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ACLY (ATP citrate lyase)

Written2012-10Marie E Beckner
Department of Pathology, Louisiana State University Health Sciences Center - Shreveport, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)ATPCL
CLATP
ACL
Other alias
HGNC (Hugo) ACLY
LocusID (NCBI) 47
Atlas_Id 50486
Location 17q21.2  [Link to chromosome band 17q21]
Location_base_pair Starts at 41866926 and ends at 41919019 bp from pter ( according to hg19-Feb_2009)  [Mapping ACLY.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ACLY (17q21.2) / DNAJC7 (17q21.2)ARHGAP8 (22q13.31) / ACLY (17q21.2)EHMT2 (6p21.33) / ACLY (17q21.2)
NTN1 (17p13.1) / ACLY (17q21.2)
Note Note that the International Union for Biochemistry and Molecular Biology (IUBMB)'s enzyme nomenclature accepts ATP citrate synthase as the name for ACLY's encoded protein (EC 2.3.3.8). However, ATP citrate lyase is more commonly used and other names include citrate cleavage enzyme, ATP-citrate (pro-S)-lyase, ATPCL, CLATP.
ACLY encodes a key metabolic enzyme that cleaves cytosolic citric acid with important consequences, such as lipogenesis, regulation of glycolysis, acetylcholine production, calcium chelation, etc.

DNA/RNA

 
  Homo sapiens ATP citrate lyase (ACLY), transcript variant 1, 4450 bp mRNA, encodes a 1101 aa protein. NCBI Reference Sequence: NM_001096. Locus NM_001096.
Description Two transcript variants have been identified and this variant (1) represents the longer ACLY transcript. It encodes the longer isoform of ACLY. Placement of code for the initiating methionine, stop codon, poly adenylation signal, boundaries of the 29 exons, and the untranslated region (hatched) are shown. Location of missing sequence in variant 2 compared to variant 1 is indicated in the diagram of the ACLY protein shown below. The sequence for ACLY has been conserved in evolution, putatively from an ancient single gene present prior to separation of animals and fungi with some fungi subsequently developing two genes to code for complete ACLY whereas animals have retained a single gene.
Transcription 4450 bp mRNA (NCBI RefSeq, May-2012). Multiple Sp1 binding sites and CAAT are present in the promoter of rat ACLY and it can be induced by a low fat/high carbohydrate diet.
Pseudogene None known at this time.

Protein

Note ACLY is a metabolic enzyme found as a tetramer of apparently identical subunits (440000 molecular weight). It was discovered in 1950's. ACLY cleaves citric acid in a multistep process with participation of cofactors to form the products, acetyl-CoA and oxaloacetate. Functional domains of ACLY resemble regions of related enzymes that can play similar roles in metabolism of other substrates.
 
  ATP citrate lyase (ACL or ACLY), variant 1. GenBank: AAH06195 protein sequence with locations of functional domains, multiple binding regions, Rossman fold (492-601), and post-translational modifications, including potential phosphorylation of tyrosines (131, 682), serines (260, 442, 455, 478, 481, 663, 839, 922, 979, 1100), threonines (445, 447, 453, 639), and a histidine (760), and N6-acetylysine (86, 546, 554, 948, 962, 968, 978, 1077). The missing sequence (476-485) in variant 2 results in the loss of 2 serines as indicated in the diagram.
Description Four of these subunits form a homotetramer.
Expression Prokaryotes and eukaryotes. The association between increased expression for ACLY and the gene encoding enolase, ENO1, is highly statistically significant. Greater expression of ACLY can be found in mammalian cells under hypoxic conditions. It is more highly expressed in many malignant tissues when compared to their benign counterparts. Aberrant expression can be found in breast, liver, colon, lung, and prostate cancers and is inversely correlated with tumor stage and differentiation so that increased ACLY expression is a negative prognostic factor. ACLY's knockdown in non-small cell lung carcinoma (NSCLC) can lead to apoptosis and differentiation in vitro and less growth in vivo.
Localisation ACLY is a relatively abundant cytoplasmic protein and can be associated with outer surfaces of mitochondria and it is also preferentially distributed to pseudopodia in migrating cells. Relatively small amounts have been found in the nuclei. Also, ACLY is found in synaptosomes.
 
