SIR5_MOUSE
ID SIR5_MOUSE Reviewed; 310 AA.
AC Q8K2C6;
DT 31-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2002, sequence version 1.
DT 03-AUG-2022, entry version 147.
DE RecName: Full=NAD-dependent protein deacylase sirtuin-5, mitochondrial {ECO:0000255|HAMAP-Rule:MF_03160};
DE EC=2.3.1.- {ECO:0000255|HAMAP-Rule:MF_03160, ECO:0000269|PubMed:24703693};
DE AltName: Full=Regulatory protein SIR2 homolog 5 {ECO:0000255|HAMAP-Rule:MF_03160};
DE AltName: Full=SIR2-like protein 5 {ECO:0000255|HAMAP-Rule:MF_03160};
DE Flags: Precursor;
GN Name=Sirt5; Synonyms=Sir2l5;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Mammary tumor;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [2]
RP PROTEIN SEQUENCE OF N-TERMINUS, FUNCTION, MUTAGENESIS OF HIS-158,
RP SUBCELLULAR LOCATION, INTERACTION WITH CPS1, DISRUPTION PHENOTYPE, AND
RP TISSUE SPECIFICITY.
RX PubMed=19410549; DOI=10.1016/j.cell.2009.02.026;
RA Nakagawa T., Lomb D.J., Haigis M.C., Guarente L.;
RT "SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea
RT cycle.";
RL Cell 137:560-570(2009).
RN [3]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, and Pancreas;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [4]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=21908771; DOI=10.1074/mcp.m111.012658;
RA Peng C., Lu Z., Xie Z., Cheng Z., Chen Y., Tan M., Luo H., Zhang Y., He W.,
RA Yang K., Zwaans B.M., Tishkoff D., Ho L., Lombard D., He T.C., Dai J.,
RA Verdin E., Ye Y., Zhao Y.;
RT "The first identification of lysine malonylation substrates and its
RT regulatory enzyme.";
RL Mol. Cell. Proteomics 10:M111.012658.01-M111.012658.12(2011).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=22076378; DOI=10.1126/science.1207861;
RA Du J., Zhou Y., Su X., Yu J.J., Khan S., Jiang H., Kim J., Woo J.,
RA Kim J.H., Choi B.H., He B., Chen W., Zhang S., Cerione R.A., Auwerx J.,
RA Hao Q., Lin H.;
RT "Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase.";
RL Science 334:806-809(2011).
RN [6]
RP FUNCTION.
RX PubMed=23085393; DOI=10.1016/j.febslet.2012.10.009;
RA Nakamura Y., Ogura M., Ogura K., Tanaka D., Inagaki N.;
RT "SIRT5 deacetylates and activates urate oxidase in liver mitochondria of
RT mice.";
RL FEBS Lett. 586:4076-4081(2012).
RN [7]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=24315375; DOI=10.1016/j.cmet.2013.11.013;
RA Rardin M.J., He W., Nishida Y., Newman J.C., Carrico C., Danielson S.R.,
RA Guo A., Gut P., Sahu A.K., Li B., Uppala R., Fitch M., Riiff T., Zhu L.,
RA Zhou J., Mulhern D., Stevens R.D., Ilkayeva O.R., Newgard C.B.,
RA Jacobson M.P., Hellerstein M., Goetzman E.S., Gibson B.W., Verdin E.;
RT "SIRT5 regulates the mitochondrial lysine succinylome and metabolic
RT networks.";
RL Cell Metab. 18:920-933(2013).
RN [8]
RP INTERACTION WITH PCCA.
RX PubMed=23438705; DOI=10.1016/j.mito.2013.02.002;
RA Wirth M., Karaca S., Wenzel D., Ho L., Tishkoff D., Lombard D.B.,
RA Verdin E., Urlaub H., Jedrusik-Bode M., Fischle W.;
RT "Mitochondrial SIRT4-type proteins in Caenorhabditis elegans and mammals
RT interact with pyruvate carboxylase and other acetylated biotin-dependent
RT carboxylases.";
RL Mitochondrion 13:705-720(2013).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, AND DISRUPTION PHENOTYPE.
