ATP citrate synthase | |||||||||
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Identifiers | |||||||||
EC no. | 2.3.3.8 | ||||||||
CAS no. | 9027-95-6 | ||||||||
Databases | |||||||||
IntEnz | IntEnz view | ||||||||
BRENDA | BRENDA entry | ||||||||
ExPASy | NiceZyme view | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
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Human ATP citrate lyase | |||||||
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Identifiers | |||||||
Symbol | ACLY | ||||||
Alt. symbols | ACL | ||||||
NCBI gene | 47 | ||||||
HGNC | 115 | ||||||
OMIM | 108728 | ||||||
PDB | 3MWE, 3PFF, 5TDE, 5TDF, 5TDM, 5TDZ, 5TE1, 5TEQ, 5TES, 5TET, 6HXH, 6HXK, 6HXL, 6HXM, 6O0H, 6QFB 3MWD, 3MWE, 3PFF, 5TDE, 5TDF, 5TDM, 5TDZ, 5TE1, 5TEQ, 5TES, 5TET, 6HXH, 6HXK, 6HXL, 6HXM, 6O0H, 6QFB | ||||||
RefSeq | NM_001096 | ||||||
UniProt | P53396 | ||||||
Other data | |||||||
EC number | 2.3.3.8 | ||||||
Locus | Chr. 17 q21.2 | ||||||
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ATP citrate synthase (also ATP citrate lyase (ACLY)) is an enzyme that in animals represents an important step in fatty acid biosynthesis.[2] By converting citrate to acetyl-CoA, the enzyme links carbohydrate metabolism, which yields citrate as an intermediate, with fatty acid biosynthesis, which consumes acetyl-CoA.[3] In plants, ATP citrate lyase generates cytosolic acetyl-CoA precursors of thousands of specialized metabolites, including waxes, sterols, and polyketides.[4]
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. In animals, the product, acetyl-CoA, is used in several important biosynthetic pathways, including lipogenesis and cholesterogenesis.[5] It is activated by insulin.[6]
In plants, ATP citrate lyase generates acetyl-CoA for cytosolically-synthesized metabolites; Acetyl-CoA is not transported across subcellular membranes of plants. Such metabolites include: elongated fatty acids (used in seed oils, membrane phospholipids, the ceramide moieties 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).[4] De novo fatty acid biosynthesis in plants occurs in plastids; thus, ATP citrate lyase is not relevant to this pathway.
ATP citrate lyase is responsible for catalyzing the conversion of citrate and Coenzyme A (CoA) to acetyl-CoA and oxaloacetate, driven by hydrolysis of ATP.[3] In the presence of ATP and CoA, citrate lyase catalyzes the cleavage of citrate to yield acetyl CoA, oxaloacetate, adenosine diphosphate (ADP), and orthophosphate (Pi):
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; a fusion of the ACLA and ACLB genes probably occurred early in the evolutionary history of this kingdom.[4]
The mammalian ATP citrate lyase has a N-terminal citrate-binding domain that adopts a Rossmann fold, followed by a CoA binding domain and CoA-ligase domain and finally a C-terminal citrate synthase domain. The cleft between the CoA binding and citrate synthase domains forms the active site of the enzyme, where both citrate and acetyl-coenzyme A bind.
In 2010, a structure of truncated human ATP citrate lyase was determined using X-ray diffraction to a resolution of 2.10 Å.[3] In 2019, a full length structure of human ACLY in complex with the substrates coenzyme A, citrate and Mg.ADP was determined by X-ray crystallography to a resolution of 3.2 Å.[1] Moreover, in 2019 a full length structure of ACLY in complex with an inhibitor was determined by cryo-EM methods to a resolution of 3.7 Å.[8] Additional structures of heteromeric ACLY-A/B from the green sulfur bacteria Chlorobium limicola and the archaeon Methanosaeta concilii show that the architecture of ACLY is evolutionarily conserved.[1] Full length ACLY structures showed that the tetrameric protein oligomerizes via its C-terminal domain. The C-terminal domain had not been observed in the previously determined truncated crystal structures. The C-terminal region of ACLY assembles in a tetrameric module that is structurally similar to citryl-CoA lyase (CCL) found in deep branching bacteria.[1][9] This CCL module catalyses the cleavage of the citryl-CoA intermediate into the products acetyl-CoA and oxaloacetate. In 2019, cryo-EM structures of human ACLY, alone or bound to substrates or products were reported as well.[10][11] ACLY forms a homotetramer with a rigid citrate synthase homology (CSH) module, flanked by four flexible acetyl-CoA synthetase homology (ASH) domains; CoA is bound at the CSH–ASH interface in mutually exclusive productive or unproductive conformations. The structure of a catalytic mutant of ACLY in the presence of ATP, citrate and CoA substrates reveals a CoA and phosphor-citrate intermediate in the N-terminal domain. Cryo-EM structures of products bound ACLY and substrates bound ACLY were also determined at 3.0 Å and 3.1 Å. An EM structure of mutant E599Q in complex with CoA and phospho-citrate intermediate was determined at resolution of 2.9 Å. Comparison between these structures of apo-ACLY and ligands bound ACLY demonstrated conformational changes on ASH domain (N-terminal domain) when different ligands bind.
The enzyme's action can be inhibited by the coenzyme A-conjugate of bempedoic acid, a compound which lowers LDL cholesterol in humans.[12] The drug was approved by the Food and Drug Administration in February 2020 for use in the United States.