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Protein

ATP-citrate synthase

Gene

ACLY

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

ATP-citrate synthase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. Has a central role in de novo lipid synthesis. In nervous tissue it may be involved in the biosynthesis of acetylcholine.1 Publication

Catalytic activityi

ADP + phosphate + acetyl-CoA + oxaloacetate = ATP + citrate + CoA.

Cofactori

Enzyme regulationi

Phosphorylation results in a 6-fold increase in V(max) and the conversion of citrate dependence from sigmoidal to hyperbolic. Fructose 6-phosphate (F6P) is also a potent activator.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei58ATP1
Binding sitei118ATP1
Metal bindingi201MagnesiumBy similarity1
Metal bindingi203MagnesiumBy similarity1
Binding sitei346Citrate; via amide nitrogen1 Publication1
Binding sitei348Citrate1 Publication1
Binding sitei379Citrate1 Publication1
Metal bindingi718MagnesiumBy similarity1
Active sitei760Tele-phosphohistidine intermediateBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi66 – 67ATP2
Nucleotide bindingi109 – 111ATP3
Nucleotide bindingi701 – 721ATPBy similarityAdd BLAST21
Nucleotide bindingi752 – 778ATPBy similarityAdd BLAST27

GO - Molecular functioni

  • ATP binding Source: BHF-UCL
  • ATP citrate synthase activity Source: BHF-UCL
  • cofactor binding Source: InterPro
  • metal ion binding Source: UniProtKB-KW

GO - Biological processi

  • acetyl-CoA biosynthetic process Source: BHF-UCL
  • cholesterol biosynthetic process Source: BHF-UCL
  • citrate metabolic process Source: BHF-UCL
  • coenzyme A metabolic process Source: BHF-UCL
  • fatty acid biosynthetic process Source: GO_Central
  • fatty-acyl-CoA biosynthetic process Source: Reactome
  • lipid biosynthetic process Source: UniProtKB
  • neutrophil degranulation Source: Reactome
  • oxaloacetate metabolic process Source: BHF-UCL
  • positive regulation of cellular metabolic process Source: Reactome

Keywordsi

Molecular functionTransferase
Biological processLipid biosynthesis, Lipid metabolism
LigandATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciMetaCyc:HS05535-MONOMER
BRENDAi2.3.3.8 2681
ReactomeiR-HSA-163765 ChREBP activates metabolic gene expression
R-HSA-6798695 Neutrophil degranulation
R-HSA-75105 Fatty acyl-CoA biosynthesis
SABIO-RKiP53396
SIGNORiP53396

Chemistry databases

SwissLipidsiSLP:000000779

Names & Taxonomyi

Protein namesi
Recommended name:
ATP-citrate synthase (EC:2.3.3.8)
Alternative name(s):
ATP-citrate (pro-S-)-lyase
Short name:
ACL
Citrate cleavage enzyme
Gene namesi
Name:ACLY
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 17

Organism-specific databases

EuPathDBiHostDB:ENSG00000131473.16
HGNCiHGNC:115 ACLY
MIMi108728 gene
neXtProtiNX_P53396

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi540K → R or Q: Decreased acetylation and increased de novo lipid synthesis; when associated with R,Q-546 and R,Q-554. 1 Publication1
Mutagenesisi546K → R or Q: Decreased acetylation and increased de novo lipid synthesis; when associated with R,Q-540 and R,Q-554. 1 Publication1
Mutagenesisi554K → R or Q: Decreased acetylation and increased de novo lipid synthesis; when associated with R,Q-540 and R,Q-546. 1 Publication1

Organism-specific databases

DisGeNETi47
OpenTargetsiENSG00000131473
PharmGKBiPA24441

Chemistry databases

ChEMBLiCHEMBL3720

Polymorphism and mutation databases

BioMutaiACLY
DMDMi116241237

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001027811 – 1101ATP-citrate synthaseAdd BLAST1101