RX PubMed=23806337; DOI=10.1016/j.molcel.2013.06.001;
RA Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y.,
RA Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.;
RT "SIRT5-mediated lysine desuccinylation impacts diverse metabolic
RT pathways.";
RL Mol. Cell 50:919-930(2013).
RN [10]
RP DISRUPTION PHENOTYPE.
RX PubMed=24076663; DOI=10.1038/srep02806;
RA Yu J., Sadhukhan S., Noriega L.G., Moullan N., He B., Weiss R.S., Lin H.,
RA Schoonjans K., Auwerx J.;
RT "Metabolic characterization of a Sirt5 deficient mouse model.";
RL Sci. Rep. 3:2806-2806(2013).
RN [11]
RP FUNCTION, DISRUPTION PHENOTYPE, AND CATALYTIC ACTIVITY.
RX PubMed=24703693; DOI=10.1016/j.cmet.2014.03.014;
RA Tan M., Peng C., Anderson K.A., Chhoy P., Xie Z., Dai L., Park J., Chen Y.,
RA Huang H., Zhang Y., Ro J., Wagner G.R., Green M.F., Madsen A.S.,
RA Schmiesing J., Peterson B.S., Xu G., Ilkayeva O.R., Muehlbauer M.J.,
RA Braulke T., Muehlhausen C., Backos D.S., Olsen C.A., McGuire P.J.,
RA Pletcher S.D., Lombard D.B., Hirschey M.D., Zhao Y.;
RT "Lysine glutarylation is a protein posttranslational modification regulated
RT by SIRT5.";
RL Cell Metab. 19:605-617(2014).
CC -!- FUNCTION: NAD-dependent lysine demalonylase, desuccinylase and
CC deglutarylase that specifically removes malonyl, succinyl and glutaryl
CC groups on target proteins (PubMed:23806337, PubMed:21908771,
CC PubMed:22076378, PubMed:24315375, PubMed:24703693). Activates CPS1 and
CC contributes to the regulation of blood ammonia levels during prolonged
CC fasting: acts by mediating desuccinylation and deglutarylation of CPS1,
CC thereby increasing CPS1 activity in response to elevated NAD levels
CC during fasting (PubMed:19410549, PubMed:24703693). Activates SOD1 by
CC mediating its desuccinylation, leading to reduced reactive oxygen
CC species (By similarity). Activates SHMT2 by mediating its
CC desuccinylation (By similarity). Modulates ketogenesis through the
CC desuccinylation and activation of HMGCS2 (PubMed:24315375). Has weak
CC NAD-dependent protein deacetylase activity; however this activity may
CC not be physiologically relevant in vivo. Can deacetylate cytochrome c
CC (CYCS) and a number of other proteins in vitro such as Uox
CC (PubMed:23085393). {ECO:0000255|HAMAP-Rule:MF_03160,
CC ECO:0000269|PubMed:19410549, ECO:0000269|PubMed:21908771,
CC ECO:0000269|PubMed:22076378, ECO:0000269|PubMed:23085393,
CC ECO:0000269|PubMed:23806337, ECO:0000269|PubMed:24315375,
CC ECO:0000269|PubMed:24703693}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N(6)-malonyl-L-lysyl-[protein] + NAD(+) = 2''-O-malonyl-
CC ADP-D-ribose + L-lysyl-[protein] + nicotinamide;
CC Xref=Rhea:RHEA:47672, Rhea:RHEA-COMP:9752, Rhea:RHEA-COMP:11878,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:17154, ChEBI:CHEBI:29969,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:87831, ChEBI:CHEBI:87833;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03160};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N(6)-succinyl-L-lysyl-[protein] + NAD(+) = 2''-O-
CC succinyl-ADP-D-ribose + L-lysyl-[protein] + nicotinamide;
CC Xref=Rhea:RHEA:47668, Rhea:RHEA-COMP:9752, Rhea:RHEA-COMP:11877,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:17154, ChEBI:CHEBI:29969,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:87830, ChEBI:CHEBI:87832;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03160};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N(6)-glutaryl-L-lysyl-[protein] + NAD(+) = 2''-O-
CC glutaryl-ADP-D-ribose + L-lysyl-[protein] + nicotinamide;
CC Xref=Rhea:RHEA:47664, Rhea:RHEA-COMP:9752, Rhea:RHEA-COMP:11875,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:17154, ChEBI:CHEBI:29969,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:87828, ChEBI:CHEBI:87829;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03160,
CC ECO:0000269|PubMed:24703693};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03160};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000255|HAMAP-Rule:MF_03160};
CC -!- SUBUNIT: Monomer. Homodimer (By similarity). Interacts with CPS1
CC (PubMed:19410549). Interacts with PCCA (PubMed:23438705).
