ID A0A3Q1M4F8_BOVIN Unreviewed; 315 AA.
AC A0A3Q1M4F8;
DT 10-APR-2019, integrated into UniProtKB/TrEMBL.
DT 10-APR-2019, sequence version 1.
DT 27-MAR-2024, entry version 21.
DE RecName: Full=NAD-dependent protein lipoamidase sirtuin-4, mitochondrial {ECO:0000256|HAMAP-Rule:MF_03161};
DE EC=2.3.1.- {ECO:0000256|HAMAP-Rule:MF_03161};
DE AltName: Full=NAD-dependent ADP-ribosyltransferase sirtuin-4 {ECO:0000256|HAMAP-Rule:MF_03161};
DE EC=2.4.2.- {ECO:0000256|HAMAP-Rule:MF_03161};
DE AltName: Full=NAD-dependent protein biotinylase sirtuin-4 {ECO:0000256|HAMAP-Rule:MF_03161};
DE EC=2.3.1.- {ECO:0000256|HAMAP-Rule:MF_03161};
DE AltName: Full=NAD-dependent protein deacetylase sirtuin-4 {ECO:0000256|HAMAP-Rule:MF_03161};
DE EC=2.3.1.286 {ECO:0000256|HAMAP-Rule:MF_03161};
DE AltName: Full=Regulatory protein SIR2 homolog 4 {ECO:0000256|HAMAP-Rule:MF_03161};
DE AltName: Full=SIR2-like protein 4 {ECO:0000256|HAMAP-Rule:MF_03161};
GN Name=SIRT4 {ECO:0000256|HAMAP-Rule:MF_03161,
GN ECO:0000313|Ensembl:ENSBTAP00000065095.1,
GN ECO:0000313|VGNC:VGNC:34633};
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913 {ECO:0000313|Ensembl:ENSBTAP00000065095.1, ECO:0000313|Proteomes:UP000009136};
RN [1] {ECO:0000313|Ensembl:ENSBTAP00000065095.1, ECO:0000313|Proteomes:UP000009136}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Hereford {ECO:0000313|Ensembl:ENSBTAP00000065095.1,
RC ECO:0000313|Proteomes:UP000009136};
RA Rosen B.D., Bickhart D.M., Koren S., Schnabel R.D., Hall R., Zimin A.,
RA Dreischer C., Schultheiss S., Schroeder S.G., Elsik C.G., Couldrey C.,
RA Liu G.E., Van Tassell C.P., Phillippy A.M., Smith T.P.L., Medrano J.F.;
RT "ARS-UCD1.2.";
RL Submitted (MAR-2018) to the EMBL/GenBank/DDBJ databases.
RN [2] {ECO:0000313|Ensembl:ENSBTAP00000065095.1}
RP IDENTIFICATION.
RC STRAIN=Hereford {ECO:0000313|Ensembl:ENSBTAP00000065095.1};
RG Ensembl;
RL Submitted (NOV-2023) to UniProtKB.
CC -!- FUNCTION: Acts as NAD-dependent protein lipoamidase, biotinylase,
CC deacetylase and ADP-ribosyl transferase. Catalyzes more efficiently
CC removal of lipoyl- and biotinyl- than acetyl-lysine modifications.
