SIR4_HUMAN
ID SIR4_HUMAN Reviewed; 314 AA.
AC Q9Y6E7; O43346; Q32M33;
DT 31-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 163.
DE RecName: Full=NAD-dependent protein lipoamidase sirtuin-4, mitochondrial {ECO:0000255|HAMAP-Rule:MF_03161, ECO:0000303|PubMed:25525879};
DE EC=2.3.1.- {ECO:0000255|HAMAP-Rule:MF_03161, ECO:0000269|PubMed:24052263, ECO:0000269|PubMed:25525879};
DE AltName: Full=NAD-dependent ADP-ribosyltransferase sirtuin-4 {ECO:0000255|HAMAP-Rule:MF_03161};
DE EC=2.4.2.- {ECO:0000255|HAMAP-Rule:MF_03161};
DE AltName: Full=NAD-dependent protein biotinylase sirtuin-4 {ECO:0000255|HAMAP-Rule:MF_03161};
DE EC=2.3.1.- {ECO:0000255|HAMAP-Rule:MF_03161, ECO:0000269|PubMed:25525879};
DE AltName: Full=NAD-dependent protein deacetylase sirtuin-4 {ECO:0000255|HAMAP-Rule:MF_03161};
DE EC=2.3.1.286 {ECO:0000255|HAMAP-Rule:MF_03161};
DE AltName: Full=Regulatory protein SIR2 homolog 4 {ECO:0000255|HAMAP-Rule:MF_03161};
DE AltName: Full=SIR2-like protein 4 {ECO:0000255|HAMAP-Rule:MF_03161};
DE Flags: Precursor;
GN Name=SIRT4 {ECO:0000255|HAMAP-Rule:MF_03161, ECO:0000312|HGNC:HGNC:14932};
GN Synonyms=SIR2L4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC TISSUE=Testis;
RX PubMed=10381378; DOI=10.1006/bbrc.1999.0897;
RA Frye R.A.;
RT "Characterization of five human cDNAs with homology to the yeast SIR2 gene:
RT Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-
RT ribosyltransferase activity.";
RL Biochem. Biophys. Res. Commun. 260:273-279(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C.,
RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R.,
RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E.,
RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y.,
RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G.,
RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H.,
RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S.,
RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M.,
RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H.,
RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q.,
RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V.,
RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E.,
RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R.,
RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E.,
RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N.,
RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N.,
RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R.,
RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S.,
RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H.,
RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P.,
RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G.,
RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E.,
RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S.,
RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O.,
RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y.,
RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A.,
RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F.,
RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L.,
RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G.,
RA Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [4]
RP PROTEIN SEQUENCE OF N-TERMINUS, FUNCTION, INTERACTION WITH GLUD1, AND
RP SUBCELLULAR LOCATION.
RX PubMed=16959573; DOI=10.1016/j.cell.2006.06.057;
RA Haigis M.C., Mostoslavsky R., Haigis K.M., Fahie K., Christodoulou D.C.,
RA Murphy A.J., Valenzuela D.M., Yancopoulos G.D., Karow M., Blander G.,
RA Wolberger C., Prolla T.A., Weindruch R., Alt F.W., Guarente L.;
RT "SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie
RT restriction in pancreatic beta cells.";
RL Cell 126:941-954(2006).
RN [5]
RP PROTEIN SEQUENCE OF N-TERMINUS, FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR
RP LOCATION, AND INTERACTION WITH IDE AND SLC25A5.
RX PubMed=17715127; DOI=10.1074/jbc.m705488200;
RA Ahuja N., Schwer B., Carobbio S., Waltregny D., North B.J., Castronovo V.,
RA Maechler P., Verdin E.;
RT "Regulation of insulin secretion by SIRT4, a mitochondrial ADP-
RT ribosyltransferase.";
RL J. Biol. Chem. 282:33583-33592(2007).
RN [6]
RP SUBCELLULAR LOCATION.
RX PubMed=16079181; DOI=10.1091/mbc.e05-01-0033;
RA Michishita E., Park J.Y., Burneskis J.M., Barrett J.C., Horikawa I.;
RT "Evolutionarily conserved and nonconserved cellular localizations and
RT functions of human SIRT proteins.";
RL Mol. Biol. Cell 16:4623-4635(2005).