Function ACLY catalyzes the following reaction: ATP + citrate + CoA = ADP + phosphate + acetyl-CoA + oxaloacetate.
ACLY is well-known for linking carbohydrate and lipid metabolism which can lead to membrane production during cell growth. However, a myriad of other consequences from the breakdown of citrate also occur and are indicated above. Systemically and locally the effects of ACLY's activity can have a powerfull impact. These include alteration of transcription. Citrate passes through nuclear pores and undergoes cleavage by the small amounts of ACLY in the nucleus to generate acetyl CoA that affects transcription via acetylation of histones and transcription factors. Cataplerosis includes citrate's transport from the mitochondria via a transporter to provide cytosolic citrate. The transfer of metabolites into mitochondria via shuttles, transporters, etc. constitutes anaplerosis so that either energy or amino acids can be formed, depending on the oxygenation state and the cell's needs. Regulation of ACLY is complex and appears to resemble that of glycogen synthase in regard to phosphorylations occurring sequentially in a hierarchical manner. The multiple sources of citrate help to explain the varying effects of ACLY. Note that exogenous citrate can come from anticoagulants. Although ACLY is susceptible to proteolysis, the lower weight (53 kDa) digestion product of ACLY retains its activity.
Loss of ACLY function in plants can result in a bonsai phenotype. Hydroxycitrate, found in the fruit of a tropical tree, Garcinia cambogia (bitter kola) that grows in Southeast Asia and southern India, is a competitive inhibitor and has been extensively used in functional studies. However, solubility issues and the large quantities of hydroxycitrate needed for inhibition of ACLY are disadvantages for using it in clinical studies. Proprietary formulations are available as weight loss supplements and at least one of these has been combined with established anti-cancer agents. The cell-penetrant gamma-lactone, SB-204990, a prodrug of SB-201076, was described in 1998 as an oral drug to inhibit ACLY and has been used in several cancer studies more recently. Radicicol and tartrate are also inhibitors of ACLY. Multiple agents, such as α-lipoic acid, statins, capsaicin, a Met kinase inhibitor (SU11274), etc., have been found to enhance the effects of ACLY inhibitors in small studies of tumors.
Homology ACLY is a member of the acyl-CoA synthetase superfamily (ADP-forming). ACLY's amino terminal region, 1-419, resembles ATP citrate (pro-S)-lyase and the region, 1-424, is homologous to the β-subunit of succinyl-CoA synthetase and the region, 486-818, is homologous to the α-subunit of succinyl-CoA synthetase. Also, the hierarchy of multiple, sequential serine/threonine phosphorylations responsible for the complex regulation of glycogen synthase is similar to the serine/threonine phosphorylations in ACLY. Sequence surrounding the histidine in ACLY's catalytic site, that is phosphorylated by nucleoside diphosphate kinase (NDPK or nm23), is similar to sequence around phosphorylation sites in other substrates of nm23, such as aldolase C. ACLY has homology with citrate synthase that catalyzes its reverse reaction. Rat ACLY is 96,3% identical to human ACLY.

Mutations

Germinal Homozygous knock-out of ACLY in mice is lethal. Heterozygous knock-out mice appear to be normal.

Implicated in

Note
  
  
Entity Bladder (transitional cell) cancer
Note A bladder cancer cell line (MBT-2) studied in a mouse syngenic cancer model has demonstrated efficacy of calcium hydrocitrate when it was used to inhibit ACLY, combined with other drugs and agents, in several small studies.
  
  
Entity Breast cancer
Note Increased expression of ACLY may play a role in the agressive breast cancers. Elevated levels were found in both primary and metastatic cell lines compared to normal cell lines and the highest expression levels occurred in metastatic cell lines.
  