CC Inhibits the pyruvate dehydrogenase complex (PDH) activity via the
CC enzymatic hydrolysis of the lipoamide cofactor from the E2 component,
CC DLAT, in a phosphorylation-independent manner. Catalyzes the transfer
CC of ADP-ribosyl groups onto target proteins, including mitochondrial
CC GLUD1, inhibiting GLUD1 enzyme activity. Acts as a negative regulator
CC of mitochondrial glutamine metabolism by mediating mono ADP-
CC ribosylation of GLUD1: expressed in response to DNA damage and
CC negatively regulates anaplerosis by inhibiting GLUD1, leading to block
CC metabolism of glutamine into tricarboxylic acid cycle and promoting
CC cell cycle arrest. In response to mTORC1 signal, SIRT4 expression is
CC repressed, promoting anaplerosis and cell proliferation. Acts as a
CC tumor suppressor. Also acts as a NAD-dependent protein deacetylase:
CC mediates deacetylation of 'Lys-471' of MLYCD, inhibiting its activity,
CC thereby acting as a regulator of lipid homeostasis. Does not seem to
CC deacetylate PC. Controls fatty acid oxidation by inhibiting PPARA
CC transcriptional activation. Impairs SIRT1-PPARA interaction probably
CC through the regulation of NAD(+) levels. Down-regulates insulin
CC secretion. {ECO:0000256|HAMAP-Rule:MF_03161}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N(6)-[(R)-lipoyl]-L-lysyl-[protein] + NAD(+) = 2''-O-
CC lipoyl-ADP-D-ribose + L-lysyl-[protein] + nicotinamide;
CC Xref=Rhea:RHEA:63640, Rhea:RHEA-COMP:9752, Rhea:RHEA-COMP:10474,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:17154, ChEBI:CHEBI:29969,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:83099, ChEBI:CHEBI:189572;
CC Evidence={ECO:0000256|HAMAP-Rule:MF_03161};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N(6)-acetyl-L-lysyl-[protein] + NAD(+) = 2''-O-acetyl-
CC ADP-D-ribose + L-lysyl-[protein] + nicotinamide;
CC Xref=Rhea:RHEA:43636, Rhea:RHEA-COMP:9752, Rhea:RHEA-COMP:10731,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:17154, ChEBI:CHEBI:29969,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:61930, ChEBI:CHEBI:83767;
CC EC=2.3.1.286; Evidence={ECO:0000256|HAMAP-Rule:MF_03161};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N(6)-biotinyl-L-lysyl-[protein] + NAD(+) = 2''-O-
CC biotinyl-ADP-D-ribose + L-lysyl-[protein] + nicotinamide;
CC Xref=Rhea:RHEA:70479, Rhea:RHEA-COMP:9752, Rhea:RHEA-COMP:10505,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:17154, ChEBI:CHEBI:29969,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:83144, ChEBI:CHEBI:189573;
CC Evidence={ECO:0000256|HAMAP-Rule:MF_03161};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-cysteinyl-[protein] + NAD(+) = H(+) + nicotinamide + S-(ADP-
CC D-ribosyl)-L-cysteinyl-[protein]; Xref=Rhea:RHEA:56612, Rhea:RHEA-
CC COMP:10131, Rhea:RHEA-COMP:14624, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:17154, ChEBI:CHEBI:29950, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:140607; Evidence={ECO:0000256|HAMAP-Rule:MF_03161};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000256|HAMAP-Rule:MF_03161};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000256|HAMAP-Rule:MF_03161};
CC -!- SUBUNIT: Interacts with GLUD1, IDE and SLC25A5. Interacts with DLAT and
CC PDHX. {ECO:0000256|HAMAP-Rule:MF_03161}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000256|HAMAP-
CC Rule:MF_03161}.
CC -!- MISCELLANEOUS: According to some authors, ADP-ribosyltransferase
CC activity of sirtuins may be an inefficient side reaction of the
CC deacetylase activity and may not be physiologically relevant.
CC {ECO:0000256|HAMAP-Rule:MF_03161}.
CC -!- SIMILARITY: Belongs to the sirtuin family. Class II subfamily.
CC {ECO:0000256|HAMAP-Rule:MF_03161}.
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DR Ensembl; ENSBTAT00000028210.4; ENSBTAP00000028210.4; ENSBTAG00000021168.4.
DR Ensembl; ENSBTAT00000070575.1; ENSBTAP00000065095.1; ENSBTAG00000021168.4.
DR VEuPathDB; HostDB:ENSBTAG00000021168; -.
DR VGNC; VGNC:34633; SIRT4.
DR GeneTree; ENSGT00940000158891; -.
DR OMA; RRHYWAR; -.
DR Reactome; R-BTA-2151201; Transcriptional activation of mitochondrial biogenesis.
DR Proteomes; UP000009136; Chromosome 17.
DR Bgee; ENSBTAG00000021168; Expressed in tongue muscle and 105 other cell types or tissues.
DR GO; GO:0005759; C:mitochondrial matrix; IBA:GO_Central.
DR GO; GO:0004407; F:histone deacetylase activity; IBA:GO_Central.
DR GO; GO:0003950; F:NAD+ ADP-ribosyltransferase activity; IEA:UniProtKB-UniRule.