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei131PhosphotyrosineCombined sources1
Modified residuei263PhosphoserineBy similarity1
Modified residuei447PhosphothreonineBy similarity1
Modified residuei451PhosphoserineBy similarity1
Modified residuei455Phosphoserine; by PKA and PKB/AKT1 or PKB/AKT2Combined sources1
Modified residuei459PhosphoserineCombined sources1
Modified residuei481PhosphoserineCombined sources1
Modified residuei540N6-acetyllysine; alternate1 Publication1
Cross-linki540Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate1 Publication
Modified residuei546N6-acetyllysine; alternateCombined sources1 Publication1
Cross-linki546Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate1 Publication
Modified residuei554N6-acetyllysine; alternateCombined sources1 Publication1
Cross-linki554Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate1 Publication
Modified residuei639PhosphothreonineCombined sources1
Modified residuei663PhosphoserineCombined sources1
Modified residuei682PhosphotyrosineCombined sources1
Modified residuei839PhosphoserineCombined sources1
Modified residuei948N6-acetyllysineCombined sources1
Modified residuei968N6-acetyllysineCombined sources1
Modified residuei978N6-acetyllysineBy similarity1
Modified residuei1077N6-acetyllysineCombined sources1
Modified residuei1100PhosphoserineCombined sources1

Post-translational modificationi

ISGylated.1 Publication
Acetylated at Lys-540, Lys-546 and Lys-554 by KAT2B/PCAF. Acetylation is promoted by glucose and stabilizes the protein, probably by preventing ubiquitination at the same sites. Acetylation promotes de novo lipid synthesis. Deacetylated by SIRT2.1 Publication
Ubiquitinated at Lys-540, Lys-546 and Lys-554 by UBR4, leading to its degradation. Ubiquitination is probably inhibited by acetylation at same site (Probable).1 Publication

Keywords - PTMi

Acetylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP53396
MaxQBiP53396
PaxDbiP53396
PeptideAtlasiP53396
PRIDEiP53396

PTM databases

CarbonylDBiP53396
iPTMnetiP53396
PhosphoSitePlusiP53396
SwissPalmiP53396

Expressioni

Gene expression databases

BgeeiENSG00000131473
CleanExiHS_ACLY
ExpressionAtlasiP53396 baseline and differential
GenevisibleiP53396 HS

Organism-specific databases

HPAiCAB007783
HPA022434
HPA022953
HPA022959
HPA028758

Interactioni

Subunit structurei

Homotetramer.2 Publications

Protein-protein interaction databases

BioGridi106563, 68 interactors
IntActiP53396, 19 interactors
MINTiP53396
STRINGi9606.ENSP00000253792

