Coenzyme A

Source: Wikipedia, the free encyclopedia.
Coenzyme A
Names
Systematic IUPAC name
[(2R,3S,4R,5R)-5-(6-Amino-9H-purin-9-yl)-4-hydroxy-3-(phosphonooxy)tetrahydro-2-furanyl]methyl (3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-({3-oxo-3-[(2-sulfanylethyl)amino]propyl}amino)butyl dihydrogen diphosphate
Identifiers
3D model (
JSmol
)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard
 100.001.472 Edit this at Wikidata
KEGG
MeSH Coenzyme+A
UNII
  • InChI=1S/C21H36N7O16P3S/c1-21(2,16(31)19(32)24-4-3-12(29)23-5-6-48)8-41-47(38,39)44-46(36,37)40-7-11-15(43-45(33,34)35)14(30)20(42-11)28-10-27-13-17(22)25-9-26-18(13)28/h9-11,14-16,20,30-31,48H,3-8H2,1-2H3,(H,23,29)(H,24,32)(H,36,37)(H,38,39)(H2,22,25,26)(H2,33,34,35)/t11-,14-,15-,16?,20-/m1/s1 checkY
    Key: RGJOEKWQDUBAIZ-DRCCLKDXSA-N checkY
  • InChI=1/C21H36N7O16P3S/c1-21(2,16(31)19(32)24-4-3-12(29)23-5-6-48)8-41-47(38,39)44-46(36,37)40-7-11-15(43-45(33,34)35)14(30)20(42-11)28-10-27-13-17(22)25-9-26-18(13)28/h9-11,14-16,20,30-31,48H,3-8H2,1-2H3,(H,23,29)(H,24,32)(H,36,37)(H,38,39)(H2,22,25,26)(H2,33,34,35)/t11-,14-,15-,16?,20-/m1/s1
    Key: RGJOEKWQDUBAIZ-DRCCLKDXBU
  • O=C(NCCS)CCNC(=O)C(O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n2cnc1c(ncnc12)N)[C@H](O)[C@@H]3OP(=O)(O)O
Properties
C21H36N7O16P3S
Molar mass 767.535
UV-vis (λmax) 259.5 nm[1]
Absorbance
ε259 = 16.8 mM−1 cm−1[1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

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 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).[2]

In

carboxylase to maintain and support the partition of pyruvate synthesis and degradation.[3]

Discovery of structure

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 won the Nobel Prize in Physiology or Medicine "for his discovery of co-enzyme A and its importance for intermediary metabolism".[6][9]

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.[10] In humans and most living organisms, pantothenate is an essential vitamin that has a variety of functions.[11] 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.[12]

In all living organisms, coenzyme A is synthesized in a five-step process that requires four molecules of ATP, pantothenate and cysteine[13] (see figure):

Details of 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.[12]
  2. A
    phosphopantothenoylcysteine synthetase (PPCS; CoaB) to form 4'-phospho-N-pantothenoylcysteine (PPC). This step is coupled with ATP hydrolysis.[12]
  3. PPC is decarboxylated to
    4′-phosphopantetheine by phosphopantothenoylcysteine decarboxylase
    (PPC-DC; CoaC)
  4. 4′-phosphopantetheine is adenylated (or more properly,
    AMPylated) to form dephospho-CoA by the enzyme phosphopantetheine adenylyl transferase
    (COASY; PPAT; CoaD)
  5. Finally, dephospho-CoA is phosphorylated to coenzyme A by the enzyme dephosphocoenzyme A kinase (COASY, DPCK; CoaE). This final step requires ATP.[12]

Enzyme nomenclature abbreviations in parentheses represent mammalian, other eukaryotic, and prokaryotic enzymes respectively. In mammals steps 4 and 5 are catalyzed by a bifunctional enzyme called COASY.[14] This pathway is regulated by product inhibition. CoA is a competitive inhibitor for Pantothenate Kinase, which normally binds ATP.[12] Coenzyme A, three ADP, one monophosphate, and one diphosphate are harvested from biosynthesis.[13]

Coenzyme A can be synthesized through alternate routes when intracellular coenzyme A level are reduced and the de novo pathway is impaired.

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 pathway allows for 4′-phosphopantetheine to be replenished in the cell and allows for the conversion to coenzyme A through enzymes, PPAT and PPCK.[16]

A 2024 article detailed a plausible chemical synthesis mechanism for the pantetheine component (the main functional part) of coenzyme A in a primordial prebiotic world.

