ID   A0A9L0T9B1_HORSE        Unreviewed;       310 AA.
AC   A0A9L0T9B1;
DT   13-SEP-2023, integrated into UniProtKB/TrEMBL.
DT   13-SEP-2023, sequence version 1.
DT   02-SEP-2026, entry version 15.
DE   RecName: Full=NAD-dependent protein deacylase sirtuin-5, mitochondrial {ECO:0000256|HAMAP-Rule:MF_03160};
DE            EC=2.3.1.- {ECO:0000256|HAMAP-Rule:MF_03160};
DE   AltName: Full=Regulatory protein SIR2 homolog 5 {ECO:0000256|HAMAP-Rule:MF_03160};
DE   AltName: Full=SIR2-like protein 5 {ECO:0000256|HAMAP-Rule:MF_03160};
GN   Name=SIRT5 {ECO:0000256|HAMAP-Rule:MF_03160};
OS   Equus caballus (Horse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Perissodactyla; Equidae; Equus.
OX   NCBI_TaxID=9796 {ECO:0000313|Ensembl:ENSECAP00000083724.1, ECO:0000313|Proteomes:UP000002281};
RN   [1] {ECO:0000313|Ensembl:ENSECAP00000083724.1, ECO:0000313|Proteomes:UP000002281}
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=Thoroughbred {ECO:0000313|Ensembl:ENSECAP00000083724.1,
RC   ECO:0000313|Proteomes:UP000002281};
RX   PubMed=19892987; DOI=10.1126/science.1178158;
RG   Broad Institute Genome Sequencing Platform;
RG   Broad Institute Whole Genome Assembly Team;
RA   Wade C.M., Giulotto E., Sigurdsson S., Zoli M., Gnerre S., Imsland F.,
RA   Lear T.L., Adelson D.L., Bailey E., Bellone R.R., Bloecker H., Distl O.,
RA   Edgar R.C., Garber M., Leeb T., Mauceli E., MacLeod J.N., Penedo M.C.T.,
RA   Raison J.M., Sharpe T., Vogel J., Andersson L., Antczak D.F., Biagi T.,
RA   Binns M.M., Chowdhary B.P., Coleman S.J., Della Valle G., Fryc S.,
RA   Guerin G., Hasegawa T., Hill E.W., Jurka J., Kiialainen A., Lindgren G.,
RA   Liu J., Magnani E., Mickelson J.R., Murray J., Nergadze S.G., Onofrio R.,
RA   Pedroni S., Piras M.F., Raudsepp T., Rocchi M., Roeed K.H., Ryder O.A.,
RA   Searle S., Skow L., Swinburne J.E., Syvaenen A.C., Tozaki T., Valberg S.J.,
RA   Vaudin M., White J.R., Zody M.C., Lander E.S., Lindblad-Toh K.;
RT   "Genome sequence, comparative analysis, and population genetics of the
RT   domestic horse.";
RL   Science 326:865-867(2009).
RN   [2] {ECO:0000313|Ensembl:ENSECAP00000083724.1}
RP   IDENTIFICATION.
RC   STRAIN=Thoroughbred {ECO:0000313|Ensembl:ENSECAP00000083724.1};
RG   Ensembl;
RL   Submitted (JAN-2026) to UniProtKB.
CC   -!- FUNCTION: NAD-dependent lysine demalonylase, desuccinylase and
CC       deglutarylase that specifically removes malonyl, succinyl and glutaryl
CC       groups on target proteins. Activates CPS1 and contributes to the
CC       regulation of blood ammonia levels during prolonged fasting: acts by
CC       mediating desuccinylation and deglutarylation of CPS1, thereby
CC       increasing CPS1 activity in response to elevated NAD levels during
CC       fasting. Activates SOD1 by mediating its desuccinylation, leading to
CC       reduced reactive oxygen species. Modulates ketogenesis through the
CC       desuccinylation and activation of HMGCS2. Has weak NAD-dependent
CC       protein deacetylase activity; however this activity may not be
CC       physiologically relevant in vivo. Can deacetylate cytochrome c (CYCS)
CC       and a number of other proteins in vitro such as Uox.
