|Human ATP citrate lyase|
Crystal structure of human ATP citrate lyase in complex with citrate, coenzyme A and Mg.ADP.
|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|
|Locus||Chr. 17 q21.2|
ATP citrate lyase (ACLY) is an enzyme that in animals represents an important step in fatty acid biosynthesis. ATP citrate lyase is important in that, by converting citrate to acetyl-CoA, it links the metabolism of carbohydrates, which yields citrate as an intermediate, and the production of fatty acids, which requires acetyl-CoA. In plants, ATP citrate lyase generates cytosolic acetyl-CoA precursor of thousands of specialized metabolites including waxes, sterols, and polyketides.
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. It is activated by insulin. 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). De novo fatty acid biosynthesis in plants is plastidic, thus ATP citrate lyase is not important for this pathway.
This enzyme was formerly listed as EC 126.96.36.199.
The enzyme is cytosolic in plants and animals.
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.
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. 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. 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. 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 evolutionary conserved. 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. This CCL module catalyses the cleavage of the citryl-CoA intermediate into the reaction products acetyl-CoA and oxaloacetate.
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