ACLY_RAT
ID ACLY_RAT Reviewed; 1100 AA.
AC P16638; Q497C7; Q8VIQ1;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-AUG-1990, sequence version 1.
DT 03-AUG-2022, entry version 183.
DE RecName: Full=ATP-citrate synthase;
DE EC=2.3.3.8 {ECO:0000269|PubMed:9116495};
DE AltName: Full=ATP-citrate (pro-S-)-lyase;
DE AltName: Full=Citrate cleavage enzyme;
GN Name=Acly;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Liver;
RX PubMed=2295639; DOI=10.1016/s0021-9258(19)40033-1;
RA Elshourbagy N.A., Near J.C., Kmetz P.J., Sathe G.M., Southan C.,
RA Strickler J.E., Gross M., Young J.F., Wells T.N.C., Groot P.H.E.;
RT "Rat ATP citrate-lyase. Molecular cloning and sequence analysis of a full-
RT length cDNA and mRNA abundance as a function of diet, organ, and age.";
RL J. Biol. Chem. 265:1430-1435(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Prostate;
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 [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 250-1100, ALTERNATIVE SPLICING, AND
RP TISSUE SPECIFICITY.
RX PubMed=8688462; DOI=10.1016/0167-4781(96)00067-x;
RA Moon Y.-A., Kim K.-S., Park S.-W., Kim Y.-S.;
RT "Cloning and identification of exon-intron organization of the rat ATP-
RT citrate lyase gene.";
RL Biochim. Biophys. Acta 1307:280-284(1996).
RN [4]
RP PROTEIN SEQUENCE OF 418-459, AND PHOSPHORYLATION AT THR-446 AND SER-450.
RX PubMed=2176822; DOI=10.1021/bi00485a011;
RA Ramakrishna S., D'Angelo G., Benjamin W.B.;
RT "Sequence of sites on ATP-citrate lyase and phosphatase inhibitor 2
RT phosphorylated by multifunctional protein kinase (a glycogen synthase
RT kinase 3 like kinase).";
RL Biochemistry 29:7617-7624(1990).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RC TISSUE=Liver;
RX PubMed=9116495; DOI=10.1006/prep.1996.0668;
RA Lord K.A., Wang X.M., Simmons S.J., Bruckner R.C., Loscig J., O'Connor B.,
RA Bentley R., Smallwood A., Chadwick C.C., Stevis P.E., Ciccarelli R.B.;
RT "Variant cDNA sequences of human ATP:citrate lyase: cloning, expression,
RT and purification from baculovirus-infected insect cells.";
RL Protein Expr. Purif. 9:133-141(1997).
RN [6]
RP PHOSPHORYLATION AT SER-454.
RX PubMed=12107176; DOI=10.1074/jbc.m204681200;
RA Berwick D.C., Hers I., Heesom K.J., Moule S.K., Tavare J.M.;
RT "The identification of ATP-citrate lyase as a protein kinase B (Akt)
RT substrate in primary adipocytes.";
RL J. Biol. Chem. 277:33895-33900(2002).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=16396499; DOI=10.1021/pr0503073;
RA Moser K., White F.M.;
RT "Phosphoproteomic analysis of rat liver by high capacity IMAC and LC-
RT MS/MS.";
RL J. Proteome Res. 5:98-104(2006).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-454; SER-480 AND SER-662, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: Catalyzes the cleavage of citrate into oxaloacetate and
CC acetyl-CoA, the latter serving as common substrate for de novo
CC cholesterol and fatty acid synthesis. {ECO:0000269|PubMed:9116495}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + ADP + oxaloacetate + phosphate = ATP + citrate +
CC CoA; Xref=Rhea:RHEA:21160, ChEBI:CHEBI:16452, ChEBI:CHEBI:16947,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:57287,
CC ChEBI:CHEBI:57288, ChEBI:CHEBI:456216; EC=2.3.3.8;
CC Evidence={ECO:0000269|PubMed:9116495};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:21162;
CC Evidence={ECO:0000305|PubMed:9116495};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:P53396};
CC -!- ACTIVITY REGULATION: Phosphorylation results in activation of its
CC activity (By similarity). Glucose 6-phosphate, fructose 6-phosphate,
CC fructose 2,6-bisphosphate, ribulose 5-phosphate, and fructose 1,6-
CC bisphosphate also act as activators (By similarity).
