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Protein

NAD-dependent protein deacylase sirtuin-5, mitochondrial

Gene

Sirt5

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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.5 Publications

Catalytic activityi

NAD+ + a malonylprotein = nicotinamide + O-malonyl-ADP-ribose + a protein.UniRule annotation
NAD+ + a succinylprotein = nicotinamide + O-succinyl-ADP-ribose + a protein.UniRule annotation

Cofactori

Zn2+UniRule annotationNote: Binds 1 zinc ion per subunit.UniRule annotation

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei102 – 1021SubstrateUniRule annotation
Binding sitei105 – 1051SubstrateUniRule annotation
Active sitei158 – 1581Proton acceptorUniRule annotation
Metal bindingi166 – 1661ZincUniRule annotation
Metal bindingi169 – 1691ZincUniRule annotation
Metal bindingi207 – 2071ZincUniRule annotation
Metal bindingi212 – 2121ZincUniRule annotation
Binding sitei293 – 2931NAD; via amide nitrogenUniRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi58 – 7720NADUniRule annotationAdd
BLAST
Nucleotide bindingi140 – 1434NADUniRule annotation
Nucleotide bindingi249 – 2513NADUniRule annotation
Nucleotide bindingi275 – 2773NADUniRule annotation

GO - Molecular functioni

  • NAD+ binding Source: MGI
  • protein-malonyllysine demalonylase activity Source: UniProtKB
  • protein-succinyllysine desuccinylase activity Source: UniProtKB
  • zinc ion binding Source: MGI

GO - Biological processi

  • negative regulation of reactive oxygen species metabolic process Source: MGI
  • peptidyl-lysine demalonylation Source: UniProtKB
  • peptidyl-lysine desuccinylation Source: UniProtKB
  • protein deacetylation Source: UniProtKB
  • protein desuccinylation Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase

Keywords - Ligandi

Metal-binding, NAD, Zinc

Names & Taxonomyi

Protein namesi
Recommended name:
NAD-dependent protein deacylase sirtuin-5, mitochondrialUniRule annotation (EC:3.5.1.-UniRule annotation)
Alternative name(s):
Regulatory protein SIR2 homolog 5UniRule annotation
SIR2-like protein 5UniRule annotation
Gene namesi
Name:Sirt5
Synonyms:Sir2l5
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589 Componenti: Chromosome 13

Organism-specific databases

MGIiMGI:1915596. Sirt5.

Subcellular locationi

  • 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.

GO - Cellular componenti

  • cytosol Source: UniProtKB
  • mitochondrial inner membrane Source: CACAO
  • mitochondrial intermembrane space Source: UniProtKB
  • mitochondrial matrix Source: UniProtKB
  • mitochondrion Source: UniProtKB
  • nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Mitochondrion, Nucleus

Pathology & Biotechi

Disruption phenotypei

Mice are born at an abnormal Mendelian ratio with the number of live-born pups reduced by 40% (PubMed:24076663). Surviving mice display a global protein hypersuccinylation in both liver and skeletal muscle, while global lysine acetylation is not significantly impacted (PubMed:22076378, PubMed:23806337). Mice display elevated levels of blood ammonia during fasting, but otherwise are metabolically similar to wild-type (PubMed:24076663). No overt phenotype observed in mice on chow or high fat diet, suggesting that Sirt5 may be dispensable for basal homeostasis under these conditions (PubMed:24076663). 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 (PubMed:22076378).5 Publications

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi158 – 1581H → Y: Loss of enzyme activity. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transit peptidei1 – 3636MitochondrionUniRule annotation1 PublicationAdd
BLAST
Chaini37 – 310274NAD-dependent protein deacylase sirtuin-5, mitochondrialPRO_0000110267Add
BLAST

Proteomic databases

MaxQBiQ8K2C6.
PaxDbiQ8K2C6.
PRIDEiQ8K2C6.

PTM databases

PhosphoSiteiQ8K2C6.

Expressioni

Tissue specificityi

Detected in brain, liver, heart, kidney, lung, thymus, spleen, skeletal muscle, intestine, pancreas and testis (at protein level).1 Publication

Gene expression databases

BgeeiQ8K2C6.
ExpressionAtlasiQ8K2C6. baseline and differential.
GenevestigatoriQ8K2C6.

Interactioni

Subunit structurei

Monomer. Homodimer. Interacts with CPS1.UniRule annotation1 Publication

Binary interactionsi

WithEntry#Exp.IntActNotes
Cps1Q8C1962EBI-2348809,EBI-2348828

Protein-protein interaction databases

IntActiQ8K2C6. 5 interactions.
MINTiMINT-4134742.

Structurei

3D structure databases

ProteinModelPortaliQ8K2C6.
SMRiQ8K2C6. Positions 34-302.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini41 – 309269Deacetylase sirtuin-typeUniRule annotationAdd
BLAST

Domaini

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.UniRule annotation

Sequence similaritiesi

Belongs to the sirtuin family. Class III subfamily.UniRule annotation
Contains 1 deacetylase sirtuin-type domain.UniRule annotation

Keywords - Domaini

Transit peptide

Phylogenomic databases

eggNOGiCOG0846.
GeneTreeiENSGT00740000115330.
HOGENOMiHOG000085950.
HOVERGENiHBG056009.
InParanoidiQ8K2C6.
KOiK11415.
OMAiLIHMHGE.
OrthoDBiEOG77Q4XG.
PhylomeDBiQ8K2C6.
TreeFamiTF106183.

