ATP citrate lyase
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ATP citrate synthase (also ATP citrate lyase (ACLY)) is an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that in animals represents an important step in
fatty acid biosynthesis Fatty is a derogatory term for someone who is obese. It may refer also to: People * Mai Fatty, Gambian politician * Roscoe Arbuckle (1887–1933), American actor and comedian * Fatty Briody (1858–1903), American Major League Baseball player ...
. By converting
citrate Citric acid is an organic compound with the chemical formula HOC(CO2H)(CH2CO2H)2. It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry, it is an intermediate in the citric acid cycle, which occurs in t ...
to
acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for ...
, the enzyme links
carbohydrate metabolism Carbohydrate metabolism is the whole of the biochemistry, biochemical processes responsible for the metabolic anabolism, formation, catabolism, breakdown, and interconversion of carbohydrates in life, living organisms. Carbohydrates are central t ...
, which yields citrate as an intermediate, with
fatty acid biosynthesis Fatty is a derogatory term for someone who is obese. It may refer also to: People * Mai Fatty, Gambian politician * Roscoe Arbuckle (1887–1933), American actor and comedian * Fatty Briody (1858–1903), American Major League Baseball player ...
, which consumes acetyl-CoA. In plants, ATP citrate lyase generates
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
ic acetyl-CoA precursors of thousands of specialized
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
s, including
waxes Waxes are a diverse class of organic compounds that are lipophilic, malleable solids near ambient temperatures. They include higher alkanes and lipids, typically with melting points above about 40 °C (104 °F), melting to give low ...
,
sterol Sterol is an organic compound with formula , whose molecule is derived from that of gonane by replacement of a hydrogen atom in position 3 by a hydroxyl group. It is therefore an alcohol of gonane. More generally, any compounds that contain the go ...
s, and
polyketide Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...
s.


Function

ATP citrate lyase is the primary enzyme responsible for the synthesis of
cytosolic The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrio ...
acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for ...
in many tissues. The enzyme is a
tetramer A tetramer () (''tetra-'', "four" + '' -mer'', "parts") is an oligomer formed from four monomers or subunits. The associated property is called ''tetramery''. An example from inorganic chemistry is titanium methoxide with the empirical formula Ti ...
of apparently identical subunits. In animals, the product, acetyl-CoA, is used in several important biosynthetic pathways, including
lipogenesis In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride syn ...
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 (used in seed oils, membrane
phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
s, the
ceramide Ceramides are a family of waxy lipid molecules. A ceramide is composed of N-acetylsphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of eukaryotic cells, since they are component lipids that make up ...
moieties of
sphingolipid Sphingolipids are a class of lipids containing a backbone of sphingoid bases, a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named after the mythological sphinx because ...
s,
cuticle A cuticle (), or cuticula, is any of a variety of tough but flexible, non-mineral outer coverings of an organism, or parts of an organism, that provide protection. Various types of "cuticle" are non- homologous, differing in their origin, structu ...
,
cutin Cutin is one of two waxy polymers that are the main components of the plant cuticle, which covers all aerial surfaces of plants. It is an insoluble substance with waterproof quality. Cutin also harbors cuticular waxes, which assist in cuticle stru ...
, and
suberin Suberin, cutin and lignins are complex, higher plant epidermis and periderm cell-wall macromolecules, forming a protective barrier. Suberin, a complex polyester biopolymer, is lipophilic, and composed of long chain fatty acids called suberin acid ...
);
flavonoid Flavonoids (or bioflavonoids; from the Latin word ''flavus'', meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans. Chemically, flavonoids ...
s;
malonic acid Malonic acid (IUPAC systematic name: propanedioic acid) is a dicarboxylic acid with structure CH2(COOH)2. The ionized form of malonic acid, as well as its esters and salts, are known as malonates. For example, diethyl malonate is malonic acid's ...
; acetylated phenolics,
alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...
s,
isoprenoid The terpenoids, also known as isoprenoids, are a class of naturally occurring organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeably with "terpenes", ...
s,
anthocyanins Anthocyanins (), also called anthocyans, are water-soluble vacuolar pigments that, depending on their pH, may appear red, purple, blue, or black. In 1835, the German pharmacist Ludwig Clamor Marquart gave the name Anthokyan to a chemical compo ...
, and
sugars Sugar is the generic name for sweet-tasting, soluble carbohydrates, many of which are used in food. Simple sugars, also called monosaccharides, include glucose, fructose, and galactose. Compound sugars, also called disaccharides or double s ...
; and, mevalonate-derived
isoprenoid The terpenoids, also known as isoprenoids, are a class of naturally occurring organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeably with "terpenes", ...
s (e.g.,
sesquiterpene Sesquiterpenes are a class of terpenes that consist of three isoprene units and often have the molecular formula C15H24. Like monoterpenes, sesquiterpenes may be cyclic or contain rings, including many unique combinations. Biochemical modificatio ...
s, sterols,
brassinosteroid Brassinosteroids (BRs or less commonly BS) are a class of polyhydroxysteroids that have been recognized as a sixth class of plant hormones and may have utility as an anticancer drug for endocrine-responsive cancers to induce apoptosis and inhibi ...
s); malonyl and acyl-derivatives (d-amino acids, malonylated flavonoids, acylated, prenylated and malonated proteins). De novo fatty acid biosynthesis in plants occurs in
plastid The plastid (Greek: πλαστός; plastós: formed, molded – plural plastids) is a membrane-bound organelle found in the Cell (biology), cells of plants, algae, and some other eukaryotic organisms. They are considered to be intracellular endosy ...
s; 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 Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...
(CoA) to acetyl-CoA and
oxaloacetate Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes ...
, driven by hydrolysis of ATP. In the presence of ATP and CoA, citrate lyase catalyzes the cleavage of
citrate Citric acid is an organic compound with the chemical formula HOC(CO2H)(CH2CO2H)2. It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry, it is an intermediate in the citric acid cycle, which occurs in t ...
to yield acetyl CoA,
oxaloacetate Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes ...
,
adenosine diphosphate Adenosine diphosphate (ADP), also known as adenosine pyrophosphate (APP), is an important organic compound in metabolism and is essential to the flow of energy in living cells. ADP consists of three important structural components: a sugar backbon ...
(ADP), and
orthophosphate A phosphoric acid, in the general sense, is a phosphorus oxoacid in which each phosphorus (P) atom is in the oxidation state +5, and is bonded to four oxygen (O) atoms, one of them through a double bond, arranged as the corners of a tetrahedron. ...
(Pi): :citrate + ATP + CoA → oxaloacetate + Acetyl-CoA + ADP + Pi This enzyme was formerly given the EC number 4.1.3.8.