CC {ECO:0000250|UniProtKB:P53396}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=155.0 uM for citrate {ECO:0000269|PubMed:9116495};
CC KM=103.0 uM for ATP {ECO:0000269|PubMed:9116495};
CC KM=15.0 uM for CoA {ECO:0000269|PubMed:9116495};
CC Vmax=1.9 umol/h/ug enzyme {ECO:0000269|PubMed:9116495};
CC -!- SUBUNIT: Homotetramer. {ECO:0000250|UniProtKB:P53396}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:P53396}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P16638-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P16638-2; Sequence=VSP_026273, VSP_026274;
CC -!- TISSUE SPECIFICITY: Expressed in the brain, kidney, mammary gland, lung
CC and liver. {ECO:0000269|PubMed:8688462}.
CC -!- PTM: Phosphorylated by PKA and GSK3 in a sequential manner;
CC phosphorylation results in activation of its activity (By similarity).
CC Phosphorylation on Thr-446 and Ser-450 depends on the phosphorylation
CC state of Ser-454 (PubMed:12107176, PubMed:2176822). Phosphorylation on
CC Ser-454 is decreased by prior phosphorylation on the other 2 residues
CC (PubMed:12107176, PubMed:2176822). {ECO:0000250|UniProtKB:P53396,
CC ECO:0000269|PubMed:12107176, ECO:0000269|PubMed:2176822}.
CC -!- PTM: The N-terminus is blocked. {ECO:0000269|PubMed:2295639}.
CC -!- PTM: ISGylated. {ECO:0000250|UniProtKB:P53396}.
CC -!- PTM: Acetylated at Lys-539, Lys-545 and Lys-553 by KAT2B/PCAF (By
CC similarity). Acetylation is promoted by glucose and stabilizes the
CC protein, probably by preventing ubiquitination at the same sites (By
CC similarity). Acetylation promotes de novo lipid synthesis (By
CC similarity). Deacetylated by SIRT2 (By similarity).
CC {ECO:0000250|UniProtKB:P53396}.
CC -!- PTM: Ubiquitinated at Lys-539, Lys-545 and Lys-553 by UBR4, leading to
CC its degradation (By similarity). Ubiquitination is probably inhibited
CC by acetylation at same site (By similarity).
CC {ECO:0000250|UniProtKB:P53396}.
CC -!- SIMILARITY: In the N-terminal section; belongs to the succinate/malate
CC CoA ligase beta subunit family. {ECO:0000305}.
CC -!- SIMILARITY: In the C-terminal section; belongs to the succinate/malate
CC CoA ligase alpha subunit family. {ECO:0000305}.
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DR EMBL; J05210; AAA74463.1; -; mRNA.
DR EMBL; BC100618; AAI00619.1; -; mRNA.
DR EMBL; AH011205; AAL34316.1; -; Genomic_DNA.
DR PIR; A35007; A35007.
DR RefSeq; NP_001104565.1; NM_001111095.1.
DR RefSeq; NP_058683.2; NM_016987.2.
DR AlphaFoldDB; P16638; -.
DR SMR; P16638; -.
DR BioGRID; 246351; 6.
DR IntAct; P16638; 3.
DR MINT; P16638; -.
DR STRING; 10116.ENSRNOP00000023447; -.
DR BindingDB; P16638; -.
DR ChEMBL; CHEMBL2745; -.
DR iPTMnet; P16638; -.
DR PhosphoSitePlus; P16638; -.
DR jPOST; P16638; -.
DR PaxDb; P16638; -.
DR PeptideAtlas; P16638; -.
DR PRIDE; P16638; -.
DR GeneID; 24159; -.
DR KEGG; rno:24159; -.
DR CTD; 47; -.
DR RGD; 2018; Acly.
DR eggNOG; KOG1254; Eukaryota.
DR InParanoid; P16638; -.
DR OrthoDB; 349367at2759; -.
