Q9NXA8 · SIR5_HUMAN
- ProteinNAD-dependent protein deacylase sirtuin-5, mitochondrial
- GeneSIRT5
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids310 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
NAD-dependent lysine demalonylase, desuccinylase and deglutarylase that specifically removes malonyl, succinyl and glutaryl groups on target proteins (PubMed:21908771, PubMed:22076378, PubMed:24703693, PubMed:29180469).
Activates CPS1 and contributes to the regulation of blood ammonia levels during prolonged fasting: acts by mediating desuccinylation and deglutarylation of CPS1, thereby increasing CPS1 activity in response to elevated NAD levels during fasting (PubMed:22076378, PubMed:24703693).
Activates SOD1 by mediating its desuccinylation, leading to reduced reactive oxygen species (PubMed:24140062).
Activates SHMT2 by mediating its desuccinylation (PubMed:29180469).
Modulates ketogenesis through the desuccinylation and activation of HMGCS2 (By similarity).
Has weak NAD-dependent protein deacetylase activity; however this activity may not be physiologically relevant in vivo. Can deacetylate cytochrome c (CYCS) and a number of other proteins in vitro such as UOX
Activates CPS1 and contributes to the regulation of blood ammonia levels during prolonged fasting: acts by mediating desuccinylation and deglutarylation of CPS1, thereby increasing CPS1 activity in response to elevated NAD levels during fasting (PubMed:22076378, PubMed:24703693).
Activates SOD1 by mediating its desuccinylation, leading to reduced reactive oxygen species (PubMed:24140062).
Activates SHMT2 by mediating its desuccinylation (PubMed:29180469).
Modulates ketogenesis through the desuccinylation and activation of HMGCS2 (By similarity).
Has weak NAD-dependent protein deacetylase activity; however this activity may not be physiologically relevant in vivo. Can deacetylate cytochrome c (CYCS) and a number of other proteins in vitro such as UOX
Miscellaneous
The mechanism of demalonylation and desuccinylation involves the presence of a 1',2'-cyclic intermediate, suggesting that sirtuins use the ADP-ribose-peptidylamidate mechanism to remove acyl groups from substrate lysine residues.
Catalytic activity
- H2O + N6-malonyl-L-lysyl-[protein] + NAD+ = 2''-O-malonyl-ADP-D-ribose + L-lysyl-[protein] + nicotinamide
- H2O + N6-succinyl-L-lysyl-[protein] + NAD+ = 2''-O-succinyl-ADP-D-ribose + L-lysyl-[protein] + nicotinamide
- H2O + N6-glutaryl-L-lysyl-[protein] + NAD+ = 2''-O-glutaryl-ADP-D-ribose + L-lysyl-[protein] + nicotinamide
Cofactor
Note: Binds 1 zinc ion per subunit.
Activity regulation
Inhibited by suramin. NAD-dependent lysine desuccinylase activity is inhibited by physiological nicotinamide concentrations, while deacetylase activity is not. In contrast, resveratrol activates deacetylase activity, while inhibiting desuccinylase activity.