CC {ECO:0000250|UniProtKB:Q9NXA8, ECO:0000255|HAMAP-Rule:MF_03160,
CC ECO:0000269|PubMed:19410549, ECO:0000269|PubMed:23438705}.
CC -!- INTERACTION:
CC Q8K2C6; Q8C196: Cps1; NbExp=2; IntAct=EBI-2348809, EBI-2348828;
CC -!- SUBCELLULAR LOCATION: Mitochondrion. Cytoplasm, cytosol. Nucleus.
CC Note=Mainly mitochondrial. Also present extramitochondrially, with a
CC fraction present in the cytosol and very small amounts also detected in
CC the nucleus.
CC -!- TISSUE SPECIFICITY: Detected in brain, liver, heart, kidney, lung,
CC thymus, spleen, skeletal muscle, intestine, pancreas and testis (at
CC protein level). {ECO:0000269|PubMed:19410549}.
CC -!- DOMAIN: In contrast to class I sirtuins, class III sirtuins have only
CC weak deacetylase activity. Difference in substrate specificity is
CC probably due to a larger hydrophobic pocket with 2 residues (Tyr-102
CC and Arg-105) that bind to malonylated and succinylated substrates and
CC define the specificity. {ECO:0000255|HAMAP-Rule:MF_03160}.
CC -!- DISRUPTION PHENOTYPE: Mice are born at an abnormal Mendelian ratio with
CC the number of live-born pups reduced by 40% (PubMed:24076663).
CC Surviving mice display a global protein hypersuccinylation and
CC hyperglutarylation in both liver and skeletal muscle, while global
CC lysine acetylation is not significantly impacted (PubMed:22076378,
CC PubMed:24315375, PubMed:23806337, PubMed:24703693). Mice display
CC elevated levels of blood ammonia during fasting, but otherwise are
CC metabolically similar to wild-type (PubMed:24076663). No overt
CC phenotype observed in mice on chow or high fat diet, suggesting that
CC Sirt5 may be dispensable for basal homeostasis under these conditions
CC (PubMed:24076663). After 48 hours of fasting, the absence of Cps1
CC activation leads to elevated blood ammonia levels, possibly due to the
CC presence of succinylation at 'Lys-1291' in Cps1 (PubMed:22076378).
CC Animals show a decrease of fatty acid oxidation and increase of
CC acylcarnitines accumulation (PubMed:24315375).
CC {ECO:0000269|PubMed:19410549, ECO:0000269|PubMed:21908771,
CC ECO:0000269|PubMed:22076378, ECO:0000269|PubMed:23806337,
CC ECO:0000269|PubMed:24076663, ECO:0000269|PubMed:24315375,
CC ECO:0000269|PubMed:24703693}.
CC -!- SIMILARITY: Belongs to the sirtuin family. Class III subfamily.