  
Entity Colon carcinoma
Note Silencing ACLY in human colon carcinoma cells (HCT116) has been shown to suppress histone acetylation.
  
  
Entity Gliomas (glial brain tumors)
Note ACLY has been demonstrated to localize preferentially to pseudopodia in U87 human glioblastoma cells. Inhibition of ACLY in U87 cells with a soluble form of hydroxycitrate suppressed their cell migration, clonogenicity and brain invasion under glycolytic conditions and enhanced the suppressive effects of a Met kinase inhibitor on cell migration. Queries of the NIH's REMBRANDT brain tumor database based on Affymetrix array data indicated that decreased patient survival correlated with increased gene expression of ACLY in gliomas.
  
  
Entity Liver (hepatocellular) carcinoma
Note Markedly increased expression of mRNA for ACLY and genes for other lipogenic enzymes have been found in hepatocellular carcinoma compared to surrounding non-cancerous liver tissue.
  
  
Entity Lung carcinoma
Note A Lewis lung cancer cell line (LL/2) studied in a mouse syngenic cancer model has demonstrated efficacy of using calcium hydrocitrate combined with other drugs and agents in several small studies. In one of these studies, results were confirmed using a human xenograft model, NCI-H69, small cell lung carcinoma, with tumor development reduced and prolonged animal survival observed. In another study with ACLY knockdown, there was inhibition of growth in vivo for non-small cell lung carcinoma along with apoptosis and differentiation. Enhancement of the anti-tumor effects was achieved by adding statins with regression of established tumors reported. Human lung adenocarcinoma samples have been shown to have significantly increased ACLY activity compared to normal lung tissue and phosphorylated ACLY overexpression correlated with stage, grade, and poorer prognosis. Growth arrest in A549 cells was achieved with RNA interference for ACLY. Inhibitory results were also achieved in A549 cells with the ACLY inhibitor, SB-204990.
  
  
Entity Melanoma
Note A melanoma cell line (B16-F10) studied in a mouse syngenic cancer model has demonstrated efficacy of using calcium hydrocitrate combined with other drugs and agents in several small studies.
  
  
Entity Ovarian carcinoma
Note Higher ACLY expression has been found in malignant ovarian tissue compared to normal ovarian tissue. Phosphorylated ACLY was also increased and the expression correlated well with tumor grade, FIGO stage, and poorer prognosis. Also knockdown of ACLY in A2780 cells inhibited their proliferation and induced cell cycle arrest.
  
  
Entity Pancreatic cancer (ductal adenocarcinoma)
Note An 80 year old woman was treated with a formulation containing hydroxycitrate to inhibit ACLY in addition to gemcitabine with favorable temporary results.
  
  
Entity Prostate carcinoma
Note Aberrant expression of ACLY has been found in prostatic cancer with levels inversely correlating with tumor stage and differentiaion. The expression of ACLY has predicted a reduced citrate level which is characteristic of prostatic cancer. Normal prostatic tissue has very high levels of citrate. Benign prostatic hypertrophy also has high levels of citrate. The change to oxidation of citrate in prostatic cancer rather than production of citrate has been viewed as a type of metabolic transformation that may provide a bioenergetic theory for prostatic malignancy.
  
  
Entity Hepatitis B Virus (HBV) infection
Note In HBV transgenic mice that replicate HBV in the liver without producing gross liver pathology, the largest functional category for upregulated genes was lipid biosynthesis, including ACLY.
  
  
Entity Obesity/fatty liver
Note Inhibition of ACLY is a strategy to counteract weight gain that has led to the development of commercially available formulations of hydroxycitrate. Inhibition of ACLY has been suggested as being helpfull for fatty liver.
  

Breakpoints

Note No breakpoints are known within ACLY. The ACLY gene is distal to the P12.3B hybrid breakpoint in RARA.

