Coenzyme A

Coenzyme A (CoA,SCoA,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 substrate, and around 4% of cellular enzymes use it (or a thioester) as a substrate. In humans, CoA biosynthesis requires cysteine, pantothenate (vitamin B5), and adenosine triphosphate (ATP).[1]

In its acetyl form, coenzyme A is highly versatile molecule, serving metabolic functions in both the anabolic and catabolic pathways. Acetyl-CoA is utilised in the post-translational regulation and allosteric regulation of pyruvate dehydrogenase and carboxylase to maintain and support the partition of pyruvate synthesis and degradation.[2]

Coenzyme A
Coenzym A
Coenzyme-A-3D-vdW
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.001.472
KEGG
MeSH Coenzyme+A
UNII
Properties
C21H36N7O16P3S
Molar mass 767.535
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Discovery of structure

Coenzym A beschriftet
Structure of coenzyme A: 1: 3'-phosphoadenosine. 2: diphosphate, organophosphate anhydride. 3: pantoic acid. 4: β-alanine. 5: cysteamine.

Coenzyme A was identified by Fritz Lipmann in 1946,[3] who also later gave it its name. Its structure was determined during the early 1950s at the Lister Institute, London, together by Lipmann and other workers at Harvard Medical School and Massachusetts General Hospital.[4] Lipmann initially intended to study acetyl transfer in animals, and from these experiments he noticed a unique factor that was not present in enzyme extracts but was evident in all organs of the animals. He was able to isolate and purify the factor from pig liver and discovered that its function was related to a coenzyme that was active in choline acetylation.[5] The coenzyme was named coenzyme A to stand for "activation of acetate". In 1953, Fritz Lipmann won the Nobel Prize in Physiology or Medicine "for his discovery of co-enzyme A and its importance for intermediary metabolism".[5][6]

Biosynthesis

Coenzyme A is naturally synthesized from pantothenate (vitamin B5), which is found in food such as meat, vegetables, cereal grains, legumes, eggs, and milk.[7] In humans and most living organisms, pantothenate is an essential vitamin that has a variety of functions.[8] In some plants and bacteria, including Escherichia coli, pantothenate can be synthesised de novo and is therefore not considered essential. These bacteria synthesize pantothenate from the amino acid aspartate and a metabolite in valine biosynthesis.[9]

In all living organisms, coenzyme A is synthesized in a five-step process that requires four molecules of ATP, pantothenate and cysteine:[10] (see Figure)

CoA Biosynthetic Pathway
Details the biosynthetic pathway of CoA synthesis from pantothenic acid.
  1. Pantothenate (vitamin B5) is phosphorylated to 4'-phosphopantothenate by the enzyme pantothenate kinase (PanK; CoaA; CoaX). This is the committed step in CoA biosynthesis and requires ATP.[9]
  2. A cysteine is added to 4'-phosphopantothenate by the enzyme phosphopantothenoylcysteine synthetase (PPCS; CoaB) to form 4'-phospho-N-pantothenoylcysteine (PPC). This step is coupled with ATP hydrolysis.[9]
  3. PPC is decarboxylated to 4'-phosphopantetheine by phosphopantothenoylcysteine decarboxylase (PPC-DC; CoaC)
  4. 4'-phosphopantetheine is adenylylated (or more properly, AMPylated) to form dephospho-CoA by the enzyme phosphopantetheine adenylyl transferase (PPAT; CoaD)
  5. Finally, dephospho-CoA is phosphorylated to coenzyme A by the enzyme dephosphocoenzyme A kinase (DPCK; CoaE). This final step requires ATP.[9]

Enzyme nomenclature abbreviations in parentheses represent eukaryotic and prokaryotic enzymes respectively. This pathway is regulated by product inhibition. CoA is a competitive inhibitor for Pantothenate Kinase, which normally binds ATP.[9] Coenzyme A, three ADP, one monophosphate, and one diphosphate are harvested from biosynthesis.[10]

New research shows that coenzyme A can be synthesized through alternate routes when intracellular coenzyme A level are reduced and the de novo pathway is impaired.[11] In these pathways, coenzyme A needs to be provided from an external source, such as food, in order to produce 4′-phosphopantetheine. Ectonucleotide pyrophosphates (ENPP) degrade coenzyme A to 4′-phosphopantetheine, a stable molecule in organisms. Acyl carrier proteins (ACP) (such as ACP synthase and ACP degradation) are also used to produce 4′-phosphopantetheine. This pathways allows for 4′-phosphopantetheine to be replenished in the cell and allows for the conversion to coenzyme A through enzymes, PPAT and PPCK.[12]