DR PhylomeDB; P16638; -.
DR Reactome; R-RNO-6798695; Neutrophil degranulation.
DR Reactome; R-RNO-75105; Fatty acyl-CoA biosynthesis.
DR PRO; PR:P16638; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0003878; F:ATP citrate synthase activity; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0006085; P:acetyl-CoA biosynthetic process; ISO:RGD.
DR GO; GO:0006084; P:acetyl-CoA metabolic process; IDA:RGD.
DR GO; GO:0006101; P:citrate metabolic process; IDA:RGD.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IDA:RGD.
DR GO; GO:0008610; P:lipid biosynthetic process; ISS:UniProtKB.
DR GO; GO:0006629; P:lipid metabolic process; IEP:RGD.
DR GO; GO:0006107; P:oxaloacetate metabolic process; ISO:RGD.
DR Gene3D; 1.10.230.10; -; 1.
DR Gene3D; 1.10.580.10; -; 1.
DR Gene3D; 3.40.50.261; -; 2.
DR InterPro; IPR014608; ATP-citrate_synthase.
DR InterPro; IPR017440; Cit_synth/succinyl-CoA_lig_AS.
DR InterPro; IPR032263; Citrate-bd.
DR InterPro; IPR016142; Citrate_synth-like_lrg_a-sub.
DR InterPro; IPR016143; Citrate_synth-like_sm_a-sub.
DR InterPro; IPR002020; Citrate_synthase.
DR InterPro; IPR036969; Citrate_synthase_sf.
DR InterPro; IPR033847; Citrt_syn/SCS-alpha_CS.
DR InterPro; IPR003781; CoA-bd.
DR InterPro; IPR005811; CoA_ligase.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR017866; Succ-CoA_synthase_bsu_CS.
DR InterPro; IPR016102; Succinyl-CoA_synth-like.
DR Pfam; PF16114; Citrate_bind; 1.
DR Pfam; PF00285; Citrate_synt; 1.
DR Pfam; PF02629; CoA_binding; 1.
DR Pfam; PF00549; Ligase_CoA; 1.
DR PIRSF; PIRSF036511; ATP_citrt_syn; 1.
DR SMART; SM00881; CoA_binding; 1.
DR SUPFAM; SSF48256; SSF48256; 1.
DR SUPFAM; SSF51735; SSF51735; 1.
DR SUPFAM; SSF52210; SSF52210; 1.
DR PROSITE; PS01216; SUCCINYL_COA_LIG_1; 1.
DR PROSITE; PS00399; SUCCINYL_COA_LIG_2; 1.
DR PROSITE; PS01217; SUCCINYL_COA_LIG_3; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; ATP-binding; Cytoplasm;
KW Direct protein sequencing; Isopeptide bond; Lipid biosynthesis;
KW Lipid metabolism; Magnesium; Metal-binding; Nucleotide-binding;
KW Phosphoprotein; Reference proteome; Transferase; Ubl conjugation.