Chemistry databases

BindingDBiP53396

Structurei

Secondary structure

11101
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi3 – 6Combined sources4
Helixi8 – 18Combined sources11
Turni26 – 29Combined sources4
Beta strandi32 – 34Combined sources3
Helixi40 – 46Combined sources7
Helixi48 – 51Combined sources4
Beta strandi55 – 59Combined sources5
Turni66 – 70Combined sources5
Beta strandi73 – 76Combined sources4
Helixi78 – 85Combined sources8
Turni86 – 90Combined sources5
Beta strandi92 – 95Combined sources4
Beta strandi98 – 101Combined sources4
Beta strandi105 – 109Combined sources5
Helixi115 – 117Combined sources3
Beta strandi118 – 126Combined sources9
Beta strandi129 – 136Combined sources8
Helixi140 – 142Combined sources3
Helixi145 – 148Combined sources4
Beta strandi150 – 155Combined sources6
Helixi162 – 168Combined sources7
Helixi175 – 177Combined sources3
Helixi178 – 194Combined sources17
Beta strandi197 – 208Combined sources12
Beta strandi211 – 214Combined sources4
Beta strandi218 – 222Combined sources5
Helixi223 – 225Combined sources3
Helixi226 – 233Combined sources8
Beta strandi242 – 244Combined sources3
Helixi248 – 258Combined sources11
Beta strandi260 – 269Combined sources10
Beta strandi274 – 277Combined sources4
Beta strandi279 – 281Combined sources3
Helixi282 – 294Combined sources13
Helixi298 – 300Combined sources3
Beta strandi303 – 309Combined sources7
Helixi313 – 327Combined sources15
Beta strandi328 – 330Combined sources3
Beta strandi336 – 340Combined sources5
Beta strandi346 – 348Combined sources3
Helixi350 – 363Combined sources14
Helixi365 – 370Combined sources6
Beta strandi373 – 378Combined sources6
Helixi384 – 398Combined sources15
Beta strandi402 – 405Combined sources4
Helixi413 – 418Combined sources6
Beta strandi499 – 503Combined sources5
Helixi506 – 518Combined sources13
Beta strandi525 – 530Combined sources6
Beta strandi536 – 543Combined sources8
Beta strandi546 – 555Combined sources10
Helixi556 – 562Combined sources7
Beta strandi568 – 571Combined sources4
Helixi575 – 585Combined sources11
Beta strandi593 – 596Combined sources4
Helixi603 – 616Combined sources14
Beta strandi619 – 621Combined sources3
Beta strandi623 – 625Combined sources3
Beta strandi628 – 630Combined sources3
Turni631 – 633Combined sources3
Beta strandi634 – 636Combined sources3
Turni637 – 640Combined sources4
Helixi643 – 648Combined sources6
Turni649 – 652Combined sources4
Beta strandi656 – 662Combined sources7
Helixi664 – 677Combined sources14
Beta strandi681 – 686Combined sources6
Beta strandi689 – 692Combined sources4
Helixi697 – 705Combined sources9
Beta strandi712 – 722Combined sources11
Helixi725 – 732Combined sources8
Beta strandi740 – 745Combined sources6
Helixi747 – 751Combined sources5
Beta strandi752 – 754Combined sources3
Helixi768 – 770Combined sources3
Helixi772 – 782Combined sources11
Helixi790 – 792Combined sources3
Helixi793 – 806Combined sources14

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3MWDX-ray2.10A1-425[»]
B487-820[»]
3MWEX-ray2.20A1-425[»]
B487-821[»]
3PFFX-ray2.30A1-817[»]
5TDEX-ray1.70A1-425[»]
B487-810[»]
5TDFX-ray1.80A1-425[»]
B487-810[»]
5TDMX-ray2.10A1-425[»]
B487-810[»]
5TDZX-ray2.00A1-425[»]
B487-810[»]
5TE1X-ray2.25A/B1-817[»]
5TEQX-ray2.30A/B1-817[»]
5TESX-ray2.40A1-425[»]
B487-810[»]
5TETX-ray2.20A1-425[»]
B487-810[»]
ProteinModelPortaliP53396
SMRiP53396
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP53396

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini4 – 265ATP-graspAdd BLAST262

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni779 – 789CoA-bindingSequence analysisAdd BLAST11

Sequence similaritiesi

In the N-terminal section; belongs to the succinate/malate CoA ligase beta subunit family.Curated
In the C-terminal section; belongs to the succinate/malate CoA ligase alpha subunit family.Curated

Phylogenomic databases

eggNOGiKOG1254 Eukaryota
COG0045 LUCA
COG0074 LUCA
COG0372 LUCA
GeneTreeiENSGT00530000063275
HOGENOMiHOG000151479
HOVERGENiHBG003318
InParanoidiP53396
KOiK01648
OMAiTCRFATV
OrthoDBiEOG091G0OYH
PhylomeDBiP53396
TreeFamiTF300560