DR GO; GO:0070403; F:NAD+ binding; IEA:UniProtKB-UniRule.
DR GO; GO:0034979; F:NAD-dependent protein deacetylase activity; IEA:UniProtKB-UniRule.
DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-UniRule.
DR CDD; cd01409; SIRT4; 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_01967; Sirtuin_ClassII; 1.
DR InterPro; IPR029035; DHS-like_NAD/FAD-binding_dom.
DR InterPro; IPR003000; Sirtuin.
DR InterPro; IPR026591; Sirtuin_cat_small_dom_sf.
DR InterPro; IPR026587; Sirtuin_class_II.
DR InterPro; IPR026590; Ssirtuin_cat_dom.
DR PANTHER; PTHR11085; NAD-DEPENDENT PROTEIN DEACYLASE SIRTUIN-5, MITOCHONDRIAL-RELATED; 1.
DR PANTHER; PTHR11085:SF2; NAD-DEPENDENT PROTEIN LIPOAMIDASE SIRTUIN-4, MITOCHONDRIAL; 1.
DR Pfam; PF02146; SIR2; 1.
DR SUPFAM; SSF52467; DHS-like NAD/FAD-binding domain; 1.
DR PROSITE; PS50305; SIRTUIN; 1.
PE 3: Inferred from homology;
KW Metal-binding {ECO:0000256|ARBA:ARBA00022723, ECO:0000256|HAMAP-
KW Rule:MF_03161}; Mitochondrion {ECO:0000256|HAMAP-Rule:MF_03161};
KW NAD {ECO:0000256|ARBA:ARBA00023027, ECO:0000256|HAMAP-Rule:MF_03161};
KW Reference proteome {ECO:0000313|Proteomes:UP000009136};
KW Transferase {ECO:0000256|ARBA:ARBA00022679, ECO:0000256|HAMAP-
KW Rule:MF_03161}; Transit peptide {ECO:0000256|HAMAP-Rule:MF_03161};
KW Zinc {ECO:0000256|ARBA:ARBA00022833, ECO:0000256|HAMAP-Rule:MF_03161}.
FT DOMAIN 38..315
FT /note="Deacetylase sirtuin-type"
FT /evidence="ECO:0000259|PROSITE:PS50305"
FT ACT_SITE 162
FT /note="Proton acceptor"
FT /evidence="ECO:0000256|HAMAP-Rule:MF_03161,
FT ECO:0000256|PROSITE-ProRule:PRU00236"
FT BINDING 63..83
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000256|HAMAP-Rule:MF_03161"
FT BINDING 144..147
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000256|HAMAP-Rule:MF_03161"
FT BINDING 170
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000256|HAMAP-Rule:MF_03161,
FT ECO:0000256|PROSITE-ProRule:PRU00236"
FT BINDING 173
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000256|HAMAP-Rule:MF_03161,
FT ECO:0000256|PROSITE-ProRule:PRU00236"
FT BINDING 221
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000256|HAMAP-Rule:MF_03161,
FT ECO:0000256|PROSITE-ProRule:PRU00236"
FT BINDING 224
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000256|HAMAP-Rule:MF_03161,
FT ECO:0000256|PROSITE-ProRule:PRU00236"
FT BINDING 261..263
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000256|HAMAP-Rule:MF_03161"
FT BINDING 287..289
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000256|HAMAP-Rule:MF_03161"
FT BINDING 305
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000256|HAMAP-Rule:MF_03161"
SQ SEQUENCE 315 AA; 35560 MW; 11EE381369C6EB81 CRC64;
MRMSFGLTFK RTAKVHWRAN FSQQCSLRST GLFVPPSPPL DPEKVKELQR FITLSKRLLV
MTGAGISTES GIPDYRSEKV GLYARTDRRP IQHGDFVRSA PVRQRYWARN FVGWPQFSSR
QPNPAHWALS NWERLGKLHW LVTQNVDALH TKAGSQRLTE LHGCMHRVLC LDCGEQTPRG
VLQERFQVLN PTWSAEAHGL APDGDVFLTE EEVQSFQVPS CSQCGGPLKP DVVFFGDTVK
PDKVDFVHKR VKEADSLLVV GSSLQVYSGY RFILTAREKK LPIVILNIGP TRSDDLASLK
LDSRCGELLP LIDPR
//
