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Protein

NAD-dependent protein deacylase sirtuin-5, mitochondrial

Gene

Sirt5

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

Functioni

NAD-dependent lysine demalonylase, desuccinylase and deglutarylase that specifically removes malonyl, succinyl and glutaryl groups on target proteins (PubMed:23806337, PubMed:21908771, PubMed:22076378, PubMed:24315375, PubMed:24703693). 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:19410549, PubMed:24703693). Activates SOD1 by mediating its desuccinylation, leading to reduced reactive oxygen species (By similarity). Activates SHMT2 by mediating its desuccinylation (By similarity). Modulates ketogenesis through the desuccinylation and activation of HMGCS2 (PubMed:24315375). 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 (PubMed:23085393).UniRule annotation7 Publications

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

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
NAD+ + a glutarylprotein = nicotinamide + O-glutaryl-ADP-ribose + a protein.UniRule annotation1 Publication

Cofactori

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

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei102SubstrateUniRule annotation1
Binding sitei105SubstrateUniRule annotation1
Active sitei158Proton acceptorUniRule annotation1
Metal bindingi166ZincUniRule annotation1
Metal bindingi169ZincUniRule annotation1
Metal bindingi207ZincUniRule annotation1
Metal bindingi212ZincUniRule annotation1
Binding sitei293NAD; via amide nitrogenUniRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi58 – 77NADUniRule annotationAdd BLAST20
Nucleotide bindingi140 – 143NADUniRule annotation4
Nucleotide bindingi249 – 251NADUniRule annotation3
Nucleotide bindingi275 – 277NADUniRule annotation3

GO - Molecular functioni

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

GO - Biological processi

  • negative regulation of cardiac muscle cell apoptotic process Source: Ensembl
  • 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 deglutarylation Source: UniProtKB
  • protein demalonylation Source: UniProtKB
  • protein desuccinylation Source: UniProtKB
  • regulation of ketone biosynthetic process Source: UniProtKB
  • response to nutrient levels Source: Ensembl

Keywordsi

Molecular functionHydrolase
LigandMetal-binding, NAD, Zinc

Names & Taxonomyi

Protein namesi
Recommended name:
NAD-dependent protein deacylase sirtuin-5, mitochondrialUniRule annotation (EC:3.5.1.-UniRule annotation1 Publication)
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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 13

Organism-specific databases

MGIiMGI:1915596 Sirt5

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

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 and hyperglutarylation in both liver and skeletal muscle, while global lysine acetylation is not significantly impacted (PubMed:22076378, PubMed:24315375, PubMed:23806337, PubMed:24703693). 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). Animals show a decrease of fatty acid oxidation and increase of acylcarnitines accumulation (PubMed:24315375).7 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi158H → Y: Loss of enzyme activity. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Transit peptidei1 – 36MitochondrionUniRule annotation1 PublicationAdd BLAST36
ChainiPRO_000011026737 – 310NAD-dependent protein deacylase sirtuin-5, mitochondrialAdd BLAST274

Proteomic databases

EPDiQ8K2C6
MaxQBiQ8K2C6
PaxDbiQ8K2C6
PeptideAtlasiQ8K2C6
PRIDEiQ8K2C6

PTM databases

iPTMnetiQ8K2C6
PhosphoSitePlusiQ8K2C6

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

BgeeiENSMUSG00000054021
ExpressionAtlasiQ8K2C6 baseline and differential
GenevisibleiQ8K2C6 MM

Interactioni

Subunit structurei

Monomer. Homodimer (By similarity). Interacts with CPS1 (PubMed:19410549). Interacts with PCCA (PubMed:23438705).UniRule annotationBy similarity2 Publications

Binary interactionsi

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

Protein-protein interaction databases

IntActiQ8K2C6, 5 interactors
MINTiQ8K2C6
STRINGi10090.ENSMUSP00000071048

Structurei

3D structure databases

ProteinModelPortaliQ8K2C6
SMRiQ8K2C6
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini41 – 309Deacetylase sirtuin-typeUniRule annotationAdd BLAST269

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

Keywords - Domaini

Transit peptide

Phylogenomic databases

eggNOGiKOG2684 Eukaryota
COG0846 LUCA
GeneTreeiENSGT00870000136443
HOGENOMiHOG000085950
HOVERGENiHBG056009
InParanoidiQ8K2C6
KOiK11415
OMAiSMQVYPA
OrthoDBiEOG091G0KF2
PhylomeDBiQ8K2C6
TreeFamiTF106183

Family and domain databases

CDDicd01412 SIRT5_Af1_CobB, 1 hit
Gene3Di3.30.1600.10, 2 hits
HAMAPiMF_01121 Sirtuin_ClassIII, 1 hit
InterProiView protein in InterPro
IPR029035 DHS-like_NAD/FAD-binding_dom
IPR003000 Sirtuin
IPR026591 Sirtuin_cat_small_dom_sf
IPR027546 Sirtuin_class_III
IPR026590 Ssirtuin_cat_dom
PfamiView protein in Pfam
PF02146 SIR2, 1 hit
SUPFAMiSSF52467 SSF52467, 1 hit
PROSITEiView protein in PROSITE
PS50305 SIRTUIN, 1 hit

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
ENSMUST00000223194; ENSMUSP00000152796; ENSMUSG00000054021
GeneIDi68346
KEGGimmu:68346
UCSCiuc007qfz.1 mouse

Similar proteinsi

Entry informationi

Entry nameiSIR5_MOUSE
AccessioniPrimary (citable) accession number: Q8K2C6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 31, 2003
Last sequence update: October 1, 2002
Last modified: May 23, 2018
This is version 126 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

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