Commercial production

Coenzyme A is produced commercially via extraction from yeast, however this is a inefficient process (yields ∼25 mg/kg) resulting in an expensive product. Various ways of producing CoA synthetically, or semi-synthetically have been investigated although none are currently operating at an industrial scale.[13]

Function

Fatty acid synthesis

Since coenzyme A is, in chemical terms, a thiol, it can react with carboxylic acids to form thioesters, thus functioning as an acyl group carrier. It assists in transferring fatty acids from the cytoplasm to mitochondria. A molecule of coenzyme A carrying an acetyl group is also referred to as acyl-CoA. When it is not attached to an acyl group, it is usually referred to as 'CoASH' or 'HSCoA'. This process facilitates the production of fatty acids in cells, which are essential in cell membrane structure.[14]

Coenzyme A is also the source of the phosphopantetheine group that is added as a prosthetic group to proteins such as acyl carrier protein and formyltetrahydrofolate dehydrogenase.[15][16]

CoA Sources and Uses
Some of the sources that CoA comes from and uses in the cell.

Energy production

Coenzyme A is one of five crucial coenzymes that are necessary in the reaction mechanism of the citric acid cycle. Its acetyl-coenzyme A form is the primary input in the citric acid cycle and is obtained from glycolysis, amino acid metabolism, and fatty acid beta oxidation. This process is the body's primary catabolic pathway and is essential in breaking down the building blocks of the cell such as carbohydrates, amino acids, and lipids.[14][17]

Regulation

When there is excess glucose, coenzyme A is used in the cytosol for synthesis of fatty acids.[18] This process is implemented by regulation of acetyl-CoA carboxylase, which catalyzes the committed step in fatty acid synthesis. Insulin stimulates acetyl-CoA carboxylase, while epinephrine and glucagon inhibit its activity.[19]

During cell starvation, coenzyme A is synthesized and transports fatty acids in the cytosol to the mitochondria. Here, acetyl-CoA is generated for oxidation and energy production.[18] In the citric acid cycle, coenzyme A works as an allosteric regulator in the stimulation of the enzyme pyruvate dehydrogenase.[14]

New research has found that protein CoAlation plays an important role in regulation of the oxidative stress response. Protein CoAlation plays a similar role to glutathionylation in the cell, and prevents the irreversible oxidation of the thiol group in cysteine on the surface of cellular proteins, while also directly regulating enzymatic activity in response to oxidative or metabolic stress.[20]

Use in biological research

Coenzyme A is available from various chemical suppliers as the free acid and lithium or sodium salts. The free acid of coenzyme A is detectably unstable, with ~5% degradation observed after 6 months when stored at −20˚C,[21] and near complete degradation after 1 month at 37˚C.[22] The lithium and sodium salts of CoA are more stable, with negligible degradation noted over several months at various temperatures.[23] Aqueous solutions of coenzyme A are unstable above pH 8, with 31% of activity lost after 24 hours at 25˚C and pH 8. CoA stock solutions are relatively stable when frozen at pH 2–6. The major route of CoA activity loss is likely the air oxidation of CoA to CoA disulfides. CoA mixed disulfides, such as CoA-S-S-glutathione, are commonly noted contaminants in commercial preparations of CoA.[21] Free CoA can be regenerated from CoA disulfide and mixed CoA disulfides with reducing agents such as DTT or BME.