RN [7]
RP FUNCTION AS A TUMOR SUPPRESSOR.
RX PubMed=23562301; DOI=10.1016/j.ccr.2013.02.024;
RA Jeong S.M., Xiao C., Finley L.W., Lahusen T., Souza A.L., Pierce K.,
RA Li Y.H., Wang X., Laurent G., German N.J., Xu X., Li C., Wang R.H., Lee J.,
RA Csibi A., Cerione R., Blenis J., Clish C.B., Kimmelman A., Deng C.X.,
RA Haigis M.C.;
RT "SIRT4 has tumor-suppressive activity and regulates the cellular metabolic
RT response to DNA damage by inhibiting mitochondrial glutamine metabolism.";
RL Cancer Cell 23:450-463(2013).
RN [8]
RP FUNCTION AS A TUMOR SUPPRESSOR.
RX PubMed=23663782; DOI=10.1016/j.cell.2013.04.023;
RA Csibi A., Fendt S.M., Li C., Poulogiannis G., Choo A.Y., Chapski D.J.,
RA Jeong S.M., Dempsey J.M., Parkhitko A., Morrison T., Henske E.P.,
RA Haigis M.C., Cantley L.C., Stephanopoulos G., Yu J., Blenis J.;
RT "The mTORC1 pathway stimulates glutamine metabolism and cell proliferation
RT by repressing SIRT4.";
RL Cell 153:840-854(2013).
RN [9]
RP FUNCTION, AND INTERACTION WITH PCCA; MCCC1 AND PC.
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 [10]
RP FUNCTION.
RX PubMed=24043310; DOI=10.1128/mcb.00087-13;
RA Laurent G., de Boer V.C., Finley L.W., Sweeney M., Lu H., Schug T.T.,
RA Cen Y., Jeong S.M., Li X., Sauve A.A., Haigis M.C.;
RT "SIRT4 represses peroxisome proliferator-activated receptor alpha activity
RT to suppress hepatic fat oxidation.";
RL Mol. Cell. Biol. 33:4552-4561(2013).
RN [11]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=24052263; DOI=10.1074/jbc.c113.511261;
RA Feldman J.L., Baeza J., Denu J.M.;
RT "Activation of the protein deacetylase SIRT6 by long-chain fatty acids and
RT widespread deacylation by mammalian sirtuins.";
RL J. Biol. Chem. 288:31350-31356(2013).
RN [12]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, INTERACTION
RP WITH DLAT AND PDHX, MUTAGENESIS OF HIS-161, AND INDUCTION BY GLUTAMINE.
RX PubMed=25525879; DOI=10.1016/j.cell.2014.11.046;
RA Mathias R.A., Greco T.M., Oberstein A., Budayeva H.G., Chakrabarti R.,
RA Rowland E.A., Kang Y., Shenk T., Cristea I.M.;
RT "Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex
RT activity.";
RL Cell 159:1615-1625(2014).
CC -!- FUNCTION: Acts as NAD-dependent protein lipoamidase, biotinylase,
CC deacetylase and ADP-ribosyl transferase (PubMed:16959573,
CC PubMed:17715127, PubMed:24052263, PubMed:25525879). Catalyzes more
CC efficiently removal of lipoyl- and biotinyl- than acetyl-lysine
CC modifications (PubMed:24052263, PubMed:25525879). Inhibits the pyruvate
CC dehydrogenase complex (PDH) activity via the enzymatic hydrolysis of
CC the lipoamide cofactor from the E2 component, DLAT, in a
CC phosphorylation-independent manner (PubMed:25525879). Catalyzes the
CC transfer of ADP-ribosyl groups onto target proteins, including
CC mitochondrial GLUD1, inhibiting GLUD1 enzyme activity (PubMed:16959573,
CC PubMed:17715127). Acts as a negative regulator of mitochondrial
CC glutamine metabolism by mediating mono ADP-ribosylation of GLUD1:
CC expressed in response to DNA damage and negatively regulates
CC anaplerosis by inhibiting GLUD1, leading to block metabolism of
CC glutamine into tricarboxylic acid cycle and promoting cell cycle arrest
CC (PubMed:16959573, PubMed:17715127). In response to mTORC1 signal, SIRT4
CC expression is repressed, promoting anaplerosis and cell proliferation
CC (PubMed:23663782). Acts as a tumor suppressor (PubMed:23562301,
CC PubMed:23663782). 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 (By similarity).
