ATPcitrate lyase is an enzyme that in animals represents an important step in fatty acid biosynthesis. 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. In plants, ATP citrate lyase generates cytosolic acetyl-CoA precursors of thousands of specialized metabolites, including waxes, sterols, and polyketides.
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. In animals, the product, acetyl-CoA, is used in several important biosynthetic pathways, including lipogenesis and cholesterogenesis. It is activated by insulin. 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 ; flavonoids; malonic acid; acetylated phenolics, alkaloids, isoprenoids, anthocyanins, and sugars; and, mevalonate-derived isoprenoids ; malonyl and acyl-derivatives. De novo fatty acid biosynthesis in plants occurs in plastids; thus, ATP citrate lyase is not relevant to this pathway.
Reaction
ATP citrate lyase is responsible for catalyzing the conversion of citrate and Coenzyme A to acetyl-CoA and oxaloacetate, driven by hydrolysis of ATP. In the presence of ATP and CoA, citrate lyase catalyzes the cleavage of citrate to yield acetyl CoA, oxaloacetate, adenosine diphosphate, and orthophosphate : This enzyme was formerly given the EC number 4.1.3.8.
Location
The enzyme is cytosolic in plants and animals.
Structure
The enzyme is composed of two subunits in green plants, 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. 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-terminalcitrate 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 bacteriaChlorobium limicola and the archaeonMethanosaeta concilii show that the architecture of ACLY is evolutionarily 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 found in deep branching bacteria. This CCL module catalyses the cleavage of the citryl-CoA intermediate into the products acetyl-CoA and oxaloacetate.