CC {ECO:0000255|HAMAP-Rule:MF_03160}.
CC -!- CAUTION: The ability to deacetylate Uox in vivo is unclear. The anti-
CC acetylated lysine antibody used in the assay is not fully specific and
CC cross-reacts with some acylated lysines. It is therefore possible that
CC it also recognizes N6-malonyllysine and N6-succinyllysine residues
CC (PubMed:23085393). {ECO:0000305|PubMed:23085393}.
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DR EMBL; BC031770; AAH31770.1; -; mRNA.
DR CCDS; CCDS26478.1; -.
DR RefSeq; NP_849179.1; NM_178848.3.
DR AlphaFoldDB; Q8K2C6; -.
DR SMR; Q8K2C6; -.
DR BioGRID; 212813; 1.
DR IntAct; Q8K2C6; 4.
DR MINT; Q8K2C6; -.
DR STRING; 10090.ENSMUSP00000071048; -.
DR iPTMnet; Q8K2C6; -.
DR PhosphoSitePlus; Q8K2C6; -.
DR EPD; Q8K2C6; -.
DR MaxQB; Q8K2C6; -.
DR PaxDb; Q8K2C6; -.
DR PeptideAtlas; Q8K2C6; -.
DR PRIDE; Q8K2C6; -.
DR ProteomicsDB; 261238; -.
DR Antibodypedia; 10177; 671 antibodies from 44 providers.
DR DNASU; 68346; -.
DR Ensembl; ENSMUST00000066804; ENSMUSP00000071048; ENSMUSG00000054021.
DR Ensembl; ENSMUST00000223194; ENSMUSP00000152796; ENSMUSG00000054021.
DR GeneID; 68346; -.
DR KEGG; mmu:68346; -.
DR UCSC; uc007qfz.1; mouse.
DR CTD; 23408; -.
DR MGI; MGI:1915596; Sirt5.
DR VEuPathDB; HostDB:ENSMUSG00000054021; -.
DR eggNOG; KOG2684; Eukaryota.
DR GeneTree; ENSGT00940000156080; -.
DR HOGENOM; CLU_023643_3_1_1; -.
DR InParanoid; Q8K2C6; -.
DR OMA; SMQVYPA; -.
DR PhylomeDB; Q8K2C6; -.
DR TreeFam; TF106183; -.
DR BRENDA; 2.3.1.B43; 3474.
DR Reactome; R-MMU-2151201; Transcriptional activation of mitochondrial biogenesis.
DR BioGRID-ORCS; 68346; 5 hits in 76 CRISPR screens.
DR ChiTaRS; Sirt5; mouse.
DR PRO; PR:Q8K2C6; -.
DR Proteomes; UP000000589; Chromosome 13.
DR RNAct; Q8K2C6; protein.
DR Bgee; ENSMUSG00000054021; Expressed in interventricular septum and 230 other tissues.
DR ExpressionAtlas; Q8K2C6; baseline and differential.
DR Genevisible; Q8K2C6; MM.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:CACAO.
DR GO; GO:0005758; C:mitochondrial intermembrane space; ISS:UniProtKB.
DR GO; GO:0005759; C:mitochondrial matrix; ISS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; TAS:UniProtKB.
DR GO; GO:0070403; F:NAD+ binding; ISO:MGI.
DR GO; GO:0034979; F:NAD-dependent protein deacetylase activity; IEA:UniProtKB-UniRule.
DR GO; GO:0061697; F:protein-glutaryllysine deglutarylase activity; IDA:UniProtKB.
DR GO; GO:0036054; F:protein-malonyllysine demalonylase activity; IDA:UniProtKB.
DR GO; GO:0036055; F:protein-succinyllysine desuccinylase activity; IDA:UniProtKB.
DR GO; GO:0016740; F:transferase activity; IEA:UniProtKB-KW.