CC       {ECO:0000256|HAMAP-Rule:MF_03160}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=N(6)-glutaryl-L-lysyl-[protein] + NAD(+) + H2O = 2''-O-
CC         glutaryl-ADP-D-ribose + nicotinamide + L-lysyl-[protein];
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:0000256|ARBA:ARBA00050628, ECO:0000256|HAMAP-
CC         Rule:MF_03160};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=N(6)-malonyl-L-lysyl-[protein] + NAD(+) + H2O = 2''-O-malonyl-
CC         ADP-D-ribose + nicotinamide + L-lysyl-[protein];
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:0000256|HAMAP-Rule:MF_03160};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=N(6)-succinyl-L-lysyl-[protein] + NAD(+) + H2O = 2''-O-
CC         succinyl-ADP-D-ribose + nicotinamide + L-lysyl-[protein];
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:0000256|HAMAP-Rule:MF_03160};
CC   -!- COFACTOR:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000256|HAMAP-
CC         Rule:MF_03160};
CC       Note=Binds 1 zinc ion per subunit. {ECO:0000256|HAMAP-Rule:MF_03160};
CC   -!- SUBUNIT: Monomer. Homodimer. Interacts with CPS1. {ECO:0000256|HAMAP-
CC       Rule:MF_03160}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC       {ECO:0000256|ARBA:ARBA00004514, ECO:0000256|HAMAP-Rule:MF_03160}.
CC       Mitochondrion {ECO:0000256|HAMAP-Rule:MF_03160}. Nucleus
CC       {ECO:0000256|ARBA:ARBA00004123, ECO:0000256|HAMAP-Rule:MF_03160}.
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. {ECO:0000256|HAMAP-Rule:MF_03160}.
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:0000256|HAMAP-Rule:MF_03160}.
CC   -!- SIMILARITY: Belongs to the sirtuin family. Class III subfamily.
CC       {ECO:0000256|HAMAP-Rule:MF_03160}.
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DR   AlphaFoldDB; A0A9L0T9B1; -.
DR   SMR; A0A9L0T9B1; -.
DR   Ensembl; ENSECAT00000146678.1; ENSECAP00000083724.1; ENSECAG00000026898.4.
DR   GeneTree; ENSGT00940000156080; -.
DR   OMA; LIHMHGE; -.
DR   OrthoDB; 424302at2759; -.
DR   Proteomes; UP000002281; Chromosome 20.
DR   ExpressionAtlas; A0A9L0T9B1; baseline.
DR   GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR   GO; GO:0005759; C:mitochondrial matrix; IBA:GO_Central.
DR   GO; GO:0005739; C:mitochondrion; IBA:GO_Central.
DR   GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR   GO; GO:0017136; F:histone deacetylase activity, NAD-dependent; IBA:GO_Central.
DR   GO; GO:0070403; F:NAD+ binding; IEA:UniProtKB-UniRule.
DR   GO; GO:0061697; F:protein-glutaryllysine deglutarylase activity; IBA:GO_Central.
DR   GO; GO:0036054; F:protein-malonyllysine demalonylase activity; IBA:GO_Central.
DR   GO; GO:0036055; F:protein-succinyllysine desuccinylase activity; IBA:GO_Central.
DR   GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-UniRule.
DR   CDD; cd01412; SIRT5_Af1_CobB; 1.
DR   FunFam; 3.30.1600.10:FF:000005; NAD-dependent protein deacylase sirtuin-5, mitochondrial; 1.
DR   Gene3D; 3.30.1600.10; SIR2/SIRT2 'Small Domain; 1.
DR   Gene3D; 3.40.50.1220; TPP-binding domain; 1.
DR   HAMAP; MF_01121; Sirtuin_ClassIII; 1.
DR   InterPro; IPR029035; DHS-like_NAD/FAD-binding_dom.
DR   InterPro; IPR050134; NAD-dep_sirtuin_deacylases.
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   NCBIfam; NF001753; PRK00481.1-3; 1.
DR   PANTHER; PTHR11085; NAD-DEPENDENT PROTEIN DEACYLASE SIRTUIN-5, MITOCHONDRIAL-RELATED; 1.