Non-exhaustive list of coenzyme A-activated acyl groups

References

  1. ^ Matthew Daugherty; Boris Polanuyer; Michael Farrell; Michael Scholle; Athanasios Lykidis; Valérie de Crécy-Lagard; Andrei Osterman (2002). "Complete Reconstitution of the Human Coenzyme A Biosynthetic Pathway via Comparative Genomics". The Journal of Biological Chemistry. 277 (24): 21431–21439. doi:10.1074/jbc.M201708200. PMID 11923312.
  2. ^ "Coenzyme A: when small is mighty". www.asbmb.org. Retrieved 2018-12-19.
  3. ^ Lipmann, Fritz; Nathan O., Kaplan (1946). "A common factor in the enzymatic acetylation of sulfanilamide and of choline". Journal of Biological Chemistry. 162.3: 743–744.
  4. ^ Baddiley, J.; Thain, E. M.; Novelli, G. D.; Lipmann, F. (1953). "Structure of Coenzyme A". Nature. 171 (4341): 76. doi:10.1038/171076a0.
  5. ^ a b Kresge, Nicole; Simoni, Robert D.; Hill, Robert L. (2005-05-27). "Fritz Lipmann and the Discovery of Coenzyme A". Journal of Biological Chemistry. 280 (21): e18–e18. ISSN 0021-9258.
  6. ^ "Fritz Lipmann - Facts". Nobelprize.org. Nobel Media AB 2014. Web. 8 Nov 2017. <http://www.nobelprize.org/nobel_prizes/medicine/laureates/1953/lipmann-facts.html>
  7. ^ "Vitamin B5 (Pantothenic acid)". University of Maryland Medical Center. Retrieved 2017-11-08.
  8. ^ "Pantothenic Acid (Vitamin B5): MedlinePlus Supplements". medlineplus.gov. Retrieved 2017-12-10.
  9. ^ a b c d e LEONARDI, ROBERTA; JACKOWSKI, SUZANNE (April 2007). "Biosynthesis of Pantothenic Acid and Coenzyme A". EcoSal Plus. 2 (2). doi:10.1128/ecosalplus.3.6.3.4. ISSN 2324-6200. PMC 4950986. PMID 26443589.
  10. ^ a b Leonardi R, Zhang YM, Rock CO, Jackowski S (2005). "Coenzyme A: back in action". Progress in Lipid Research. 44 (2–3): 125–153. doi:10.1016/j.plipres.2005.04.001. PMID 15893380.
  11. ^ de Villiers, Marianne; Strauss, Erick (October 2015). "Metabolism: Jump-starting CoA biosynthesis". Nature Chemical Biology. 11 (10): 757–758. doi:10.1038/nchembio.1912. ISSN 1552-4469. PMID 26379022.
  12. ^ Sibon, Ody C. M.; Strauss, Erick (October 2016). "Coenzyme A: to make it or uptake it?". Nature Reviews. Molecular Cell Biology. 17 (10): 605–606. doi:10.1038/nrm.2016.110. ISSN 1471-0080. PMID 27552973.
  13. ^ Mouterde, Louis M. M.; Stewart, Jon D. (19 December 2018). "Isolation and Synthesis of One of the Most Central Cofactors in Metabolism: Coenzyme A". Organic Process Research & Development. doi:10.1021/acs.oprd.8b00348.
  14. ^ a b c Ahern, Kevin; Rajagopal, Indira; Tan, Taralyn (2017). Biochemistry Free For All (PDF). Creative Commons.
  15. ^ Elovson J, Vagelos PR (July 1968). "Acyl carrier protein. X. Acyl carrier protein synthetase". J. Biol. Chem. 243 (13): 3603–11. PMID 4872726.
  16. ^ Strickland KC, Hoeferlin LA, Oleinik NV, Krupenko NI, Krupenko SA (January 2010). "Acyl carrier protein-specific 4'-phosphopantetheinyl transferase activates 10-formyltetrahydrofolate dehydrogenase". J. Biol. Chem. 285 (3): 1627–33. doi:10.1074/jbc.M109.080556. PMC 2804320. PMID 19933275.
  17. ^ Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter (2002). "How Cells Obtain Energy from Food".
  18. ^ a b Shi, Lei; Tu, Benjamin P. (April 2015). "Acetyl-CoA and the Regulation of Metabolism: Mechanisms and Consequences". Current Opinion in Cell Biology. 33: 125–131. doi:10.1016/j.ceb.2015.02.003. ISSN 0955-0674. PMC 4380630. PMID 25703630.
  19. ^ Berg, Jeremy M.; Tymoczko, John L.; Stryer, Lubert (2002). "Acetyl Coenzyme A Carboxylase Plays a Key Role in Controlling Fatty Acid Metabolism".
  20. ^ Tsuchiya, Yugo; Peak-Chew, Sew Yeu; Newell, Clare; Miller-Aidoo, Sheritta; Mangal, Sriyash; Zhyvoloup, Alexander; Bakovic´, Jovana; Malanchuk, Oksana; Pereira, Gonçalo C. (2017-07-15). "Protein CoAlation: a redox-regulated protein modification by coenzyme A in mammalian cells". Biochemical Journal. 474 (14): 2489–2508. doi:10.1042/BCJ20170129. ISSN 0264-6021. PMC 5509381. PMID 28341808.
  21. ^ a b Dawson, R. M. C. (1989). Data for biochemical research. Oxford: Clarendon Press. pp. 118–119. ISBN 0-19-855299-8.
  22. ^ "Datasheet for free acid coenzyme A" (PDF). Oriental Yeast Co., LTD.
  23. ^ "Datasheet for lithium salt coenzyme A" (PDF). Oriental Yeast Co., LTD.

