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Atlas of Genetics and Cytogenetics in Oncology and Haematology INIST-CNRS OPEN ACCESS JOURNAL Gene Section Review ACLY (ATP citrate lyase) Marie E Beckner Department of Pathology, Louisiana State University Health Sciences Center - Shreveport, USA (MEB) Published in Atlas Database: October 2012 Online updated version : http://AtlasGeneticsOncology.org/Genes/ACLYID50486ch17q21.html DOI: 10.4267/2042/48862 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity DNA/RNA Other names: ACL, ATPCL, CLATP HGNC (Hugo): ACLY Location: 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. 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. 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. Atlas Genet Cytogenet Oncol Haematol. 2013; 17(4) 231 ACLY (ATP citrate lyase) Beckner ME 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. 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. 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. Function Pseudogene 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. 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. 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 Atlas Genet Cytogenet Oncol Haematol. 2013; 17(4) 232 ACLY (ATP citrate lyase) Beckner ME 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 cellpenetrant 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. Mutations Germinal Homozygous knock-out of ACLY in mice is lethal. Heterozygous knock-out mice appear to be normal. Implicated in 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. Homology Breast cancer 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. Atlas Genet Cytogenet Oncol Haematol. 2013; 17(4) 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. Colon carcinoma Note Silencing ACLY in human colon carcinoma cells (HCT116) has been shown to suppress histone acetylation. Gliomas (glial brain tumors) Note ACLY has been demonstrated to localize preferentially to pseudopodia in U87 human glioblastoma cells. 233 ACLY (ATP citrate lyase) Beckner ME 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. 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. 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. 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. 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. 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. 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. 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. References Hoffmann GE, Andres H, Weiss L, Kreisel C, Sander R. Properties and organ distribution of ATP citrate (pro-3S)-lyase. Biochim Biophys Acta. 1980 Oct 6;620(1):151-8 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. Atlas Genet Cytogenet Oncol Haematol. 2013; 17(4) Ranganathan NS, Srere PA, Linn TC. Comparison of phosphoand dephospho-ATP citrate lyase. Arch Biochem Biophys. 1980 Oct 1;204(1):52-8 Szutowicz A, Lysiak W. 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Atlas Genet Cytogenet Oncol Haematol. 2013; 17(4):231-236. 236