CC Does not seem to deacetylate PC (PubMed:23438705). Controls fatty acid
CC oxidation by inhibiting PPARA transcriptional activation
CC (PubMed:24043310). Impairs SIRT1-PPARA interaction probably through the
CC regulation of NAD(+) levels (PubMed:24043310). Down-regulates insulin
CC secretion (PubMed:17715127). {ECO:0000255|HAMAP-Rule:MF_03161,
CC ECO:0000269|PubMed:16959573, ECO:0000269|PubMed:17715127,
CC ECO:0000269|PubMed:23438705, ECO:0000269|PubMed:23562301,
CC ECO:0000269|PubMed:23663782, ECO:0000269|PubMed:24043310,
CC ECO:0000269|PubMed:24052263, ECO:0000269|PubMed:25525879}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(R)-N(6)-lipoyl-L-lysyl-[protein] + H2O + 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:0000255|HAMAP-Rule:MF_03161,
CC ECO:0000269|PubMed:24052263, ECO:0000269|PubMed:25525879};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63641;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03161,
CC ECO:0000269|PubMed:24052263, ECO:0000269|PubMed:25525879};
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:0000255|HAMAP-Rule:MF_03161,
CC ECO:0000269|PubMed:25525879};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70480;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03161,
CC ECO:0000269|PubMed:25525879};
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:0000255|HAMAP-Rule:MF_03161,
CC ECO:0000305|PubMed:16959573};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:43637;
CC Evidence={ECO:0000305|PubMed:16959573};
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:0000255|HAMAP-Rule:MF_03161,
CC ECO:0000269|PubMed:17715127};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03161};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000255|HAMAP-Rule:MF_03161};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=719 uM for a peptide of H3 biotinylated at 'Lys-9'
CC {ECO:0000269|PubMed:25525879};
CC KM=814 uM for a peptide of H3 lipoylated at 'Lys-9'
CC {ECO:0000269|PubMed:25525879};
CC KM=239 uM for a peptide of DLAT lipoylated at 'Lys-259'
CC {ECO:0000269|PubMed:25525879};
CC Note=kcat is 0.0019 sec(-1) for the delipoylation of H3 'Lys-9'. kcat
CC is 0.0005 sec(-1) for the debiotinylation of H3 'Lys-9'. kcat is
CC 0.0018 sec(-1) for the delipoylation of DLAT 'Lys-259'.
CC {ECO:0000269|PubMed:25525879};
CC -!- SUBUNIT: Interacts with GLUD1, IDE and SLC25A5 (PubMed:16959573,
CC PubMed:17715127). Interacts with DLAT and PDHX (PubMed:25525879).
CC Interacts with MCCC1 (via the biotin carboxylation domain)
CC (PubMed:23438705). Interacts with PCCA and PC (PubMed:23438705).
CC {ECO:0000255|HAMAP-Rule:MF_03161, ECO:0000269|PubMed:16959573,
CC ECO:0000269|PubMed:17715127, ECO:0000269|PubMed:23438705,
CC ECO:0000269|PubMed:25525879}.
CC -!- INTERACTION:
CC Q9Y6E7; P10515: DLAT; NbExp=6; IntAct=EBI-2606540, EBI-2959723;
CC Q9Y6E7; O00330: PDHX; NbExp=4; IntAct=EBI-2606540, EBI-751566;
CC Q9Y6E7; P05141: SLC25A5; NbExp=2; IntAct=EBI-2606540, EBI-355133;
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000255|HAMAP-
CC Rule:MF_03161, ECO:0000269|PubMed:16079181,
CC ECO:0000269|PubMed:16959573, ECO:0000269|PubMed:17715127}.
CC -!- TISSUE SPECIFICITY: Detected in vascular smooth muscle and striated
CC muscle. Detected in insulin-producing beta-cells in pancreas islets of
CC Langerhans (at protein level). Widely expressed. Weakly expressed in
CC leukocytes and fetal thymus. {ECO:0000269|PubMed:10381378}.
CC -!- INDUCTION: Induced by glutamine (at protein level).
CC {ECO:0000269|PubMed:25525879}.