Family and domain databases

Gene3Di1.10.230.10, 1 hit
3.40.50.261, 2 hits
InterProiView protein in InterPro
IPR014608 ATP-citrate_synthase
IPR017440 Cit_synth/succinyl-CoA_lig_AS
IPR032263 Citrate-bd
IPR016143 Citrate_synth-like_sm_a-sub
IPR002020 Citrate_synthase
IPR036969 Citrate_synthase_sf
IPR033847 Citrt_syn/SCS-alpha_CS
IPR003781 CoA-bd
IPR005811 CoA_ligase
IPR036291 NAD(P)-bd_dom_sf
IPR017866 Succ-CoA_synthase_bsu_CS
IPR016102 Succinyl-CoA_synth-like
PfamiView protein in Pfam
PF16114 Citrate_bind, 1 hit
PF00285 Citrate_synt, 1 hit
PF02629 CoA_binding, 1 hit
PF00549 Ligase_CoA, 1 hit
PIRSFiPIRSF036511 ATP_citrt_syn, 1 hit
SMARTiView protein in SMART
SM00881 CoA_binding, 1 hit
SUPFAMiSSF48256 SSF48256, 2 hits
SSF51735 SSF51735, 1 hit
SSF52210 SSF52210, 1 hit
PROSITEiView protein in PROSITE
PS01216 SUCCINYL_COA_LIG_1, 1 hit
PS00399 SUCCINYL_COA_LIG_2, 1 hit
PS01217 SUCCINYL_COA_LIG_3, 1 hit

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P53396-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MSAKAISEQT GKELLYKFIC TTSAIQNRFK YARVTPDTDW ARLLQDHPWL
60 70 80 90 100
LSQNLVVKPD QLIKRRGKLG LVGVNLTLDG VKSWLKPRLG QEATVGKATG
110 120 130 140 150
FLKNFLIEPF VPHSQAEEFY VCIYATREGD YVLFHHEGGV DVGDVDAKAQ
160 170 180 190 200
KLLVGVDEKL NPEDIKKHLL VHAPEDKKEI LASFISGLFN FYEDLYFTYL
210 220 230 240 250
EINPLVVTKD GVYVLDLAAK VDATADYICK VKWGDIEFPP PFGREAYPEE
260 270 280 290 300
AYIADLDAKS GASLKLTLLN PKGRIWTMVA GGGASVVYSD TICDLGGVNE
310 320 330 340 350
LANYGEYSGA PSEQQTYDYA KTILSLMTRE KHPDGKILII GGSIANFTNV
360 370 380 390 400
AATFKGIVRA IRDYQGPLKE HEVTIFVRRG GPNYQEGLRV MGEVGKTTGI
410 420 430 440 450
PIHVFGTETH MTAIVGMALG HRPIPNQPPT AAHTANFLLN ASGSTSTPAP
460 470 480 490 500
SRTASFSESR ADEVAPAKKA KPAMPQDSVP SPRSLQGKST TLFSRHTKAI
510 520 530 540 550
VWGMQTRAVQ GMLDFDYVCS RDEPSVAAMV YPFTGDHKQK FYWGHKEILI
560 570 580 590 600
PVFKNMADAM RKHPEVDVLI NFASLRSAYD STMETMNYAQ IRTIAIIAEG
610 620 630 640 650
IPEALTRKLI KKADQKGVTI IGPATVGGIK PGCFKIGNTG GMLDNILASK
660 670 680 690 700
LYRPGSVAYV SRSGGMSNEL NNIISRTTDG VYEGVAIGGD RYPGSTFMDH
710 720 730 740 750
VLRYQDTPGV KMIVVLGEIG GTEEYKICRG IKEGRLTKPI VCWCIGTCAT
760 770 780 790 800
MFSSEVQFGH AGACANQASE TAVAKNQALK EAGVFVPRSF DELGEIIQSV
810 820 830 840 850
YEDLVANGVI VPAQEVPPPT VPMDYSWARE LGLIRKPASF MTSICDERGQ
860 870 880 890 900
ELIYAGMPIT EVFKEEMGIG GVLGLLWFQK RLPKYSCQFI EMCLMVTADH
910 920 930 940 950
GPAVSGAHNT IICARAGKDL VSSLTSGLLT IGDRFGGALD AAAKMFSKAF
960 970 980 990 1000
DSGIIPMEFV NKMKKEGKLI MGIGHRVKSI NNPDMRVQIL KDYVRQHFPA
1010 1020 1030 1040 1050
TPLLDYALEV EKITTSKKPN LILNVDGLIG VAFVDMLRNC GSFTREEADE
1060 1070 1080 1090 1100
YIDIGALNGI FVLGRSMGFI GHYLDQKRLK QGLYRHPWDD ISYVLPEHMS