DR   PANTHER; PTHR11085:SF10; NAD-DEPENDENT PROTEIN DEACYLASE SIRTUIN-5, MITOCHONDRIAL-RELATED; 1.
DR   Pfam; PF02146; SIR2; 1.
DR   SUPFAM; SSF52467; DHS-like NAD/FAD-binding domain; 1.
DR   PROSITE; PS50305; SIRTUIN; 1.
PE   1: Evidence at protein level;
KW   Cytoplasm {ECO:0000256|ARBA:ARBA00022490, ECO:0000256|HAMAP-Rule:MF_03160};
KW   Metal-binding {ECO:0000256|ARBA:ARBA00022723, ECO:0000256|HAMAP-
KW   Rule:MF_03160};
KW   Mitochondrion {ECO:0000256|ARBA:ARBA00023128, ECO:0000256|HAMAP-
KW   Rule:MF_03160};
KW   NAD {ECO:0000256|ARBA:ARBA00023027, ECO:0000256|HAMAP-Rule:MF_03160};
KW   Nucleus {ECO:0000256|ARBA:ARBA00023242, ECO:0000256|HAMAP-Rule:MF_03160};
KW   Proteomics identification {ECO:0007829|PeptideAtlas:A0A9L0T9B1};
KW   Reference proteome {ECO:0000313|Proteomes:UP000002281};
KW   Transferase {ECO:0000256|ARBA:ARBA00022679, ECO:0000256|HAMAP-
KW   Rule:MF_03160};
KW   Transit peptide {ECO:0000256|ARBA:ARBA00022946, ECO:0000256|HAMAP-
KW   Rule:MF_03160};
KW   Zinc {ECO:0000256|ARBA:ARBA00022833, ECO:0000256|HAMAP-Rule:MF_03160}.
FT   DOMAIN          33..307
FT                   /note="Deacetylase sirtuin-type"
FT                   /evidence="ECO:0000259|PROSITE:PS50305"
FT   ACT_SITE        158
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000256|HAMAP-Rule:MF_03160,
FT                   ECO:0000256|PROSITE-ProRule:PRU00236"
FT   BINDING         58..77
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000256|HAMAP-Rule:MF_03160"
FT   BINDING         102
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000256|HAMAP-Rule:MF_03160"
FT   BINDING         105
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000256|HAMAP-Rule:MF_03160"
FT   BINDING         140..143
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000256|HAMAP-Rule:MF_03160"
FT   BINDING         166
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000256|HAMAP-Rule:MF_03160,
FT                   ECO:0000256|PROSITE-ProRule:PRU00236"
FT   BINDING         169
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000256|HAMAP-Rule:MF_03160,
FT                   ECO:0000256|PROSITE-ProRule:PRU00236"
FT   BINDING         207
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000256|HAMAP-Rule:MF_03160,
FT                   ECO:0000256|PROSITE-ProRule:PRU00236"
FT   BINDING         212
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000256|HAMAP-Rule:MF_03160,
FT                   ECO:0000256|PROSITE-ProRule:PRU00236"
FT   BINDING         249..251
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000256|HAMAP-Rule:MF_03160"
FT   BINDING         275..277
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000256|HAMAP-Rule:MF_03160"
FT   BINDING         293
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000256|HAMAP-Rule:MF_03160"
SQ   SEQUENCE   310 AA;  33952 MW;  152766CDAE0FDB94 CRC64;
     MRPLQIVHSR LISRLCCGLK SAASTQTKIC LTMARPSSNM ADFRKFFAKA KHIVVISGAG
     ISAESGVPTF RGAGGYWRKW KAQDLATPQA FARNPSQVWE FYHYRREVVQ TKEPNPGHLA
     IAQCEARLHK QGRRVVVITQ NIDELHRKAG TKNLLEIHGS LFKTRCTSCG VVAENYKSPI
     CPALSGKGSP DPETQSARIP AENLPRCEEA GCGGLLRPHV VWFGENLDPA ILEEVDRELA
     LCDLCLVVGT SSVVYPAAMF APQVSARGVP VAEFNMETTP ATSRFRFHFQ GPCGTTLPEA
     LAPHETETVS
//