FT CHAIN 1..1100
FT /note="ATP-citrate synthase"
FT /id="PRO_0000102783"
FT DOMAIN 4..265
FT /note="ATP-grasp"
FT REGION 442..485
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 442..457
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 759
FT /note="Tele-phosphohistidine intermediate"
FT BINDING 58
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 66..67
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 109..111
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 118
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 201
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250"
FT BINDING 203
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250"
FT BINDING 346
FT /ligand="citrate"
FT /ligand_id="ChEBI:CHEBI:16947"
FT /evidence="ECO:0000250"
FT BINDING 348
FT /ligand="citrate"
FT /ligand_id="ChEBI:CHEBI:16947"
FT /evidence="ECO:0000250"
FT BINDING 379
FT /ligand="citrate"
FT /ligand_id="ChEBI:CHEBI:16947"
FT /evidence="ECO:0000250"
FT BINDING 700..720
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 717
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250"
FT BINDING 751..777
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 778..788
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000255"
FT MOD_RES 131
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P53396"
FT MOD_RES 263
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q91V92"
FT MOD_RES 446
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:2176822"
FT MOD_RES 450
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:2176822"
FT MOD_RES 454
FT /note="Phosphoserine; by PKA and PKB/AKT1 or PKB/AKT2"
FT /evidence="ECO:0000269|PubMed:12107176,
FT ECO:0007744|PubMed:22673903"
FT MOD_RES 458
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P53396"
FT MOD_RES 480
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 539
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P53396"
FT MOD_RES 545
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P53396"
FT MOD_RES 553
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P53396"
FT MOD_RES 638
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P53396"
FT MOD_RES 662
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 681
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P53396"
FT MOD_RES 838
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P53396"
FT MOD_RES 947
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P53396"
FT MOD_RES 967
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P53396"
FT MOD_RES 977
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q91V92"
FT MOD_RES 1076
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P53396"
FT MOD_RES 1099
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P53396"
FT CROSSLNK 539
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000250|UniProtKB:P53396"
FT CROSSLNK 545
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000250|UniProtKB:P53396"
FT CROSSLNK 553
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000250|UniProtKB:P53396"
FT VAR_SEQ 419..422
FT /note="WAPA -> LGHRP (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_026273"
FT VAR_SEQ 475..484
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_026274"
FT CONFLICT 116
FT /note="A -> V (in Ref. 2; AAI00619)"
FT /evidence="ECO:0000305"
FT CONFLICT 367
FT /note="S -> P (in Ref. 2; AAI00619)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1100 AA; 120636 MW; 2C6BE4BC1F53BDD2 CRC64;
MSAKAISEQT GKELLYKYIC TTSAIQNRFK YARVTPDTDW AHLLQDHPWL LSQSLVVKPD
QLIKRRGKLG LVGVNLSLDG VKSWLKPRLG HEATVGKAKG FLKNFLIEPF VPHSQAEEFY
VCIYATREGD YVLFHHEGGV DVGDVDTKAQ KLLVGVDEKL NAEDIKRHLL VHAPEDKKEI
LASFISGLFN FYEDLYFTYL EINPLVVTKD GVYILDLAAK VDATADYICK VKWGDIEFPP
PFGREAYPEE AYIADLDAKS GASLKLTLLN PKGRIWTMVA GGGASVVYSD TICDLGGVNE
LANYGEYSGA PSEQQTYDYA KTILSLMTRE KHPDGKILII GGSIANFTNV AATFKGIVRA
IRDYQGSLKE HEVTIFVRRG GPNYQEGLRV MGEVGKTTGI PIHVFGTETH MTAIVGMAWA
PAIPNQPPTA AHTANFLLNA SGSTSTPAPS RTASFSESRA DEVAPAKKAK PAMPQDSVPS
PRSLQGKSAT LFSRHTKAIV WGMQTRAVQG MLDFDYVCSR DEPSVAAMVY PFTGDHKQKF
YWGHKEILIP VFKNMADAMK KHPEVDVLIN FASLRSAYDS TMETMNYAQI RTIAIIAEGI
PEALTRKLIK KADQKGVTII GPATVGGIKP GCFKIGNTGG MLDNILASKL YRPGSVAYVS
RSGGMSNELN NIISRTTDGV YEGVAIGGDR YPGSTFMDHV LRYQDTPGVK MIVVLGEIGG
TEEYKICRGI KEGRLTKPVV CWCIGTCATM FSSEVQFGHA GACANQASET AVAKNQALKE
AGVFVPRSFD ELGEIIQSVY EDLVAKGAIV PAQEVPPPTV PMDYSWAREL GLIRKPASFM
TSICDERGQE LIYAGMPITE VFKEEMGIGG VLGLLWFQRR LPKYSCQFIE MCLMVTADHG
PAVSGAHNTI ICARAGKDLV SSLTSGLLTI GDRFGGALDA AAKMFSKAFD SGIIPMEFVN
KMKKEGKLIM GIGHRVKSIN NPDMRVQILK DFVKQHFPAT PLLDYALEVE KITTSKKPNL
ILNVDGFIGV AFVDMLRNCG SFTREEADEY VDIGALNGVF VLGRSMGFIG HYLDQKRLKQ
GLYRHPWDDI SYVLPEHMSM
