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Q8K2C6 (SIR5_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 93. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
NAD-dependent protein deacylase sirtuin-5, mitochondrial

EC=3.5.1.-
Alternative name(s):
Regulatory protein SIR2 homolog 5
SIR2-like protein 5
Gene names
Name:Sirt5
Synonyms:Sir2l5
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length310 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

NAD-dependent lysine demalonylase and desuccinylase that specifically removes malonyl and succinyl groups on target proteins. Activates CPS1 and contributes to the regulation of blood ammonia levels during prolonged fasting: acts by mediating desuccinylation of CPS1, thereby increasing CPS1 activity in response to elevated NAD levels during fasting. Activates SOD1 by mediating its desuccinylation, leading to reduced reactive oxygen species. 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. Ref.2 Ref.3 Ref.4 Ref.5 Ref.6

Catalytic activity

NAD+ + a malonylprotein = nicotinamide + O-malonyl-ADP-ribose + a protein. HAMAP-Rule MF_03160

NAD+ + a succinylprotein = nicotinamide + O-succinyl-ADP-ribose + a protein. HAMAP-Rule MF_03160

Cofactor

Binds 1 zinc ion per subunit By similarity. HAMAP-Rule MF_03160

Subunit structure

Monomer. Homodimer. Interacts with CPS1. Ref.2

Subcellular location

Mitochondrion. Cytoplasmcytosol. Nucleus. Note: Mainly mitochondrial. Also present extramitochondrially: a fraction is present in the cytosol and very small amounts are also detected in the nucleus. Ref.2 Ref.6

Tissue specificity

Detected in brain, liver, heart, kidney, lung, thymus, spleen, skeletal muscle, intestine, pancreas and testis (at protein level). Ref.2

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 By similarity. HAMAP-Rule MF_03160

Disruption phenotype

Mice are born at an abnormal Mendelian ratio with the number of live-born pups reduced by 40% (Ref.7). Surviving mice display a global protein hypersuccinylation in both liver and skeletal muscle, while global lysine acetylation is not significantly impacted (Ref.4, Ref.6). Mice display elevated levels of blood ammonia during fasting, but otherwise are metabolically similar to wild-type (Ref.7). No overt phenotype observed in mice on chow or high fat diet, suggesting that Sirt5 may be dispensable for basal homeostasis under these conditions (Ref.7). After 48 hours of fasting, the absence of Cps1 activation leads to elevated blood ammonia levels, possibly due to the presence of succinylation at 'Lys-1291' in Cps1 (Ref.4). Ref.2 Ref.3 Ref.4 Ref.6 Ref.7

Sequence similarities

Belongs to the sirtuin family. Class III subfamily.

Contains 1 deacetylase sirtuin-type domain.

Caution

The ability to deacetylate Uox in vivo is unclear. The anti-acetylated lysine antibody used in the assay is not fully specific and cross-reacts with some acylated lysines. It is therefore possible that it also recognizes N6-malonyllysine and N6-succinyllysine residues (Ref.5).

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Cps1Q8C1962EBI-2348809,EBI-2348828

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Transit peptide1 – 3636Mitochondrion Ref.2
Chain37 – 310274NAD-dependent protein deacylase sirtuin-5, mitochondrial HAMAP-Rule MF_03160
PRO_0000110267

Regions

Domain41 – 309269Deacetylase sirtuin-type
Nucleotide binding58 – 7720NAD By similarity
Nucleotide binding140 – 1434NAD By similarity
Nucleotide binding249 – 2513NAD By similarity
Nucleotide binding275 – 2773NAD By similarity

Sites

Active site1581Proton acceptor By similarity
Metal binding1661Zinc By similarity
Metal binding1691Zinc By similarity
Metal binding2071Zinc By similarity
Metal binding2121Zinc By similarity
Binding site1021Substrate By similarity
Binding site1051Substrate By similarity
Binding site2931NAD; via amide nitrogen By similarity

Experimental info

Mutagenesis1581H → Y: Loss of enzyme activity. Ref.2

Sequences

Sequence LengthMass (Da)Tools
Q8K2C6 [UniParc].