DR GO; GO:0008270; F:zinc ion binding; ISO:MGI.
DR GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; ISO:MGI.
DR GO; GO:2000378; P:negative regulation of reactive oxygen species metabolic process; ISO:MGI.
DR GO; GO:0036047; P:peptidyl-lysine demalonylation; IMP:UniProtKB.
DR GO; GO:0036049; P:peptidyl-lysine desuccinylation; IMP:UniProtKB.
DR GO; GO:0006476; P:protein deacetylation; ISS:UniProtKB.
DR GO; GO:0061698; P:protein deglutarylation; IDA:UniProtKB.
DR GO; GO:0036046; P:protein demalonylation; IDA:UniProtKB.
DR GO; GO:0036048; P:protein desuccinylation; IDA:UniProtKB.
DR GO; GO:0010566; P:regulation of ketone biosynthetic process; IMP:UniProtKB.
DR GO; GO:1904229; P:regulation of succinate dehydrogenase activity; IMP:MGI.
DR GO; GO:0002931; P:response to ischemia; IMP:MGI.
DR CDD; cd01412; SIRT5_Af1_CobB; 1.
DR Gene3D; 3.30.1600.10; -; 1.
DR HAMAP; MF_01121; Sirtuin_ClassIII; 1.
DR InterPro; IPR029035; DHS-like_NAD/FAD-binding_dom.
DR InterPro; IPR003000; Sirtuin.
DR InterPro; IPR026591; Sirtuin_cat_small_dom_sf.
DR InterPro; IPR027546; Sirtuin_class_III.
DR InterPro; IPR026590; Ssirtuin_cat_dom.
DR Pfam; PF02146; SIR2; 1.
DR SUPFAM; SSF52467; SSF52467; 1.
DR PROSITE; PS50305; SIRTUIN; 1.
PE 1: Evidence at protein level;
KW Cytoplasm; Direct protein sequencing; Metal-binding; Mitochondrion; NAD;
KW Nucleus; Reference proteome; Transferase; Transit peptide; Zinc.
FT TRANSIT 1..36
FT /note="Mitochondrion"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03160,
FT ECO:0000269|PubMed:19410549"
FT CHAIN 37..310
FT /note="NAD-dependent protein deacylase sirtuin-5,
FT mitochondrial"
FT /id="PRO_0000110267"
FT DOMAIN 41..309
FT /note="Deacetylase sirtuin-type"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03160"
FT ACT_SITE 158
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03160"
FT BINDING 58..77
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03160"
FT BINDING 102
FT /ligand="substrate"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03160"
FT BINDING 105
FT /ligand="substrate"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03160"
FT BINDING 140..143
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03160"
FT BINDING 166
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03160"
FT BINDING 169
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03160"
FT BINDING 207
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03160"
FT BINDING 212
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03160"
FT BINDING 249..251
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03160"
FT BINDING 275..277
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03160"
FT BINDING 293
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03160"
FT MUTAGEN 158
FT /note="H->Y: Loss of enzyme activity."
FT /evidence="ECO:0000269|PubMed:19410549"
SQ SEQUENCE 310 AA; 34134 MW; A0C4962D5E6F8729 CRC64;
MRPLLIAPGR FISQLCCRRK PPASPQSKIC LTMARPSSNM ADFRKCFANA KHIAIISGAG
VSAESGVPTF RGAGGYWRKW QAQDLATPQA FARNPSQVWE FYHYRREVMR SKEPNPGHLA
IAQCEARLRD QGRRVVVITQ NIDELHRKAG TKNLLEIHGT LFKTRCTSCG TVAENYRSPI
CPALAGKGAP EPETQDARIP VDKLPRCEEA GCGGLLRPHV VWFGENLDPA ILEEVDRELA
LCDLCLVVGT SSVVYPAAMF APQVASRGVP VAEFNMETTP ATDRFRFHFP GPCGKTLPEA
LAPHETERTS