Location

The enzyme is
cytosolic The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrio ...
in plants and animals.


Structure

The enzyme is composed of two subunits in green plants (including
Chlorophyceae The Chlorophyceae are one of the classes of green algae, distinguished mainly on the basis of ultrastructural morphology. They are usually green due to the dominance of pigments chlorophyll a and chlorophyll b. The chloroplast may be discoid, p ...
, Marchantimorpha,
Bryopsida The Bryopsida constitute the largest class of mosses, containing 95% of all moss species. It consists of approximately 11,500 species, common throughout the whole world. The group is distinguished by having spore capsules with teeth that are '' ...
,
Pinaceae The Pinaceae, or pine family, are conifer trees or shrubs, including many of the well-known conifers of commercial importance such as Cedrus, cedars, firs, Tsuga, hemlocks, larches, pines and spruces. The family is included in the order Pinales, ...
,
monocotyledon Monocotyledons (), commonly referred to as monocots, (Lilianae ''sensu'' Chase & Reveal) are grass and grass-like flowering plants (angiosperms), the seeds of which typically contain only one embryonic leaf, or cotyledon. They constitute one of ...
s, and
eudicot The eudicots, Eudicotidae, or eudicotyledons are a clade of flowering plants mainly characterized by having two seed leaves upon germination. The term derives from Dicotyledons. Traditionally they were called tricolpates or non-magnoliid dicot ...
s), species of
fungi A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...
,
glaucophyte The glaucophytes, also known as glaucocystophytes or glaucocystids, are a small group of unicellular algae found in freshwater and moist terrestrial environments, less common today than they were during the Proterozoic. The stated number of spe ...
s, ''
Chlamydomonas ''Chlamydomonas'' is a genus of green algae consisting of about 150 speciesSmith, G.M. 1955 ''Cryptogamic Botany Volume 1. Algae and Fungi'' McGraw-Hill Book Company Inc of unicellular flagellates, found in stagnant water and on damp soil, ...
'', and
prokaryote A prokaryote () is a single-celled organism that lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek πρό (, 'before') and κάρυον (, 'nut' or 'kernel').Campbell, N. "Biology:Concepts & Connec ...
s. Animal ACL enzymes are homomeric; a
fusion Fusion, or synthesis, is the process of combining two or more distinct entities into a new whole. Fusion may also refer to: Science and technology Physics *Nuclear fusion, multiple atomic nuclei combining to form one or more different atomic nucl ...
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 The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
citrate-binding domain that adopts a
Rossmann fold The Rossmann fold is a tertiary fold found in proteins that bind nucleotides, such as enzyme cofactors FAD, NAD+, and NADP+. This fold is composed of alternating beta strands and alpha helical segments where the beta strands are hydrogen bonded ...
, followed by a CoA binding domain and CoA-ligase domain and finally a
C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
citrate synthase domain. The cleft between the CoA binding and citrate synthase domains forms the
active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
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 X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...
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 The green sulfur bacteria are a phylum of obligately anaerobic photoautotrophic bacteria that metabolize sulfur. Green sulfur bacteria are nonmotile (except ''Chloroherpeton thalassium'', which may glide) and capable of anoxygenic photosynthesi ...
'' Chlorobium limicola'' and the
archaeon Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaebact ...
''
Methanosaeta concilii ''Methanosaeta concilii'' is an archaeum in the disputed genus ''Methanosaeta''. It is obligately anaerobic, gram-negative and non-motile Motility is the ability of an organism to move independently, using metabolic energy. Definitions M ...
'' show that the architecture of ACLY is
evolutionarily conserved In evolutionary biology, conserved sequences are identical or similar sequences in nucleic acids ( DNA and RNA) or proteins across species ( orthologous sequences), or within a genome ( paralogous sequences), or between donor and receptor tax ...
. 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 products acetyl-CoA and oxaloacetate. In 2019, cryo-EM structures of human ACLY, alone or bound to substrates or products were reported as well. 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.


Pharmacology

The enzyme's action can be inhibited by the coenzyme A-conjugate of
bempedoic acid Bempedoic acid, sold under the brand name Nexletol among others, is a medication for the treatment of hypercholesterolemia (high blood cholesterol levels). Text was copied from this source which is © European Medicines Agency. Reproduction is a ...
, a compound which lowers
LDL cholesterol Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...
in humans. The drug was approved by the
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
in February 2020 for use in the United States.


References


Further reading

* * *


External links

* {{Lipid metabolism enzymes EC 2.3.3 Citric acid cycle