SIRT3
Encyclopedia
NAD-dependent deacetylase sirtuin-3, mitochondrial also known as SIRT3 is a protein
that in humans is encoded by the SIRT3 gene
[sirtuin (silent mating type information regulation 2 homolog) 3 (S. cerevisiae)]. SIRT3 is member of the mammalian sirtuin
family of proteins, which are homologs to the yeast Sir2 protein. SIRT3 exhibits NAD+-dependent deacetylase
activity.
Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes, and the protein encoded by this gene is included in class I of the sirtuin family. The human sirtuins have a range of molecular functions and have emerged as important proteins in aging, stress resistance and metabolic regulation. Yeast sirtuin proteins are known to regulate epigenetic
gene silencing
and suppress recombination of rDNA
. In addition to protein deacetylation, studies have shown that the human sirtuins may also function as intracellular regulatory proteins with mono ADP ribosyltransferase
activity.
, and contains a mitochondrial processing peptide at the N-terminus. A set of crystal structures of human SIRT3 have been solved, including an apo-structure with no substrate, a structure with a peptide containing acetyl
lysine
of its natural substrate acetyl-CoA synthetase 2
, a reaction intermediate structure trapped by a thioacetyl peptide and a structure with the dethioacetylated peptide bond. These structures show the conformational
changes induced by the two substrates required for the reaction, the acetylated substrate peptide and NAD+
. In addition, a binding study by isothermal titration calorimetry
suggests that the acetylated peptide is the first substrate to bind to SIRT3, prior to NAD+.
and SIRT5
, are located in mitochondria and have been implicated in regulating metabolic processes. Endogenous SIRT3 is a soluble protein located in the mitochondrial matrix. Overexpression of SIRT3 in cultured cells increases respiration and decreases the production of reactive oxygen species. Fasting increases SIRT3 expression in white
and brown adipose tissue
(WAT and BAT, respectively) and overexpression of SIRT3 in HIB1B brown adipocytes increases the expression of PGC-1α
and UCP1
, suggesting a role for SIRT3 in adaptive thermogenesis
BAT. BAT is different from WAT because it harbors large numbers of mitochondria and is important for thermogenesis in rodents. Thermogenesis in BAT is mediated by the uncoupling protein 1 (UCP1), which induces proton leakage and thereby generates heat instead of ATP. Mechanistic insights into how SIRT3 affects thermogenesis in BAT is lacking and whether SIRT3 affects UCP1 activity directly is not known.
In addition to controlling metabolism at the transcriptional level, sirtuins also directly control the activity of metabolic enzymes. In Salmonella enterica
, the bacterial sirtuin CobB regulates the activity of the enzyme acetyl-coenzyme A (acetyl-CoA
) synthetase
. As mentioned above, orthologs of acetyl-CoA synthetase exist in the cytoplasm (AceCS1) and in mitochondria (AceCS2) in mammals. The presence of the sirtuin deacetylase SIRT3 in the mitochondrial matrix suggests the existence of lysine acetylated mitochondrial proteins. Indeed, SIRT3 deacetylates and activates the mammalian mitochondrial acetyl-coA synthetase (AceCS2). Furthermore, SIRT3 and AceCS2 are found complexed with one another, suggesting a critical role for control of AceCS2 activity by SIRT3.
activity. The observation that SIRT3 has nuclear activity came from a report that SIRT3 protected cardiomyocytes from stress mediated cell death and that this effect was due to deacetylation of a nuclear factor, Ku-70
.
function, aging, and carcinogeneis.
Sirt3 functions as a mitochondrial tumor suppressor
protein. Damaged and aberrant mitochondrial function, similar to gene mutations, may be an early event that ultimately leads to the development of cancers. Mice genetically altered to delete Sirt3 develop estrogen
and progesterone
receptor (ER/PR) positive breast mammary tumors. In tumor samples from women with breast cancer, SIRT3 expression was decreased, as compared to normal breast tissues. Thus, the Sirt3 knockout
model may be used to investigate ER/PR positive breast tumor development.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the SIRT3 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
[sirtuin (silent mating type information regulation 2 homolog) 3 (S. cerevisiae)]. SIRT3 is member of the mammalian sirtuin
Sirtuin
Sirtuin or Sir2 proteins are a class of proteins that possess either histone deacetylase or mono-ribosyltransferase activity. Sirtuins regulate important biological pathways in bacteria, archaea and eukaryotes...
family of proteins, which are homologs to the yeast Sir2 protein. SIRT3 exhibits NAD+-dependent deacetylase
Protein deacetylase
Protein deacetylase; any enzyme that removes acetyl groups from lysine amino acids in proteins.The main ones are histone deacetylases and sirtuins ....
activity.
Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes, and the protein encoded by this gene is included in class I of the sirtuin family. The human sirtuins have a range of molecular functions and have emerged as important proteins in aging, stress resistance and metabolic regulation. Yeast sirtuin proteins are known to regulate epigenetic
Epigenetics
In biology, and specifically genetics, epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence – hence the name epi- -genetics...
gene silencing
Gene silencing
Gene silencing is a general term describing epigenetic processes of gene regulation. The term gene silencing is generally used to describe the "switching off" of a gene by a mechanism other than genetic modification...
and suppress recombination of rDNA
Ribosomal DNA
Ribosomal DNA codes for ribosomal RNA. The ribosome is an intracellular macromolecule that produces proteins or polypeptide chains. The ribosome itself consists of a composite of proteins and RNA. As shown in the figure, rDNA consists of a tandem repeat of a unit segment, an operon, composed of...
. In addition to protein deacetylation, studies have shown that the human sirtuins may also function as intracellular regulatory proteins with mono ADP ribosyltransferase
Nucleoside ribosyltransferase
In enzymology, a nucleoside ribosyltransferase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are D-ribosyl-base1 and base2, whereas its two products are D-ribosyl-base2 and base1....
activity.
Structure
SIRT3 is a soluble protein located in the mitochondrial matrixMitochondrial matrix
In the mitochondrion, the matrix contains soluble enzymes that catalyze the oxidation of pyruvate and other small organic molecules.The mitochondrial matrix also contains the mitochondria's DNA and ribosomes. The word "matrix" stems from the fact that this space is viscous, compared to the...
, and contains a mitochondrial processing peptide at the N-terminus. A set of crystal structures of human SIRT3 have been solved, including an apo-structure with no substrate, a structure with a peptide containing acetyl
Acetyl
In organic chemistry, acetyl is a functional group, the acyl with chemical formula COCH3. It is sometimes represented by the symbol Ac . The acetyl group contains a methyl group single-bonded to a carbonyl...
lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
of its natural substrate acetyl-CoA synthetase 2
ACSL5
Long-chain-fatty-acid—CoA ligase 5 is an enzyme that in humans is encoded by the ACSL5 gene.-Further reading:...
, a reaction intermediate structure trapped by a thioacetyl peptide and a structure with the dethioacetylated peptide bond. These structures show the conformational
Conformational isomerism
In chemistry, conformational isomerism is a form of stereoisomerism in which the isomers can be interconverted exclusively by rotations about formally single bonds...
changes induced by the two substrates required for the reaction, the acetylated substrate peptide and NAD+
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...
. In addition, a binding study by isothermal titration calorimetry
Isothermal Titration Calorimetry
Isothermal titration calorimetry is a physical technique used to determine the thermodynamic parameters of interactions in solution. It is most often used to study the binding of small molecules to larger macromolecules .-Thermodynamic measurements:ITC is a quantitative technique that can...
suggests that the acetylated peptide is the first substrate to bind to SIRT3, prior to NAD+.
Mitochondrial
Three sirtuins, SIRT3, SIRT4SIRT4
Sirtuin 4, also known as SIRT4 is a protein which in humans is encoded by the SIRT4 gene.-Function:This gene encodes a member of the sirtuin family of proteins which are homologs of the Sir2 gene in budding yeast. Members of the sirtuin family are characterized by a sirtuin core domain and grouped...
and SIRT5
SIRT5
Sirtuin 5 , also known as SIRT5 is a protein which in humans in encoded by the SIRT5 gene and in other species by the Sirt5 gene....
, are located in mitochondria and have been implicated in regulating metabolic processes. Endogenous SIRT3 is a soluble protein located in the mitochondrial matrix. Overexpression of SIRT3 in cultured cells increases respiration and decreases the production of reactive oxygen species. Fasting increases SIRT3 expression in white
White adipose tissue
White adipose tissue or white fat is one of the two types of adipose tissue found in mammals. The other kind of adipose tissue is brown adipose tissue....
and brown adipose tissue
Brown adipose tissue
Brown adipose tissue or brown fat is one of two types of fat or adipose tissue found in mammals....