Kinetics
KM | SUBSTRATE | pH | TEMPERATURE[C] | NOTES | EVIDENCE | |
---|---|---|---|---|---|---|
6.1 μM | a synthetic histone H3K9 malonyllysine peptide | |||||
5.8 μM | a synthetic histone H3K9 succinyllysine peptide | |||||
8.7 μM | a synthetic GLUD1 peptide malonylated at 'Lys-503' | |||||
14 μM | a synthetic GLUD1 peptide succinylated at 'Lys-503' | |||||
150 μM | a synthetic ACSS1 peptide malonylated at 'Lys-628' | |||||
450 μM | a synthetic ACSS1 peptide succinylated at 'Lys-628' |
Features
Showing features for binding site, active site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 58-77 | NAD+ (UniProtKB | ChEBI) | ||||
Sequence: GAGVSAESGVPTFRGAGGYW | ||||||
Binding site | 102 | substrate | ||||
Sequence: Y | ||||||
Binding site | 105 | substrate | ||||
Sequence: R | ||||||
Binding site | 140-143 | NAD+ (UniProtKB | ChEBI) | ||||
Sequence: QNID | ||||||
Active site | 158 | Proton acceptor | ||||
Sequence: H | ||||||
Binding site | 166 | Zn2+ (UniProtKB | ChEBI) | ||||
Sequence: C | ||||||
Binding site | 169 | Zn2+ (UniProtKB | ChEBI) | ||||
Sequence: C | ||||||
Binding site | 207 | Zn2+ (UniProtKB | ChEBI) | ||||
Sequence: C | ||||||
Binding site | 212 | Zn2+ (UniProtKB | ChEBI) | ||||
Sequence: C | ||||||
Binding site | 249-251 | NAD+ (UniProtKB | ChEBI) | ||||
Sequence: GTS | ||||||
Binding site | 275-277 | NAD+ (UniProtKB | ChEBI) | ||||
Sequence: NTE | ||||||
Binding site | 293 | NAD+ (UniProtKB | ChEBI) | ||||
Sequence: C |
GO annotations
Keywords
- Molecular function
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameNAD-dependent protein deacylase sirtuin-5, mitochondrial
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ9NXA8
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Note: Mainly mitochondrial. Also present extramitochondrially, with a fraction present in the cytosol and very small amounts also detected in the nucleus.
Isoform 1
Isoform 2
Keywords
- Cellular component
Disease & Variants
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 69 | Abolishes enzyme activity. | ||||
Sequence: T → A | ||||||
Mutagenesis | 102 | Increases the KM for desuccinylation. | ||||
Sequence: Y → F | ||||||
Mutagenesis | 105 | Increases the KM for desuccinylation. Does not affect deacetylase activity. | ||||
Sequence: R → M | ||||||
Mutagenesis | 158 | Abolishes desuccinylation and deglutarylation activity. | ||||
Sequence: H → A | ||||||
Natural variant | VAR_029042 | 285 | in dbSNP:rs9464003 | |||
Sequence: F → L | ||||||
Natural variant | VAR_051980 | 305 | in dbSNP:rs34162626 | |||
Sequence: E → G |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 393 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for transit peptide, chain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Transit peptide | 1-36 | Mitochondrion | ||||
Sequence: MRPLQIVPSRLISQLYCGLKPPASTRNQICLKMARP | ||||||
Chain | PRO_0000110266 | 37-310 | NAD-dependent protein deacylase sirtuin-5, mitochondrial | |||
Sequence: SSSMADFRKFFAKAKHIVIISGAGVSAESGVPTFRGAGGYWRKWQAQDLATPLAFAHNPSRVWEFYHYRREVMGSKEPNAGHRAIAECETRLGKQGRRVVVITQNIDELHRKAGTKNLLEIHGSLFKTRCTSCGVVAENYKSPICPALSGKGAPEPGTQDASIPVEKLPRCEEAGCGGLLRPHVVWFGENLDPAILEEVDRELAHCDLCLVVGTSSVVYPAAMFAPQVAARGVPVAEFNTETTPATNRFRFHFQGPCGTTLPEALACHENETVS |
Proteomic databases
PTM databases
Expression
Tissue specificity
Widely expressed.
