ATP citrate lyase
ATP citrate lyase 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|
Crystal structure of truncated human ATP-citrate lyase.
|Locus||Chr. 17 q21.2|
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.
- citrate + ATP + CoA → oxaloacetate + Acetyl-CoA + ADP + Pi
This enzyme was formerly listed as EC 184.108.40.206.
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.
A structure of truncated human ATP citrate lyase was determined using X-ray diffraction to a resolution of 2.10 Å. A full length structure of ACLY in complex with an inhibitor was determined by cryo-EM methods to a resolution of 3.7 Å. The full length structure showed that the tetrameric protein oligomerizes via its C-terminal domain. The C-terminal domain had not been observed in the truncated X-ray structures. The C-terminal domain of ACLY is structurally similar to citryl Co-A lyase.
- "Identification of the citrate-binding site of human ATP-citrate lyase using X-ray crystallography". The Journal of Biological Chemistry. 285 (35): 27418–28. doi:10.1074/jbc.M109.078667. PMC 2930740. PMID 20558738. ; Sun T, Hayakawa K, Bateman KS, Fraser ME (August 2010).
- 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". European Journal of Biochemistry. 204 (2): 491–9. doi:10.1111/j.1432-1033.1992.tb16659.x. PMID 1371749. Archived from the original on 2013-01-18.
- 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 Physiology. 130 (2): 740–56. doi:10.1104/pp.008110. PMC 166603. PMID 12376641.
- "Entrez Gene: ATP citrate lyase".
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- ATP+Citrate+Lyase at the US National Library of Medicine Medical Subject Headings (MeSH)
- Wei J, Leit S, Kuai J, Therrien E, Rafi S, Harwood HJ, DeLaBarre B, Tong L (April 2019). "An allosteric mechanism for potent inhibition of human ATP-citrate lyase". Nature. doi:10.1038/s41586-019-1094-6. PMID 30944472.
- Ray KK, Bays HE, Catapano AL, Lalwani ND, Bloedon LT, Sterling LR, Robinson PL, Ballantyne CM, et al. (CLEAR Harmony Trial) (March 2019). "Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol". The New England Journal of Medicine. 380 (11): 1022–1032. doi:10.1056/NEJMoa1803917. PMID 30865796.