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Citation

This paper should be referenced as such :
Beckner, ME
ACLY (ATP citrate lyase)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(4):231-236.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/ACLYID50486ch17q21.html


External links

Nomenclature
HGNC (Hugo)ACLY   115
Cards
AtlasACLYID50486ch17q21
Entrez_Gene (NCBI)ACLY  47  ATP citrate lyase
AliasesACL; ATPCL; CLATP
GeneCards (Weizmann)ACLY
Ensembl hg19 (Hinxton)ENSG00000131473 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000131473 [Gene_View]  chr17:41866926-41919019 [Contig_View]  ACLY [Vega]
ICGC DataPortalENSG00000131473
TCGA cBioPortalACLY
AceView (NCBI)ACLY
Genatlas (Paris)ACLY
WikiGenes47
SOURCE (Princeton)ACLY
Genetics Home Reference (NIH)ACLY
Genomic and cartography
GoldenPath hg38 (UCSC)ACLY  -     chr17:41866926-41919019 -  17q21.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ACLY  -     17q21.2   [Description]    (hg19-Feb_2009)
EnsemblACLY - 17q21.2 [CytoView hg19]  ACLY - 17q21.2 [CytoView hg38]
Mapping of homologs : NCBIACLY [Mapview hg19]  ACLY [Mapview hg38]
OMIM108728   
Gene and transcription
Genbank (Entrez)AB210035 AK095084 AK295675 AK304802 AK312315
RefSeq transcript (Entrez)NM_001096 NM_001303274 NM_001303275 NM_198830
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)ACLY
Cluster EST : UnigeneHs.387567 [ NCBI ]
CGAP (NCI)Hs.387567
Alternative Splicing GalleryENSG00000131473
Gene ExpressionACLY [ NCBI-GEO ]   ACLY [ EBI - ARRAY_EXPRESS ]   ACLY [ SEEK ]   ACLY [ MEM ]
Gene Expression Viewer (FireBrowse)ACLY [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)47
GTEX Portal (Tissue expression)ACLY
Human Protein AtlasENSG00000131473-ACLY [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP53396   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP53396  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP53396
Splice isoforms : SwissVarP53396
Catalytic activity : Enzyme2.3.3.8 [ Enzyme-Expasy ]   2.3.3.82.3.3.8 [ IntEnz-EBI ]   2.3.3.8 [ BRENDA ]   2.3.3.8 [ KEGG ]   
PhosPhoSitePlusP53396
Domaine pattern : Prosite (Expaxy)SUCCINYL_COA_LIG_1 (PS01216)    SUCCINYL_COA_LIG_2 (PS00399)    SUCCINYL_COA_LIG_3 (PS01217)   
Domains : Interpro (EBI)###############################################################################################################################################################################################################################################################                                                   
Domain families : Pfam (Sanger)Citrate_bind (PF16114)    Citrate_synt (PF00285)    CoA_binding (PF02629)    Ligase_CoA (PF00549)   
Domain families : Pfam (NCBI)pfam16114    pfam00285    pfam02629    pfam00549   
Domain families : Smart (EMBL)CoA_binding (SM00881)  
Conserved Domain (NCBI)ACLY
DMDM Disease mutations47
Blocks (Seattle)ACLY
PDB (SRS)3MWD    3MWE    3PFF   
PDB (PDBSum)3MWD    3MWE    3PFF   
PDB (IMB)3MWD    3MWE    3PFF   
PDB (RSDB)3MWD    3MWE    3PFF   
Structural Biology KnowledgeBase3MWD    3MWE    3PFF   
SCOP (Structural Classification of Proteins)3MWD    3MWE    3PFF   
CATH (Classification of proteins structures)3MWD    3MWE    3PFF   
SuperfamilyP53396
Human Protein Atlas [tissue]ENSG00000131473-ACLY [tissue]
Peptide AtlasP53396
HPRD00155
IPIIPI00021290   IPI00394838   IPI00935456   IPI00983296   
Protein Interaction databases
DIP (DOE-UCLA)P53396
IntAct (EBI)P53396
FunCoupENSG00000131473
BioGRIDACLY
STRING (EMBL)ACLY
ZODIACACLY
Ontologies - Pathways
QuickGOP53396