Gene expression databases
Organism-specific databases
Structure
Family & Domains
Features
Showing features for domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 37-307 | Deacetylase sirtuin-type | ||||
Sequence: SSSMADFRKFFAKAKHIVIISGAGVSAESGVPTFRGAGGYWRKWQAQDLATPLAFAHNPSRVWEFYHYRREVMGSKEPNAGHRAIAECETRLGKQGRRVVVITQNIDELHRKAGTKNLLEIHGSLFKTRCTSCGVVAENYKSPICPALSGKGAPEPGTQDASIPVEKLPRCEEAGCGGLLRPHVVWFGENLDPAILEEVDRELAHCDLCLVVGTSSVVYPAAMFAPQVAARGVPVAEFNTETTPATNRFRFHFQGPCGTTLPEALACHENE |
Domain
In contrast to class I sirtuins, class III sirtuins have only weak deacetylase activity. Difference in substrate specificity is probably due to a larger hydrophobic pocket with 2 residues (Tyr-102 and Arg-105) that bind to malonylated and succinylated substrates and define the specificity (PubMed:22076378).
Sequence similarities
Belongs to the sirtuin family. Class III subfamily.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence & Isoforms
- Sequence statusComplete
- Sequence processingThe displayed sequence is further processed into a mature form.
This entry describes 4 isoforms produced by Alternative splicing.
Q9NXA8-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- Length310
- Mass (Da)33,881
- Last updated2003-10-31 v2
- Checksum022DA32CDB43AC3A
Q9NXA8-2
- Name2
Q9NXA8-3
- Name3
- Differences from canonical
- 189-206: Missing
Q9NXA8-4
- Name4
- Differences from canonical
- 1-108: Missing
Computationally mapped potential isoform sequences
There are 11 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A0A7P0T9N1 | A0A7P0T9N1_HUMAN | SIRT5 | 283 | ||
A0A7P0T9X1 | A0A7P0T9X1_HUMAN | SIRT5 | 247 | ||
A0A7P0T915 | A0A7P0T915_HUMAN | SIRT5 | 313 | ||
A0A7P0T877 | A0A7P0T877_HUMAN | SIRT5 | 163 | ||
A0A7P0TBF5 | A0A7P0TBF5_HUMAN | SIRT5 | 223 | ||
A0A7P0TA05 | A0A7P0TA05_HUMAN | SIRT5 | 224 | ||
A0A7P0Z4N6 | A0A7P0Z4N6_HUMAN | SIRT5 | 201 | ||
A0A7P0Z490 | A0A7P0Z490_HUMAN | SIRT5 | 253 | ||
A0A7P0Z4F6 | A0A7P0Z4F6_HUMAN | SIRT5 | 216 | ||
U3KQT8 | U3KQT8_HUMAN | SIRT5 | 41 | ||
Q7Z3A0 | Q7Z3A0_HUMAN | SIRT5 | 79 |
Features
Showing features for alternative sequence, sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_042291 | 1-108 | in isoform 4 | |||
Sequence: Missing | ||||||
Sequence conflict | 53 | in Ref. 2; BAG63757 | ||||
Sequence: I → M | ||||||
Alternative sequence | VSP_042292 | 189-206 | in isoform 3 | |||
Sequence: Missing | ||||||
Alternative sequence | VSP_008730 | 286-299 | in isoform 2 | |||
Sequence: RFHFQGPCGTTLPE → SHLISISSLIIIKN | ||||||
Alternative sequence | VSP_008731 | 300-310 | in isoform 2 | |||
Sequence: Missing |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF083110 EMBL· GenBank· DDBJ | AAD40853.1 EMBL· GenBank· DDBJ | mRNA | ||
AK000355 EMBL· GenBank· DDBJ | BAA91107.1 EMBL· GenBank· DDBJ | mRNA | ||
AK294162 EMBL· GenBank· DDBJ | BAG57485.1 EMBL· GenBank· DDBJ | mRNA | ||
AK302467 EMBL· GenBank· DDBJ | BAG63757.1 EMBL· GenBank· DDBJ | mRNA | ||
AM393414 EMBL· GenBank· DDBJ | CAL38292.1 EMBL· GenBank· DDBJ | mRNA | ||
AL441883 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
CH471087 EMBL· GenBank· DDBJ | EAW55332.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC000126 EMBL· GenBank· DDBJ | AAH00126.1 EMBL· GenBank· DDBJ | mRNA |