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 of the
sirtuin family of proteins,
homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and belong to the class III of the
istone deacetylasesuperfamily, and are dependent on
NAD+
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 aden ...
as
co-factor of enzymatic activities. SIRT5 is one of the three sirtuins localized primarily to the
mitochondrion
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 used ...
.
Structure
Alternative splicing of this gene results in two transcript variants.
The protein structure of SIRT5 has been resolved and shows high degrees of structural conservation with other sirtuins, such as the ancestral yeast protein and human SIRT2.
Function
SIRT5 has been found to exhibit enzymatic activities as a deacetylase, desuccinylase, and demalonylase, capable of removing
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, ...
,
succinyl
Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. The name derives from Latin ''succinum'', meaning amber. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological ro ...
, and
malonyl groups from the
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 −C ...
residues of proteins. SIRT5 deacetylases and regulates
carbamoyl phosphate synthetase (CPS1), the rate-limiting and initiating step of the urea cycle in liver mitochondria. Deacetylation of CPS1 stimulates its enzymatic activity. Mice with deletion of SIRT5 show elevated ammonia levels after a prolonged fast, whereas in contrast, mice overexpressing SIRT5 show increased CPS1 activity, suggesting one of the functions of SIRT5 may be to regulate the urea cycle. SIRT5 also interacts with and deacetylates
cytochrome c
The cytochrome complex, or cyt ''c'', is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins and plays a major role in cell apoptosis. Cytochrome c is hig ...
.
Large-scale profiling studies of SIRT5 deacetylase activity have uncovered over 700 protein substrates, including proteins localized to the mitochondria, the cytosol and other sub cellular localization. The identities of SIRT5 desuccinylation substrates suggest that SIRT5-mediated desuccinylation may be involved in energy metabolism.
The physiological consequences of SIRT5 molecular functions in human is under investigation but may involved regulations of mitochondrial metabolism.
Interactions
NAD+
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 aden ...
Cytochrome c
The cytochrome complex, or cyt ''c'', is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins and plays a major role in cell apoptosis. Cytochrome c is hig ...
(CPS1)
References
Further reading
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