Bibliography

  • Nelson, David L.; Cox, Michael M. (2005). Lehninger: Principles of Biochemistry (4th ed.). New York: W.H. Freeman. ISBN 0-7167-4339-6.
3-hydroxyacyl-CoA dehydrogenase

In enzymology, a 3-hydroxyacyl-CoA dehydrogenase (EC 1.1.1.35) is an enzyme that catalyzes the chemical reaction

(S)-3-hydroxyacyl-CoA + NAD+ 3-oxoacyl-CoA + NADH + H+

Thus, the two substrates of this enzyme are (S)-3-hydroxyacyl-CoA and NAD+, whereas its 3 products are 3-oxoacyl-CoA, NADH, and H+.

This enzyme belongs to the family of oxidoreductases, to be specific those acting on the CH-OH group of donor with NAD+ or NADP+ as acceptor.

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 energy production. Coenzyme A (CoASH or CoA) consists of a β-mercaptoethylamine group linked to the vitamin pantothenic acid through an amide linkage and 3'-phosphorylated ADP. The acetyl group (indicated in blue in the structural diagram on the right) of acetyl-CoA is linked to the sulfhydryl substituent of the β-mercaptoethylamine group. This thioester linkage is a "high energy" bond, which is particularly reactive. Hydrolysis of the thioester bond is exergonic (−31.5 kJ/mol).

CoA is acetylated to acetyl-CoA by the breakdown of carbohydrates through glycolysis and by the breakdown of fatty acids through β-oxidation. Acetyl-CoA then enters the citric acid cycle, where the acetyl group is oxidized to carbon dioxide and water, and the energy released captured in the form of 11 ATP and one GTP per acetyl group.

Konrad Bloch and Feodor Lynen were awarded the 1964 Nobel Prize in Physiology and Medicine for their discoveries linking acetyl-CoA and fatty acid metabolism. Fritz Lipmann won the Nobel Prize in 1953 for his discovery of the cofactor coenzyme A.

Acyl-CoA

Acyl-CoA is a group of coenzymes involved in the metabolism of fatty acids. It is a temporary compound formed when coenzyme A (CoA) attaches to the end of a long-chain fatty acid inside living cells. The compound undergoes beta oxidation, forming one or more molecules of acetyl-CoA. This, in turn, enters the citric acid cycle, eventually forming several molecules of ATP.

Acyl CoA dehydrogenase

Acyl-CoA dehydrogenases (ACADs) are a class of enzymes that function to catalyze the initial step in each cycle of fatty acid β-oxidation in the mitochondria of cells. Their action results in the introduction of a trans double-bond between C2 (α) and C3 (β) of the acyl-CoA thioester substrate. Flavin adenine dinucleotide (FAD) is a required co-factor in addition to the presence of an active site glutamate in order for the enzyme to function.

The following reaction is the oxidation of the fatty acid by FAD to afford an α,β-unsaturated fatty acid thioester of Coenzyme A:

ACADs can be categorized into three distinct groups based on their specificity for short-, medium-, or long-chain fatty acid acyl-CoA substrates. While different dehydrogenases target fatty acids of varying chain length, all types of ACADs are mechanistically similar. Differences in the enzyme occur based on the location of the active site along the amino acid sequence.ACADs are an important class of enzymes in mammalian cells because of their role in metabolizing fatty acids present in ingested food materials. This enzyme's action represents the first step in fatty acid metabolism (the process of breaking long chains of fatty acids into acetyl CoA molecules). Deficiencies in these enzymes are linked to genetic disorders involving fatty acid oxidation (i.e. metabolic disorders).ACAD enzymes have been identified in animals (of which there are 9 major eukaryotic classes), as well as plants, nematodes, fungi, and bacteria. Five of these nine classes are involved in fatty acid β-oxidation (SCAD, MCAD, LCAD, VLCAD, and VLCAD2), and the other four are involved in branched chain amino acid metabolism (i3VD, i2VD, GD, and iBD). Most acyl-CoA dehydrogenases are α4 homotetramers, and in two cases (for very long chain fatty acid substrates) they are α2 homodimers. An additional class of acyl-CoA dehydrogenase was discovered that catalyzes α,β-unsaturation reactions with steroid-CoA thioesters in certain types of bacteria. This class of ACAD was demonstrated to form α2β2 heterotetramers, rather than the usual α4 homotetramer, a protein architecture that evolved in order to accommodate a much larger steroid-CoA substrate.ACADs are classified as EC 1.3.99.3.

Beta-Hydroxy beta-methylbutyryl-CoA

β-Hydroxy β-methylbutyryl-coenzyme A (HMB-CoA), also known as 3-hydroxyisovaleryl-CoA, is a metabolite of L-leucine that is produced in the human body. Its immediate precursors are β-hydroxy β-methylbutyric acid (HMB) and β-methylcrotonoyl-CoA (MC-CoA). It can be metabolized into HMB, MC-CoA, and HMG-CoA in humans.

Coumaroyl-CoA

Coumaroyl-coenzyme A is a chemical compound found in plants. The compound is the thioester of coenzyme-A and coumaric acid.

Enoyl-CoA hydratase

Enoyl-CoA hydratase (ECH) or crotonase is an enzyme that hydrates the double bond between the second and third carbons on 2-trans/cis-enoyl-CoA:

ECH is essential to metabolizing fatty acids in beta oxidation to produce both acetyl CoA and energy in the form of ATP.ECH of rats is a hexameric protein (this trait is not universal, but human enzyme is also hexameric), which leads to the efficiency of this enzyme as it has 6 active sites. This enzyme has been discovered to be highly efficient, and allows people to metabolize fatty acids into energy very quickly. In fact this enzyme is so efficient that the rate for short chain fatty acids is equivalent to that of diffusion-controlled reactions.

HMG-CoA

β-Hydroxy β-methylglutaryl-CoA (HMG-CoA), also known as 3-hydroxy-3-methylglutaryl-CoA, is an intermediate in the mevalonate and ketogenesis pathways. It is formed from acetyl CoA and acetoacetyl CoA by HMG-CoA synthase. The research of Minor J. Coon and Bimal Kumar Bachhawat in the 1950s at University of Illinois led to its discovery.HMG-CoA is a metabolic intermediate in the metabolism of the branched-chain amino acids, which include leucine, isoleucine, and valine. Its immediate precursors are β-methylglutaconyl-CoA (MG-CoA) and β-hydroxy β-methylbutyryl-CoA (HMB-CoA).

HMG-CoA reductase

HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, officially abbreviated HMGCR) is the rate-controlling enzyme (NADH-dependent, EC 1.1.1.88; NADPH-dependent, EC 1.1.1.34) of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. Normally in mammalian cells this enzyme is suppressed by cholesterol derived from the internalization and degradation of low density lipoprotein (LDL) via the LDL receptor as well as oxidized species of cholesterol. Competitive inhibitors of the reductase induce the expression of LDL receptors in the liver, which in turn increases the catabolism of plasma LDL and lowers the plasma concentration of cholesterol, which is considered, by those who accept the standard lipid hypothesis, an important determinant of atherosclerosis. This enzyme is thus the target of the widely available cholesterol-lowering drugs known collectively as the statins.

HMG-CoA reductase is anchored in the membrane of the endoplasmic reticulum, and was long regarded as having seven transmembrane domains, with the active site located in a long carboxyl terminal domain in the cytosol. More recent evidence shows it to contain eight transmembrane domains.In humans, the gene for HMG-CoA reductase is located on the long arm of the fifth chromosome (5q13.3-14). Related enzymes having the same function are also present in other animals, plants and bacteria.

Isovaleryl-CoA dehydrogenase

In enzymology, an isovaleryl-CoA dehydrogenase (EC 1.3.8.4) is an enzyme that catalyzes the chemical reaction

3-methylbutanoyl-CoA + acceptor 3-methylbut-2-enoyl-CoA + reduced acceptor

Thus, the two substrates of this enzyme are 3-methylbutanoyl-CoA and acceptor, whereas its two products are 3-methylbut-2-enoyl-CoA and reduced acceptor.

This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-CH group of donor with other acceptors. The systematic name of this enzyme class is 3-methylbutanoyl-CoA:acceptor oxidoreductase. Other names in common use include isovaleryl-coenzyme A dehydrogenase, isovaleroyl-coenzyme A dehydrogenase, and 3-methylbutanoyl-CoA:(acceptor) oxidoreductase. This enzyme participates in valine, leucine and isoleucine degradation. It employs one cofactor, FAD.

Malonyl-CoA

Malonyl-CoA is a coenzyme A derivative of malonic acid.

Methylmalonyl-CoA mutase

Methylmalonyl-CoA mutase (MCM), mitochondrial, also known as methylmalonyl-CoA isomerase, is a protein that in humans is encoded by the MUT gene. This vitamin B12-dependent enzyme catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA in humans. Mutations in MUT gene may lead to various types of methylmalonic aciduria.MCM was first identified in rat liver and sheep kidney in 1955. In its latent form, it is 750 amino acids in length. Upon entry to the mitochondria, the 32 amino acid mitochondrial leader sequence at the N-terminus of the protein is cleaved, forming the fully processed monomer. The monomers then associate into homodimers, and bind AdoCbl (one for each monomer active site) to form the final, active holoenzyme form.

Palmitoyl-CoA

Palmitoyl-CoA is an acyl-CoA thioester used in the biosynthesis of sphingosine:

Palmitoyl-CoA is part of the carnitine shuttle system, which transports other fatty acyl-CoA molecules into the mitochondria for β-oxidation.

Propionyl-CoA

Propionyl-CoA is a coenzyme A derivative of propionic acid.

Short-chain acyl-CoA dehydrogenase

Short-chain acyl-CoA dehydrogenase (EC 1.3.8.1, butyryl-CoA dehydrogenase, butanoyl-CoA dehydrogenase, butyryl dehydrogenase, unsaturated acyl-CoA reductase, ethylene reductase, enoyl-coenzyme A reductase, unsaturated acyl coenzyme A reductase, butyryl coenzyme A dehydrogenase, short-chain acyl CoA dehydrogenase, short-chain acyl-coenzyme A dehydrogenase, 3-hydroxyacyl CoA reductase, butanoyl-CoA:(acceptor) 2,3-oxidoreductase, ACADS (gene).) is an enzyme with systematic name short-chain acyl-CoA:electron-transfer flavoprotein 2,3-oxidoreductase. This enzyme catalyses the following chemical reaction

a short-chain acyl-CoA + electron-transfer flavoprotein a short-chain trans-2,3-dehydroacyl-CoA + reduced electron-transfer flavoprotein

This enzyme contains FAD as prosthetic group.

Succinyl-CoA

Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a combination of succinic acid and coenzyme A.

Succinyl coenzyme A synthetase

Succinyl coenzyme A synthetase (SCS, also known as succinyl-CoA synthetase or succinate thiokinase or succinate-CoA ligase) is an enzyme that catalyzes the reversible reaction of succinyl-CoA to succinate. The enzyme facilitates the coupling of this reaction to the formation of a nucleoside triphosphate molecule (either GTP or ATP) from an inorganic phosphate molecule and a nucleoside diphosphate molecule (either GDP or ADP). It plays a key role as one of the catalysts involved in the citric acid cycle, a central pathway in cellular metabolism, and it is located within the mitochondrial matrix of a cell.

Thiolase

Thiolases, also known as acetyl-coenzyme A acetyltransferases (ACAT), are enzymes which convert two units of acetyl-CoA to acetoacetyl CoA in the mevalonate pathway.

Thiolases are ubiquitous enzymes that have key roles in many vital biochemical pathways, including the beta oxidation pathway of fatty acid degradation and various biosynthetic pathways. Members of the thiolase family can be divided into two broad categories: degradative thiolases (EC 2.3.1.16) and biosynthetic thiolases (EC 2.3.1.9). These two different types of thiolase are found both in eukaryotes and in prokaryotes: acetoacetyl-CoA thiolase (EC:2.3.1.9) and 3-ketoacyl-CoA thiolase (EC:2.3.1.16). 3-ketoacyl-CoA thiolase (also called thiolase I) has a broad chain-length specificity for its substrates and is involved in degradative pathways such as fatty acid beta-oxidation. Acetoacetyl-CoA thiolase (also called thiolase II) is specific for the thiolysis of acetoacetyl-CoA and involved in biosynthetic pathways such as beta-hydroxybutyric acid synthesis or steroid biogenesis.

The formation of a carbon–carbon bond is a key step in the biosynthetic pathways by which fatty acids and polyketide are made. The thiolase superfamily enzymes catalyse the carbon–carbon-bond formation via a thioester-dependent Claisen condensation reaction mechanism.

Very long-chain acyl-coenzyme A dehydrogenase deficiency

Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCADD) is a fatty-acid metabolism disorder which prevents the body from converting certain fats to energy, particularly during periods without food.Those affected by this disorder have inadequate levels of an enzyme that breaks down a group of fats called very long-chain fatty acids.

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