(WAT and BAT, respectively) and overexpression of SIRT3 in HIB1B brown adipocytes increases the expression of PGC-1α
PPARGC1A
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha is a protein that in humans is encoded by the PPARGC1A gene....
and UCP1
Thermogenin
Thermogenin is an uncoupling protein found in the mitochondria of brown adipose tissue . It is used to generate heat by non-shivering thermogenesis...
, suggesting a role for SIRT3 in adaptive thermogenesis
Thermogenesis
Thermogenesis is the process of heat production in organisms. It occurs mostly in warm-blooded animals, but a few species of thermogenic plants exist.-Types:...
BAT. BAT is different from WAT because it harbors large numbers of mitochondria and is important for thermogenesis in rodents. Thermogenesis in BAT is mediated by the uncoupling protein 1 (UCP1), which induces proton leakage and thereby generates heat instead of ATP. Mechanistic insights into how SIRT3 affects thermogenesis in BAT is lacking and whether SIRT3 affects UCP1 activity directly is not known.
In addition to controlling metabolism at the transcriptional level, sirtuins also directly control the activity of metabolic enzymes. In Salmonella enterica
Salmonella enterica
Salmonella enterica is a rod-shaped flagellated, facultative anaerobic, Gram-negative bacterium, and a member of the genus Salmonella.- Epidemiology :...
, the bacterial sirtuin CobB regulates the activity of the enzyme acetyl-coenzyme A (acetyl-CoA
Acetyl-CoA
Acetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...
) synthetase
Acetyl Co-A synthetase
Acetyl—CoA synthetase or Acetate—CoA ligase is an enzyme involved in metabolism of carbon sugars. It is in the ligase class of enzymes, meaning that it catalyzes the formation of a new chemical bond between two large molecules.-Reaction:...
. As mentioned above, orthologs of acetyl-CoA synthetase exist in the cytoplasm (AceCS1) and in mitochondria (AceCS2) in mammals. The presence of the sirtuin deacetylase SIRT3 in the mitochondrial matrix suggests the existence of lysine acetylated mitochondrial proteins. Indeed, SIRT3 deacetylates and activates the mammalian mitochondrial acetyl-coA synthetase (AceCS2). Furthermore, SIRT3 and AceCS2 are found complexed with one another, suggesting a critical role for control of AceCS2 activity by SIRT3.
Nuclear
In addition to its reported mitochondrial function, some researchers have proposed a very small pool of active nuclear SIRT3 exists. This pool is reported to consist of the long form of SIRT3 and has been suggested to have histone deacetylaseHistone deacetylase
Histone deacetylases are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone...
activity. The observation that SIRT3 has nuclear activity came from a report that SIRT3 protected cardiomyocytes from stress mediated cell death and that this effect was due to deacetylation of a nuclear factor, Ku-70
Ku (protein)
Ku is a protein that binds to DNA double-strand break ends and is required for the non-homologous end joining pathway of DNA repair. Ku is evolutionarily conserved from bacteria to human. The ancestral bacterial Ku is a homodimer...
.
Clinical significance
There is a strong association between SIRT3 alleles and longevity in males.Aging and carcinogenesis
There is also a significant body of published literature suggesting a strong mechanistic link between mitochondrialMitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
function, aging, and carcinogeneis.
Sirt3 functions as a mitochondrial tumor suppressor
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
protein. Damaged and aberrant mitochondrial function, similar to gene mutations, may be an early event that ultimately leads to the development of cancers. Mice genetically altered to delete Sirt3 develop estrogen
Estrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
and progesterone
Progesterone receptor
The progesterone receptor also known as NR3C3 , is an intracellular steroid receptor that specifically binds progesterone...
receptor (ER/PR) positive breast mammary tumors. In tumor samples from women with breast cancer, SIRT3 expression was decreased, as compared to normal breast tissues. Thus, the Sirt3 knockout
Knockout
A knockout is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, Muay Thai, mixed martial arts, Karate and others sports involving striking...
model may be used to investigate ER/PR positive breast tumor development.