ATP citrate lyase

ATP citrate lyase
Crystal structure of truncated human ATP-citrate lyase.^[1]
Identifiers
Symbol	ACLY
Entrez	47
HUGO	115
OMIM	108728
RefSeq	NM_001096
UniProt	P53396
Other data
EC number	2.3.3.8
Locus	Chr. 17 q21.2

ATP citrate lyase is an enzyme that in animals represents an important step in fatty acid biosynthesis.^[2] This step in fatty acid biosynthesis occurs because ATP citrate lyase is the link between the metabolism of carbohydrates (which causes energy) and the production of fatty acids.^[1] In plants, ATP citrate lyase generates cytosolic acetyl-CoA precursor of thousands of specialized metabolites including waxes, sterols, and polyketides.^[3]

Function

ATP citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. The enzyme is a tetramer of apparently identical subunits. The product, acetyl-CoA, in animals serves several important biosynthetic pathways, including lipogenesis and cholesterogenesis.^[4] It is activated by insulin.^[5] In plants, ATP citrate lyase generates the acetyl-CoA for cytosolically-synthesized metabolites. (Acetyl-CoA is not transported across subcellular membranes of plants.) These include: elongated fatty acids (used in seed oils, membrane phospholipids, the ceramide moiety of sphingolipids, cuticle, cutin, and suberin); flavonoids; malonic acid; acetylated phenolics, alkaloids, isoprenoids, anthocyanins, and sugars; and, mevalonate-derived isoprenoids (e.g., sesquiterpenes, sterols, brassinosteroids); malonyl and acyl-derivatives (d-amino acids, malonylated flavonoids, acylated, prenylated and malonated proteins).^[3] De novo fatty acid biosynthesis in plants is plastidic, thus ATP citrate lyase is not important for this pathway.

ATP-citrate lyase is responsible for catalyzing the conversion of citrate and CoA into acetyl-CoA and oxaloacetate, along with the hydrolysis of ATP.^[1]

Reaction

In the presence of ATP and Coenzyme A, citrate lyase catalyzes the cleavage of citrate to yield acetyl CoA, oxaloacetate, ADP, and orthophosphate:

citrate + ATP + CoA + H2O-->oxaloacetate + Acetyl-CoA + ADP + Pi.

This enzyme was formerly listed as EC 4.1.3.8.^[6]

Location

The enzyme is cytosolic in plants^[3] and animals.

Structure

The enzyme is composed of two subunits in green plants (including Chlorophyceae, Marchantimorpha, Bryopsida, Pinaceae, monocotyledons, and eudicots), species of fungi, Glaucophytes, Chlamydomonas, and prokaryotes.

Animal ACL enzymes are homomeric, presumably an evolutionary fusion of the ACLA and ACLB genes probably occurred early in the evolutionary history of this kingdom.^[3]

A structure of human ATP citrate lyase was determined using X-ray diffraction to a resolution of 2.10 Å. The enzyme is composed of two polymer chains which are polypeptides. Chain A of the first polymer is 425 amino acids in length. Chain B of the second polymer is 334 amino acids in length.^[1]

References

1 2 3 4 PDB: 3MWE; Sun T, Hayakawa K, Bateman KS, Fraser ME (August 2010). "Identification of the citrate-binding site of human ATP-citrate lyase using X-ray crystallography". J. Biol. Chem. 285 (35): 27418–27428. doi:10.1074/jbc.M109.078667. PMC 2930740. PMID 20558738.
↑ Elshourbagy NA, Near JC, Kmetz PJ, Wells TN, Groot PH, Saxty BA, Hughes SA, Franklin M, Gloger IS (March 1992). "Cloning and expression of a human ATP-citrate lyase cDNA". Eur. J. Biochem. 204 (2): 491–499. doi:10.1111/j.1432-1033.1992.tb16659.x. PMID 1371749.
1 2 3 4 Fatland BL, Ke J, Anderson MD, Mentzen WI, Cui LW, Allred CC, Johnston JL, Nikolau BJ, Wurtele ES (October 2002). "Molecular characterization of a heteromeric ATP-citrate lyase that generates cytosolic acetyl-coenzyme A in Arabidopsis". Plant Physiol. 130 (2): 740–756. doi:10.1104/pp.008110. PMC 166603. PMID 12376641.
↑ "Entrez Gene: ATP citrate lyase".
↑ Guay C, Madiraju SR, Aumais A, Joly E, Prentki M (December 2007). "A role for ATP-citrate lyase, malic enzyme, and pyruvate/citrate cycling in glucose-induced insulin secretion". J. Biol. Chem. 282 (49): 35657–35665. doi:10.1074/jbc.M707294200. PMID 17928289.
↑ ATP Citrate Lyase at the US National Library of Medicine Medical Subject Headings (MeSH)

External links

ATP Citrate Lyase at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

Ramachandran Plot of ATP Citrate Lyase http://www.rcsb.org/pdb/images/3MWD_ram_m_500.pdf

Transferases: acyltransferases (EC 2.3)

2.3.1: other than amino-acyl groups	acetyltransferases: Acetyl-Coenzyme A acetyltransferase N-Acetylglutamate synthase Choline acetyltransferase Dihydrolipoyl transacetylase Acetyl-CoA C-acyltransferase Beta-galactoside transacetylase Chloramphenicol acetyltransferase N-acetyltransferase Serotonin N-acetyl transferase HGSNAT ARD1A Histone acetyltransferase P300/CBP NAT2 palmitoyltransferases: Carnitine O-palmitoyltransferase CPT1 CPT2 Serine C-palmitoyltransferase SPTLC1 SPTLC2 other: Acyltransferase like 2 Aminolevulinic acid synthase Beta-ketoacyl-ACP synthase Glyceronephosphate O-acyltransferase Lecithin—cholesterol acyltransferase Glycerol-3-phosphate O-acyltransferase 1-acylglycerol-3-phosphate O-acyltransferase 2-acylglycerol-3-phosphate O-acyltransferase ABHD5

2.3.2: Aminoacyltransferases	Gamma-glutamyl transpeptidase Peptidyl transferase Transglutaminase Tissue transglutaminase Keratinocyte transglutaminase Factor XIII

2.3.3: converted into alkyl on transfer	Citrate synthase ATP citrate lyase HMG-CoA synthase Malate synthase

Enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list)

Metabolism: lipid metabolism / fatty acid metabolism, triglyceride and fatty acid enzymes

Synthesis

Malonyl-CoA synthesis	ATP citrate lyase Acetyl-CoA carboxylase

Fatty acid synthesis/ Fatty acid synthase	Beta-ketoacyl-ACP synthase Β-Ketoacyl ACP reductase 3-Hydroxyacyl ACP dehydrase Enoyl ACP reductase

Fatty acid desaturases	Stearoyl-CoA desaturase-1

Triacyl glycerol	Glycerol-3-phosphate dehydrogenase Thiokinase

Degradation

Acyl transport

Beta oxidation

General	Acyl CoA dehydrogenase (ACADL ACADM ACADS ACADVL ACADSB) Enoyl-CoA hydratase MTP: HADH HADHA HADHB Acetyl-CoA C-acyltransferase

Unsaturated	Enoyl CoA isomerase 2,4 Dienoyl-CoA reductase

Odd chain	Propionyl-CoA carboxylase

Other	Hydroxyacyl-Coenzyme A dehydrogenase

To acetyl-CoA

Malonyl-CoA decarboxylase

Aldehydes

Long-chain-aldehyde dehydrogenase

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