Commercial production

Coenzyme A is produced commercially via extraction from yeast, however this is an inefficient process (yields approximately 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.[17]

Function

Fatty acid synthesis

Since coenzyme A is, in chemical terms, a

mitochondria. A molecule of coenzyme A carrying an acyl 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.

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.[18][19]

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.[20]

Regulation

When there is excess glucose, coenzyme A is used in the cytosol for synthesis of fatty acids.

epinephrine and glucagon inhibit its activity.[22]

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.[21] In the citric acid cycle, coenzyme A works as an allosteric regulator in the stimulation of the enzyme pyruvate dehydrogenase.

Antioxidant function and regulation

Discovery of the novel antioxidant function of coenzyme A highlights its protective role during cellular stress. Mammalian and Bacterial cells subjected to oxidative and metabolic stress show significant increase in the covalent modification of protein cysteine residues by coenzyme A.[23][24] This reversible modification is termed protein CoAlation (Protein-S-SCoA), which plays a similar role to protein S-glutathionylation by preventing the irreversible oxidation of the thiol group of cysteine residues.

Using anti-coenzyme A antibody[25] and liquid chromatography tandem mass spectrometry (LC-MS/MS) methodologies, more than 2,000 CoAlated proteins were identified from stressed mammalian and bacterial cells.[26] The majority of these proteins are involved in cellular metabolism and stress response.[26] Different research studies have focused on deciphering the coenzyme A-mediated regulation of proteins. Upon protein CoAlation, inhibition of the catalytic activity of different proteins (e.g. metastasis suppressor NME1, peroxiredoxin 5, GAPDH, among others) is reported.[27][28][24][29] To restore the protein's activity, antioxidant enzymes that reduce the disulfide bond between coenzyme A and the protein cysteine residue play an important role. This process is termed protein deCoAlation. So far, two bacterial proteins, Thioredoxin A and Thioredoxin-like protein (YtpP), are shown to deCoAlate proteins.[30]

Use in biological research

Coenzyme A is available from various chemical suppliers as the free acid and

2-mercaptoethanol
.

Non-exhaustive list of coenzyme A-activated acyl groups

See also: Category:Thioesters of coenzyme A

References

  1. ^
    ISBN 978-0-19-855299-4
    .
  2. PMID 11923312
    .
  3. ^ "Coenzyme A: when small is mighty". www.asbmb.org. Archived from the original on 2018-12-20. Retrieved 2018-12-19.
  4. doi:10.1016/S0021-9258(17)41419-0
    .
  5. S2CID 630898
    .
  6. ^
    ISSN 0021-9258. Archived from the original
    on 2019-04-12. Retrieved 2017-10-24.
  7. PMID 20287921
    .
  8. PMID 14778827
    .
  9. ^ "Fritz Lipmann – Facts". Nobelprize.org. Nobel Media AB. 2014. Retrieved 8 November 2017.
  10. ^ "Vitamin B5 (Pantothenic acid)". University of Maryland Medical Center. Archived from the original on 2017-10-18. Retrieved 2017-11-08.
  11. ^ "Pantothenic Acid (Vitamin B5): MedlinePlus Supplements". medlineplus.gov. Archived from the original on 2017-12-22. Retrieved 2017-12-10.
  12. ^
    PMID 26443589
    .
  13. ^
    PMID 15893380
    .
  14. S2CID 27153945
    .
  15. PMID 26379022
    .
  16. S2CID 10344527
    .
  17. S2CID 92802641
    .
  18. PMID 4872726
    .
  19. PMID 19933275
    .
  20. ^ Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002). "Chapter 2: How Cells Obtain Energy from Food". Molecular Biology of the Cell (4th ed.). Garland Science.
  21. ^
    PMID 25703630
    .
  22. ^ Berg JM, Tymoczko JL, Stryer L (2002). "Acetyl Coenzyme A Carboxylase Plays a Key Role in Controlling Fatty Acid Metabolism". Biochemistry.
  23. PMID 28341808
    .
  24. ^
    PMID 29626155
    .
  25. ISSN 0233-7657
    .
  26. ^
    PMID 35883853
    .
  27. PMID 33339386
    .
  28. PMID 33903070
    .
  29. PMID 31375973
    .
  30. PMID 37107313
    .
  31. ^ "Datasheet for free acid coenzyme A" (PDF). Oriental Yeast Co., LTD.
  32. ^ "Datasheet for lithium salt coenzyme A" (PDF). Oriental Yeast Co., LTD.

Bibliography

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