Ontology : AmiGOATP citrate synthase activity  ATP citrate synthase activity  protein binding  ATP binding  extracellular region  nucleoplasm  cytosol  cytosol  cytosol  plasma membrane  acetyl-CoA biosynthetic process  citrate metabolic process  oxaloacetate metabolic process  fatty acid biosynthetic process  cholesterol biosynthetic process  lipid biosynthetic process  citrate lyase complex  membrane  positive regulation of cellular metabolic process  long-chain fatty-acyl-CoA biosynthetic process  azurophil granule lumen  neutrophil degranulation  metal ion binding  cofactor binding  extracellular exosome  ficolin-1-rich granule lumen  
Ontology : EGO-EBIATP citrate synthase activity  ATP citrate synthase activity  protein binding  ATP binding  extracellular region  nucleoplasm  cytosol  cytosol  cytosol  plasma membrane  acetyl-CoA biosynthetic process  citrate metabolic process  oxaloacetate metabolic process  fatty acid biosynthetic process  cholesterol biosynthetic process  lipid biosynthetic process  citrate lyase complex  membrane  positive regulation of cellular metabolic process  long-chain fatty-acyl-CoA biosynthetic process  azurophil granule lumen  neutrophil degranulation  metal ion binding  cofactor binding  extracellular exosome  ficolin-1-rich granule lumen  
Pathways : BIOCARTAShuttle for transfer of acetyl groups from mitochondria to the cytosol [Genes]   
Pathways : KEGGCitrate cycle (TCA cycle)   
REACTOMEP53396 [protein]
REACTOME PathwaysR-HSA-75105 [pathway]   
NDEx NetworkACLY
Atlas of Cancer Signalling NetworkACLY
Wikipedia pathwaysACLY
Orthology - Evolution
OrthoDB47
GeneTree (enSembl)ENSG00000131473
Phylogenetic Trees/Animal Genes : TreeFamACLY
HOVERGENP53396
HOGENOMP53396
Homologs : HomoloGeneACLY
Homology/Alignments : Family Browser (UCSC)ACLY
Gene fusions - Rearrangements
Fusion : MitelmanACLY/DNAJC7 [17q21.2/17q21.2]  
Fusion : COSMICNTN1 [17p13.1]  -  ACLY [17q21.2]  [fusion_726]  [fusion_727]  
Fusion: TCGAACLY 17q21.2 DNAJC7 17q21.2 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerACLY [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ACLY
dbVarACLY
ClinVarACLY
1000_GenomesACLY 
Exome Variant ServerACLY
ExAC (Exome Aggregation Consortium)ENSG00000131473
GNOMAD BrowserENSG00000131473
Genetic variants : HAPMAP47
Genomic Variants (DGV)ACLY [DGVbeta]
DECIPHERACLY [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisACLY 
Mutations
ICGC Data PortalACLY 
TCGA Data PortalACLY 
Broad Tumor PortalACLY
OASIS PortalACLY [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICACLY  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDACLY
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)MSeqDR-LSDB Mitochondrial Disease Locus Specific Database
BioMutasearch ACLY
DgiDB (Drug Gene Interaction Database)ACLY
DoCM (Curated mutations)ACLY (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)ACLY (select a term)
intoGenACLY
NCG5 (London)ACLY
Cancer3DACLY(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM108728   
Orphanet
MedgenACLY
Genetic Testing Registry ACLY
NextProtP53396 [Medical]
TSGene47
GENETestsACLY
Target ValidationACLY
Huge Navigator ACLY [HugePedia]
snp3D : Map Gene to Disease47
BioCentury BCIQACLY
ClinGenACLY
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD47
Chemical/Pharm GKB GenePA24441
Clinical trialACLY
Miscellaneous
canSAR (ICR)ACLY (select the gene name)
Probes
Litterature
PubMed86 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineACLY
EVEXACLY
GoPubMedACLY
iHOPACLY
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Thu Oct 12 16:15:08 CEST 2017

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