CC -!- MISCELLANEOUS: Expression is down-regulated in a number of cancers,
CC while overexpression reduces cell proliferation, transformation, and
CC tumor development (PubMed:23562301, PubMed:23663782).
CC {ECO:0000305|PubMed:23562301, ECO:0000305|PubMed:23663782}.
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:0000255|HAMAP-Rule:MF_03161}.
CC -!- SIMILARITY: Belongs to the sirtuin family. Class II subfamily.
CC {ECO:0000255|HAMAP-Rule:MF_03161}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB95634.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; AF083109; AAD40852.1; -; mRNA.
DR EMBL; AC003982; AAB95634.1; ALT_SEQ; Genomic_DNA.
DR EMBL; BC109319; AAI09320.1; -; mRNA.
DR EMBL; BC109320; AAI09321.1; -; mRNA.
DR CCDS; CCDS9194.1; -.
DR RefSeq; NP_036372.1; NM_012240.2.
DR RefSeq; XP_006719371.1; XM_006719308.2.
DR RefSeq; XP_006719372.1; XM_006719309.3.
DR AlphaFoldDB; Q9Y6E7; -.
DR SMR; Q9Y6E7; -.
DR BioGRID; 116981; 24.
DR IntAct; Q9Y6E7; 110.
DR STRING; 9606.ENSP00000202967; -.
DR ChEMBL; CHEMBL2163185; -.
DR iPTMnet; Q9Y6E7; -.
DR PhosphoSitePlus; Q9Y6E7; -.
DR BioMuta; SIRT4; -.
DR DMDM; 38258657; -.
DR MassIVE; Q9Y6E7; -.
DR PaxDb; Q9Y6E7; -.
DR PeptideAtlas; Q9Y6E7; -.
DR PRIDE; Q9Y6E7; -.
DR ProteomicsDB; 86660; -.
DR Antibodypedia; 31464; 391 antibodies from 39 providers.
DR DNASU; 23409; -.
DR Ensembl; ENST00000202967.4; ENSP00000202967.4; ENSG00000089163.4.
DR GeneID; 23409; -.
DR KEGG; hsa:23409; -.
DR MANE-Select; ENST00000202967.4; ENSP00000202967.4; NM_012240.3; NP_036372.1.
DR UCSC; uc001tyc.4; human.
DR CTD; 23409; -.
DR DisGeNET; 23409; -.
DR GeneCards; SIRT4; -.
DR HGNC; HGNC:14932; SIRT4.
DR HPA; ENSG00000089163; Low tissue specificity.
DR MIM; 604482; gene.
DR neXtProt; NX_Q9Y6E7; -.
DR OpenTargets; ENSG00000089163; -.
DR PharmGKB; PA37937; -.
DR VEuPathDB; HostDB:ENSG00000089163; -.
DR eggNOG; KOG2683; Eukaryota.
DR GeneTree; ENSGT00940000158891; -.
DR HOGENOM; CLU_023643_3_2_1; -.
DR InParanoid; Q9Y6E7; -.
DR OMA; RRHYWAR; -.
DR OrthoDB; 1407693at2759; -.
DR PhylomeDB; Q9Y6E7; -.
DR TreeFam; TF106182; -.
DR PathwayCommons; Q9Y6E7; -.
DR Reactome; R-HSA-2151201; Transcriptional activation of mitochondrial biogenesis.
DR SignaLink; Q9Y6E7; -.
DR SIGNOR; Q9Y6E7; -.
DR BioGRID-ORCS; 23409; 40 hits in 1090 CRISPR screens.
DR ChiTaRS; SIRT4; human.
DR GeneWiki; SIRT4; -.
DR GenomeRNAi; 23409; -.
DR Pharos; Q9Y6E7; Tbio.
DR PRO; PR:Q9Y6E7; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; Q9Y6E7; protein.
DR Bgee; ENSG00000089163; Expressed in apex of heart and 117 other tissues.
DR ExpressionAtlas; Q9Y6E7; baseline and differential.
DR Genevisible; Q9Y6E7; HS.
DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:Ensembl.
DR GO; GO:0005759; C:mitochondrial matrix; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0019213; F:deacetylase activity; IBA:GO_Central.
DR GO; GO:0061690; F:lipoamidase activity; IEA:Ensembl.