Family and domain databases

Gene3Di3.30.1600.10. 2 hits.
3.40.50.1220. 3 hits.
HAMAPiMF_01121. Sirtuin_ClassIII.
InterProiIPR029035. DHS-like_NAD/FAD-binding_dom.
IPR003000. Sirtuin.
IPR026591. Sirtuin_cat_small_dom.
IPR027546. Sirtuin_class_III.
IPR026590. Ssirtuin_cat_dom.
[Graphical view]
PANTHERiPTHR11085. PTHR11085. 1 hit.
PfamiPF02146. SIR2. 1 hit.
[Graphical view]
SUPFAMiSSF52467. SSF52467. 1 hit.
PROSITEiPS50305. SIRTUIN. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q8K2C6-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MRPLLIAPGR FISQLCCRRK PPASPQSKIC LTMARPSSNM ADFRKCFANA
60 70 80 90 100
KHIAIISGAG VSAESGVPTF RGAGGYWRKW QAQDLATPQA FARNPSQVWE
110 120 130 140 150
FYHYRREVMR SKEPNPGHLA IAQCEARLRD QGRRVVVITQ NIDELHRKAG
160 170 180 190 200
TKNLLEIHGT LFKTRCTSCG TVAENYRSPI CPALAGKGAP EPETQDARIP
210 220 230 240 250
VDKLPRCEEA GCGGLLRPHV VWFGENLDPA ILEEVDRELA LCDLCLVVGT
260 270 280 290 300
SSVVYPAAMF APQVASRGVP VAEFNMETTP ATDRFRFHFP GPCGKTLPEA
310
LAPHETERTS
Length:310
Mass (Da):34,134
Last modified:October 1, 2002 - v1
Checksum:iA0C4962D5E6F8729
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC031770 mRNA. Translation: AAH31770.1.
CCDSiCCDS26478.1.
RefSeqiNP_849179.1. NM_178848.3.
UniGeneiMm.35325.

Genome annotation databases

EnsembliENSMUST00000066804; ENSMUSP00000071048; ENSMUSG00000054021.
GeneIDi68346.
KEGGimmu:68346.
UCSCiuc007qfz.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BC031770 mRNA. Translation: AAH31770.1.
CCDSiCCDS26478.1.
RefSeqiNP_849179.1. NM_178848.3.
UniGeneiMm.35325.

3D structure databases

ProteinModelPortaliQ8K2C6.
SMRiQ8K2C6. Positions 34-302.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiQ8K2C6. 5 interactions.
MINTiMINT-4134742.

PTM databases

PhosphoSiteiQ8K2C6.

Proteomic databases

MaxQBiQ8K2C6.
PaxDbiQ8K2C6.
PRIDEiQ8K2C6.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000066804; ENSMUSP00000071048; ENSMUSG00000054021.
GeneIDi68346.
KEGGimmu:68346.
UCSCiuc007qfz.1. mouse.

Organism-specific databases

CTDi23408.
MGIiMGI:1915596. Sirt5.

Phylogenomic databases

eggNOGiCOG0846.
GeneTreeiENSGT00740000115330.
HOGENOMiHOG000085950.
HOVERGENiHBG056009.
InParanoidiQ8K2C6.
KOiK11415.
OMAiLIHMHGE.
OrthoDBiEOG77Q4XG.
PhylomeDBiQ8K2C6.
TreeFamiTF106183.

Miscellaneous databases

NextBioi327033.
PROiQ8K2C6.
SOURCEiSearch...

Gene expression databases

BgeeiQ8K2C6.
ExpressionAtlasiQ8K2C6. baseline and differential.
GenevestigatoriQ8K2C6.

Family and domain databases

Gene3Di3.30.1600.10. 2 hits.
3.40.50.1220. 3 hits.
HAMAPiMF_01121. Sirtuin_ClassIII.
InterProiIPR029035. DHS-like_NAD/FAD-binding_dom.
IPR003000. Sirtuin.
IPR026591. Sirtuin_cat_small_dom.
IPR027546. Sirtuin_class_III.
IPR026590. Ssirtuin_cat_dom.
[Graphical view]
PANTHERiPTHR11085. PTHR11085. 1 hit.
PfamiPF02146. SIR2. 1 hit.
[Graphical view]
SUPFAMiSSF52467. SSF52467. 1 hit.
PROSITEiPS50305. SIRTUIN. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  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. 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. Cited for: DISRUPTION PHENOTYPE.

Entry informationi

Entry nameiSIR5_MOUSE
AccessioniPrimary (citable) accession number: Q8K2C6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 31, 2003
Last sequence update: October 1, 2002
Last modified: April 29, 2015
This is version 102 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

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 (PubMed:23085393).1 Publication

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.