins. HDACs allow histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. HDAC's action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins. In general, they suppress gene expression.

Leonard Pershing Guarente is an American biologist best known for his research on life span extension in the budding yeast Saccharomyces cerevisiae, roundworms, and mice. He is a Novartis Professor of Biology at the Massachusetts Institute of Technology.

Histone deacetylase inhibitors are chemical compounds that inhibit histone deacetylases. Since deacetylation of histones produces transcriptionally silenced heterochromatin, HDIs can render chromatin more transcriptionally active and induce epigenomic changes.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">ADP-ribosylation</span> Addition of one or more ADP-ribose moieties to a protein.

ADP-ribosylation is the addition of one or more ADP-ribose moieties to a protein. It is a reversible post-translational modification that is involved in many cellular processes, including cell signaling, DNA repair, gene regulation and apoptosis. Improper ADP-ribosylation has been implicated in some forms of cancer. It is also the basis for the toxicity of bacterial compounds such as cholera toxin, diphtheria toxin, and others.

<span class="mw-page-title-main">Nicotinamide phosphoribosyltransferase</span> Human protein and coding gene

Nicotinamide phosphoribosyltransferase, formerly known as pre-B-cell colony-enhancing factor 1 (PBEF1) or visfatin for its extracellular form (eNAMPT), is an enzyme that in humans is encoded by the NAMPT gene. The intracellular form of this protein (iNAMPT) is the rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD+) salvage pathway that converts nicotinamide to nicotinamide mononucleotide (NMN) which is responsible for most of the NAD+ formation in mammals. iNAMPT can also catalyze the synthesis of NMN from phosphoribosyl pyrophosphate (PRPP) when ATP is present. eNAMPT has been reported to be a cytokine (PBEF) that activates TLR4, that promotes B cell maturation, and that inhibits neutrophil apoptosis.

<span class="mw-page-title-main">Sirtuin 1</span> Protein

Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.

<span class="mw-page-title-main">Sirtuin 2</span> Protein-coding gene in the species Homo sapiens

NAD-dependent deacetylase sirtuin 2 is an enzyme that in humans is encoded by the SIRT2 gene. SIRT2 is an NAD+ -dependent deacetylase. Studies of this protein have often been divergent, highlighting the dependence of pleiotropic effects of SIRT2 on cellular context. The natural polyphenol resveratrol is known to exert opposite actions on neural cells according to their normal or cancerous status. Similar to other sirtuin family members, SIRT2 displays a ubiquitous distribution. SIRT2 is expressed in a wide range of tissues and organs and has been detected particularly in metabolically relevant tissues, including the brain, muscle, liver, testes, pancreas, kidney, and adipose tissue of mice. Of note, SIRT2 expression is much higher in the brain than all other organs studied, particularly in the cortex, striatum, hippocampus, and spinal cord.

<span class="mw-page-title-main">NNMT</span> Protein-coding gene in humans

Nicotinamide N-methyltransferase (NNMT) is an enzyme that in humans is encoded by the NNMT gene. NNMT catalyzes the methylation of nicotinamide and similar compounds using the methyl donor S-adenosyl methionine (SAM-e) to produce S-adenosyl-L-homocysteine (SAH) and 1-methylnicotinamide.

<span class="mw-page-title-main">Sirtuin 3</span> Protein-coding gene in the species Homo sapiens

NAD-dependent deacetylase sirtuin-3, mitochondrial also known as SIRT3 is a protein that in humans is encoded by the SIRT3 gene [sirtuin 3 ]. SIRT3 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein. SIRT3 exhibits NAD+-dependent deacetylase activity.

<span class="mw-page-title-main">Sirtuin 5</span> Protein-coding gene in the species Homo sapiens

Sirtuin 5 , also known as SIRT5 is a protein which in humans in encoded by the SIRT5 gene and in other species by the orthologous Sirt5 gene.

<span class="mw-page-title-main">Sirtuin 7</span> Protein-coding gene in the species Homo sapiens

NAD-dependent deacetylase sirtuin 7 is an enzyme that in humans is encoded by the SIRT7 gene. SIRT7 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein.

<span class="mw-page-title-main">Sirtuin 6</span> Protein-coding gene in the species Homo sapiens

Sirtuin 6 is a stress responsive protein deacetylase and mono-ADP ribosyltransferase enzyme encoded by the SIRT6 gene. In laboratory research, SIRT6 appears to function in multiple molecular pathways related to aging, including DNA repair, telomere maintenance, glycolysis and inflammation. SIRT6 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein.

<span class="mw-page-title-main">Sirtuin 4</span> Protein-coding gene in the species Homo sapiens

Sirtuin 4, also known as SIRT4, is a mitochondrial protein which in humans is encoded by the SIRT4 gene. SIRT4 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein. SIRT4 exhibits NAD+-dependent deacetylase activity.

Sirtuin-activating compounds (STAC) are chemical compounds having an effect on sirtuins, a group of enzymes that use NAD+ to remove acetyl groups from proteins. They are caloric restriction mimetic compounds that may be helpful in treating various aging-related diseases.

<span class="mw-page-title-main">CobB</span> Bacterial protein

CobB is a bacterial protein that belongs to the sirtuin family, a broadly conserved family of NAD+-dependent protein deacetylases.

<span class="mw-page-title-main">Genetics of aging</span> Overview of the genetics of aging

Genetics of aging is generally concerned with life extension associated with genetic alterations, rather than with accelerated aging diseases leading to reduction in lifespan.

SilentInformationRegulator (SIR) proteins are involved in regulating gene expression. SIR proteins organize heterochromatin near telomeres, ribosomal DNA (rDNA), and at silent loci including hidden mating type loci in yeast. The SIR family of genes encodes catalytic and non-catalytic proteins that are involved in de-acetylation of histone tails and the subsequent condensation of chromatin around a SIR protein scaffold. Some SIR family members are conserved from yeast to humans.

<span class="mw-page-title-main">MIR34A</span> Non-coding RNA in the species Homo sapiens

MicroRNA 34a (miR-34a) is a microRNA that in humans is encoded by the MIR34A gene.

References

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