DR GO; GO:0003950; F:NAD+ ADP-ribosyltransferase activity; IDA:UniProtKB.
DR GO; GO:0070403; F:NAD+ binding; IEA:UniProtKB-UniRule.
DR GO; GO:0106420; F:NAD-dependent protein biotinidase activity; IDA:UniProtKB.
DR GO; GO:0106419; F:NAD-dependent protein lipoamidase activity; IDA:UniProtKB.
DR GO; GO:0033558; F:protein lysine deacetylase activity; IEA:UniProtKB-EC.
DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-UniRule.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; ISS:UniProtKB.
DR GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl.
DR GO; GO:0006541; P:glutamine metabolic process; ISS:UniProtKB.
DR GO; GO:0007005; P:mitochondrion organization; TAS:Reactome.
DR GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; IEA:Ensembl.
DR GO; GO:0046322; P:negative regulation of fatty acid oxidation; IMP:UniProtKB.
DR GO; GO:0046676; P:negative regulation of insulin secretion; IMP:UniProtKB.
DR GO; GO:1903217; P:negative regulation of protein processing involved in protein targeting to mitochondrion; IEA:Ensembl.
DR GO; GO:0034983; P:peptidyl-lysine deacetylation; ISS:UniProtKB.
DR GO; GO:0046889; P:positive regulation of lipid biosynthetic process; ISS:UniProtKB.
DR GO; GO:0006471; P:protein ADP-ribosylation; ISS:UniProtKB.
DR GO; GO:0006476; P:protein deacetylation; IBA:GO_Central.
DR GO; GO:0000820; P:regulation of glutamine family amino acid metabolic process; IEA:Ensembl.
DR GO; GO:1904182; P:regulation of pyruvate dehydrogenase activity; IDA:UniProtKB.
DR GO; GO:0072350; P:tricarboxylic acid metabolic process; ISS:UniProtKB.
DR Gene3D; 3.30.1600.10; -; 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 Pfam; PF02146; SIR2; 1.
DR SUPFAM; SSF52467; SSF52467; 1.
DR PROSITE; PS50305; SIRTUIN; 1.
PE 1: Evidence at protein level;
KW Direct protein sequencing; DNA damage; Glycosyltransferase; Metal-binding;
KW Mitochondrion; NAD; Nucleotidyltransferase; Reference proteome;
KW Transferase; Transit peptide; Tumor suppressor; Zinc.
FT TRANSIT 1..28
FT /note="Mitochondrion"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03161,
FT ECO:0000269|PubMed:16959573, ECO:0000269|PubMed:17715127"
FT CHAIN 29..314
FT /note="NAD-dependent protein lipoamidase sirtuin-4,
FT mitochondrial"
FT /id="PRO_0000110264"
FT DOMAIN 45..314
FT /note="Deacetylase sirtuin-type"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03161"
FT ACT_SITE 161
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03161"
FT BINDING 62..82
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03161"
FT BINDING 143..146
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03161"
FT BINDING 169
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03161"
FT BINDING 172
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03161"
FT BINDING 220
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03161"
FT BINDING 223
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03161"
FT BINDING 260..262
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03161"
FT BINDING 286..288
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03161"
FT BINDING 304
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03161"
FT MUTAGEN 161
FT /note="H->Y: Abolishes inhibition of PDH complex activity."
FT /evidence="ECO:0000269|PubMed:25525879"
SQ SEQUENCE 314 AA; 35188 MW; 2B76963AD2C3B354 CRC64;
MKMSFALTFR SAKGRWIANP SQPCSKASIG LFVPASPPLD PEKVKELQRF ITLSKRLLVM
TGAGISTESG IPDYRSEKVG LYARTDRRPI QHGDFVRSAP IRQRYWARNF VGWPQFSSHQ
PNPAHWALST WEKLGKLYWL VTQNVDALHT KAGSRRLTEL HGCMDRVLCL DCGEQTPRGV
LQERFQVLNP TWSAEAHGLA PDGDVFLSEE QVRSFQVPTC VQCGGHLKPD VVFFGDTVNP
DKVDFVHKRV KEADSLLVVG SSLQVYSGYR FILTAWEKKL PIAILNIGPT RSDDLACLKL
NSRCGELLPL IDPC