Last modified October 1, 2002. Version 1.
Checksum: A0C4962D5E6F8729

FASTA31034,134
        10         20         30         40         50         60 
MRPLLIAPGR FISQLCCRRK PPASPQSKIC LTMARPSSNM ADFRKCFANA KHIAIISGAG 

        70         80         90        100        110        120 
VSAESGVPTF RGAGGYWRKW QAQDLATPQA FARNPSQVWE FYHYRREVMR SKEPNPGHLA 

       130        140        150        160        170        180 
IAQCEARLRD QGRRVVVITQ NIDELHRKAG TKNLLEIHGT LFKTRCTSCG TVAENYRSPI 

       190        200        210        220        230        240 
CPALAGKGAP EPETQDARIP VDKLPRCEEA GCGGLLRPHV VWFGENLDPA ILEEVDRELA 

       250        260        270        280        290        300 
LCDLCLVVGT SSVVYPAAMF APQVASRGVP VAEFNMETTP ATDRFRFHFP GPCGKTLPEA 

       310 
LAPHETERTS 

« Hide

References

« Hide 'large scale' references
[1]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Mammary tumor.
[2]"SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle."
Nakagawa T., Lomb D.J., Haigis M.C., Guarente L.
Cell 137:560-570(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF N-TERMINUS, FUNCTION, MUTAGENESIS OF HIS-158, SUBCELLULAR LOCATION, INTERACTION WITH CPS1, DISRUPTION PHENOTYPE, TISSUE SPECIFICITY.
[3]"The first identification of lysine malonylation substrates and its regulatory enzyme."
Peng C., Lu Z., Xie Z., Cheng Z., Chen Y., Tan M., Luo H., Zhang Y., He W., Yang K., Zwaans B.M., Tishkoff D., Ho L., Lombard D., He T.C., Dai J., Verdin E., Ye Y., Zhao Y.
Mol. Cell. Proteomics 10:M111.012658.01-M111.012658.12(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[4]"Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase."
Du J., Zhou Y., Su X., Yu J.J., Khan S., Jiang H., Kim J., Woo J., Kim J.H., Choi B.H., He B., Chen W., Zhang S., Cerione R.A., Auwerx J., Hao Q., Lin H.
Science 334:806-809(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[5]"SIRT5 deacetylates and activates urate oxidase in liver mitochondria of mice."
Nakamura Y., Ogura M., Ogura K., Tanaka D., Inagaki N.
FEBS Lett. 586:4076-4081(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[6]"SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways."
Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y., Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.
Mol. Cell 50:919-930(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE.
[7]"Metabolic characterization of a Sirt5 deficient mouse model."
Yu J., Sadhukhan S., Noriega L.G., Moullan N., He B., Weiss R.S., Lin H., Schoonjans K., Auwerx J.
Sci. Rep. 3:2806-2806(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
BC031770 mRNA. Translation: AAH31770.1.
RefSeqNP_849179.1. NM_178848.3.
UniGeneMm.35325.

3D structure databases

ProteinModelPortalQ8K2C6.
SMRQ8K2C6. Positions 34-302.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

IntActQ8K2C6. 5 interactions.
MINTMINT-4134742.

PTM databases

PhosphoSiteQ8K2C6.

Proteomic databases

PaxDbQ8K2C6.
PRIDEQ8K2C6.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000066804; ENSMUSP00000071048; ENSMUSG00000054021.
GeneID68346.
KEGGmmu:68346.
UCSCuc007qfz.1. mouse.

Organism-specific databases

CTD23408.
MGIMGI:1915596. Sirt5.

Phylogenomic databases

eggNOGCOG0846.
GeneTreeENSGT00740000115330.
HOGENOMHOG000085950.
HOVERGENHBG056009.
InParanoidQ8K2C6.
KOK11415.
OMAVLHMHGE.
OrthoDBEOG77Q4XG.
PhylomeDBQ8K2C6.
TreeFamTF106183.

Gene expression databases

ArrayExpressQ8K2C6.
BgeeQ8K2C6.
GenevestigatorQ8K2C6.

Family and domain databases

Gene3D3.30.1600.10. 2 hits.
HAMAPMF_01121. Sirtuin_ClassIII.
InterProIPR003000. Sirtuin.
IPR026591. Sirtuin_cat_small_dom.
IPR027546. Sirtuin_class_III.
IPR026590. Ssirtuin_cat_dom.
[Graphical view]
PANTHERPTHR11085. PTHR11085. 1 hit.
PfamPF02146. SIR2. 1 hit.
[Graphical view]
PROSITEPS50305. SIRTUIN. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio327033.
PROQ8K2C6.
SOURCESearch...

Entry information

Entry nameSIR5_MOUSE
AccessionPrimary (citable) accession number: Q8K2C6
Entry history
Integrated into UniProtKB/Swiss-Prot: October 31, 2003
Last sequence update: October 1, 2002
Last modified: April 16, 2014
This is version 93 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot