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Coenzyme A

|Section2={{Chembox Properties | Formula = C21H36N7O16P3S | MolarMass = 767.535 | Appearance = | Density = | MeltingPt = | BoilingPt = }} |Section3={{Chembox Hazards | MainHazards = | FlashPt = | AutoignitionPt = }} }} Coenzyme A (CoA, CoASH, or HSCoA) 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, such as acetyl-CoA) as a substrate. In humans, CoA biosynthesis requires cysteine, pantothenate, and adenosine triphosphate (ATP).

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. In all living organisms, Coenzyme A is synthesized in a five-step process that requires four molecules of ATP, from pantothenate and cysteine:
  1. Pantothenate (vitamin B5) is phosphorylated to 4'-phosphopantothenate by the enzyme pantothenate kinase (PanK; CoaA; CoaX)
  2. A cysteine is added to 4'-phosphopantothenate by the enzyme phosphopantothenoylcysteine synthetase (PPCS; CoaB) to form 4'-phospho-N-pantothenoylcysteine (PPC).
  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).
Enzyme nomenclature abbreviations in parentheses represent eukaryotic and prokaryotic enzymes respectively. In some plants and bacteria, including Escherichia coli, pantothenate can be synthesised de novo and is therefore not considered essential. New research shows that Coenzyme A can be synthesized through alternate routes (such as the nexus metabolite pathway) when intracellular Coenzyme A level are reduced and the de novo pathway is impaired. In this pathway, 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.

Discovery of structure

The structure of coenzyme A was identified in the early 1950s at the Lister Institute, London, together by Fritz Lipmann and other workers at Harvard Medical School and Massachusetts General Hospital. 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. 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"."Fritz Lipmann - Facts". Nobelprize.org. Nobel Media AB 2014. Web. 8 Nov 2017.

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 acetyl-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 protecting the cell and play an important role in cell membrane structure. 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.

Energy Production

Coenzyme A is one of five essential coenzymes that is 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, animo 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. During this process, Coenzyme A also works as an allosteric regulator in the stimulation of the enzyme pyruvate dehydrogenase.

Use in biological research

Coenzyme A is available from various chemical suppliers as the free acid and or 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, and near complete degradation after 1 month at 37˚C. The lithium and sodium salts of CoA are more stable, with negligible degradation noted over several months at various temperatures 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., 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

Bibliography

"green air" © 2007 - Ingo Malchow, Webdesign Neustrelitz
This article based upon the http://en.wikipedia.org/wiki/Coenzyme_A, the free encyclopaedia Wikipedia and is licensed under the GNU Free Documentation License.
Further informations available on the list of authors and history: http://en.wikipedia.org/w/index.php?title=Coenzyme_A&action=history
presented by: Ingo Malchow, Mirower Bogen 22, 17235 Neustrelitz, Germany