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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)
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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)
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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.
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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)
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Atlas Genet Cytogenet Oncol Haematol. 2013; 17(4)
This article should be referenced as such:
Beckner ME. ACLY (ATP citrate lyase). Atlas Genet Cytogenet
Oncol Haematol. 2013; 17(4):231-236.
236