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NAD-dependent deacetylase sirtuin-3, mitochondrial also known as SIRT3 is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
that in humans is encoded by the ''SIRT3''
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
irtuin (silent mating type information regulation 2 homolog) 3 (S. cerevisiae) SIRT3 is member of the mammalian
sirtuin Sirtuins are a family of signaling proteins involved in metabolic regulation. They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life. Chemically, sirtuins are a class of proteins ...
family of proteins, which are homologs to the yeast Sir2 protein. SIRT3 exhibits NAD+-dependent
deacetylase A protein deacetylase is any enzyme that removes acetyl groups from lysine amino acids in proteins. The main ones are histone deacetylases (HDACs) and sirtuins (SIRT1,2,3,5). Because histone proteins were the first known substrate for protein ...
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 In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are " ...
gene silencing Gene silencing is the regulation of gene expression in a cell to prevent the expression of a certain gene. Gene silencing can occur during either Transcription (genetics), transcription or Translation (biology), translation and is often used in res ...
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.


Structure

SIRT3 is a soluble protein located in the
mitochondrial matrix In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ri ...
, and contains a mitochondrial processing peptide at the
N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
. A set of
crystal structures A crystal or crystalline solid is a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a highly ordered microscopic structure, forming a crystal lattice that extends in all directions. In addition, macros ...
of human SIRT3 have been solved, including an apo-structure with no
substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (locomotion), the surface over which an organism lo ...
, a structure with a peptide containing
acetyl In organic chemistry, acetyl is a functional group with the chemical formula and the structure . It is sometimes represented by the symbol Ac (not to be confused with the element actinium). In IUPAC nomenclature, acetyl is called ethanoyl ...
lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated &minu ...
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 Isothermal titration calorimetry (ITC) 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 (such as medicinal compounds) to larger macro ...
suggests that the acetylated peptide is the first substrate to bind to SIRT3, prior to NAD+.


Function


Mitochondrial

Three sirtuins, SIRT3, SIRT4 and
SIRT5 Sirtuin (silent mating type information regulation 2 homolog) 5 (S. cerevisiae), 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. This gene encodes a member ...
, 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 is the lightness, lightest color and is achromatic (having no hue). It is the color of objects such as snow, chalk, and milk, and is the opposite of black. White objects fully diffuse reflection, reflect and scattering, scatter all the ...
and
brown adipose tissue Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue (or white fat). Brown adipose tissue is found in almost all mammals. Classification of brown fat refers to two distinct cell populations with si ...
(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 Thermogenesis is the process of heat production in organisms. It occurs in all warm-blooded animals, and also in a few species of thermogenic plants such as the Eastern skunk cabbage, the Voodoo lily ('' Sauromatum venosum''), and the giant w ...
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'' (formerly ''Salmonella choleraesuis'') is a rod-headed, flagellate, facultative anaerobic, Gram-negative bacterium and a species of the genus '' Salmonella''. A number of its serovars are serious human pathogens. Epidem ...
'', the bacterial sirtuin CobB regulates the activity of the enzyme acetyl-coenzyme A (
acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized fo ...
)
synthetase In biochemistry, a ligase is an enzyme that can catalyze the joining ( ligation) of two large molecules by forming a new chemical bond. This is typically via hydrolysis of a small pendant chemical group on one of the larger molecules or the enz ...
. 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. Activation of the
NMNAT2 Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is an enzyme that in humans is encoded by the ''NMNAT2'' gene. This gene product belongs to the nicotinamide-nucleotide adenylyltransferase (NMNAT) enzyme family, members of which catalyz ...
enzyme which catalyze an essential step in the
nicotinamide adenine dinucleotide 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 ...
(NAD+) biosynthetic pathway by SIRT3 may be a means of inhibiting axon degeneration and dysfunction.


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 deacetylase Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around h ...
activity. The observation that SIRT3 has nuclear activity came from a report that SIRT3 protected
cardiomyocyte Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle tha ...
s from stress mediated cell death and that this effect was due to deacetylation of a nuclear factor, Ku-70.


Clinical significance


Aging

There is a strong association between SIRT3 alleles and longevity in males. Activation of SIRT3 inhibits the apoptosis leading to age-related
macular degeneration Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, som ...
. SIRT3 induced
mitophagy Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. The process of mitophagy was first described over a hundred years ago by Margaret Reed Lewis and Warren Har ...
, inhibiting cell death and thus could be used to treat neurodegenerative diseases.


Carcinogenesis

There is a significant body of published literature suggesting a strong mechanistic link between
mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
function, aging, and carcinogenesis. SIRT3 inhibits cancers that depend upon glycolysis, but promotes cancers that depend upon
oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine t ...
. Sirt3 functions as a mitochondrial
tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or re ...
protein. Although some evidence attributes SIRT3 activity in bypassing growth arrest in bladder carcinoma cells via regulation of p53 in the mitochondria. 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 or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal a ...
and
progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
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 A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, muay thai, mixed martial arts, karate, some forms of taekwondo and other sports involving striking, a ...
model may be used to investigate ER/PR positive breast tumor development.


References


Further reading

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