M
Length:1,101
Mass (Da):120,839
Last modified:October 17, 2006 - v3
Checksum:i12BB4416A30DC30C
GO
Isoform 2 (identifier: P53396-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     476-485: Missing.

Show »
Length:1,091
Mass (Da):119,772
Checksum:i04EB8D05059409E5
GO
Isoform 3 (identifier: P53396-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     95-355: Missing.
     476-485: Missing.

Note: No experimental confirmation available.
Show »
Length:830
Mass (Da):91,099
Checksum:i1F3758EEAACA3730
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti75N → D in CAA45614 (PubMed:1371749).Curated1
Sequence conflicti111V → A in CAA45614 (PubMed:1371749).Curated1
Sequence conflicti245E → V in CAA45614 (PubMed:1371749).Curated1
Sequence conflicti419 – 423LGHRP → WAPA in CAA45614 (PubMed:1371749).Curated5
Sequence conflicti442 – 444SGS → QRE in CAA45614 (PubMed:1371749).Curated3
Sequence conflicti457 – 459SES → YESMVDEV in CAA45614 (PubMed:1371749).Curated3
Sequence conflicti653 – 656RPGS → PQAA in CAA45614 (PubMed:1371749).Curated4
Sequence conflicti728C → S in CAA45614 (PubMed:1371749).Curated1
Sequence conflicti872V → A in CAA45614 (PubMed:1371749).Curated1
Sequence conflicti916 – 919AGKD → TAVE in CAA45614 (PubMed:1371749).Curated4

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_028230175E → D3 PublicationsCorresponds to variant dbSNP:rs2304497Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_05723095 – 355Missing in isoform 3. 1 PublicationAdd BLAST261
Alternative sequenceiVSP_042201476 – 485Missing in isoform 2 and isoform 3. 1 Publication10

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X64330 mRNA Translation: CAA45614.1
U18197 mRNA Translation: AAB60340.1
AK295675 mRNA Translation: BAG58532.1
AK304802 mRNA Translation: BAG65552.1
AC091172 Genomic DNA No translation available.
AC125257 Genomic DNA No translation available.
BC006195 mRNA Translation: AAH06195.1
CCDSiCCDS11412.1 [P53396-1]
CCDS11413.1 [P53396-2]
PIRiS21173
RefSeqiNP_001087.2, NM_001096.2 [P53396-1]
NP_001290203.1, NM_001303274.1
NP_001290204.1, NM_001303275.1
NP_942127.1, NM_198830.1 [P53396-2]
XP_005257452.1, XM_005257395.1 [P53396-1]
UniGeneiHs.387567

Genome annotation databases

EnsembliENST00000352035; ENSP00000253792; ENSG00000131473 [P53396-1]
ENST00000353196; ENSP00000345398; ENSG00000131473 [P53396-2]
ENST00000393896; ENSP00000377474; ENSG00000131473 [P53396-2]
ENST00000537919; ENSP00000445349; ENSG00000131473 [P53396-3]
ENST00000590151; ENSP00000466259; ENSG00000131473 [P53396-1]
GeneIDi47
KEGGihsa:47
UCSCiuc002hyg.4 human [P53396-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiACLY_HUMAN
AccessioniPrimary (citable) accession number: P53396
Secondary accession number(s): B4DIM0
, B4E3P0, Q13037, Q9BRL0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 17, 2006
Last modified: May 23, 2018
This is version 195 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 17
    Human chromosome 17: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

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