Acetyl-CoA

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Acetyl-CoA
Acetyl-CoA-2D colored.svg
Names
IUPAC name
S-[2-[3-[[(2R)-4-[[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-hydroxy-3-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-2-hydroxy-3,3-dimethylbutanoyl]amino]propanoylamino]ethyl] ethanethioate
Identifiers
72-89-9 YesY
3D model (Jmol) Interactive image
Interactive image
ChEBI CHEBI:15351 YesY
ChemSpider 392413 YesY
ECHA InfoCard 100.000.719
3038
KEGG C00024 N
MeSH Acetyl+Coenzyme+A
PubChem 444493
Properties
C23H38N7O17P3S
Molar mass 809.57 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references
Acetyl CoA Space-filled Model

Acetyl coenzyme A or acetyl-CoA is an important molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism.[1] 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. 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 during breakdown of carbohydrates through glycolysis, as well as by the beta-oxidation of fatty acids. It then enters the citric acid cycle, where the acetyl group is further oxidized to carbon dioxide and water, with the energy thus released captured in the form of 11 ATP and 1 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.

Direct synthesis[edit]

The acetylation of CoA is determined by the carbon sources.[2][3]

Extramitochondrial[edit]

  • Under high glucose level, glycolysis takes place rapidly, thus increasing the amount of citrate produced from TCA cycle. This citrate is then exported to other cellular compartments outside mitochondria to be cleaved into acetyl-CoA and oxaloacetate by the enzyme ATP-citrate lyase (ACL). This reaction is coupled with the hydrolysis of ATP.[4][5]
  • Under low glucose level:
    • CoA is acetylated by acetyl-CoA synthetase (ACS), also coupled with ATP hydrolysis.[6]
    • Ethanol also serves as a carbon source for acetylation of CoA utilizing the enzyme alcohol dehydrogenase.[7]
    • Degradation of branched-chain ketogenic amino acids such as valine, leucine, and isoleucine. These amino acids are converted to alpha ketoacid by transamination and eventually to isovaleryl-CoA through oxidative decarboxylation by alpha-ketoacid dehydrogenase complex. Isovaleryl CoA undergoes dehydrogenation, carboxylation and hydration to form another CoA-derivative intermediate before it is cleaved into acetyl CoA and acetoacetate.[8]

Intramitochondrial[edit]

  • Under high glucose level, acetyl CoA is produced through glycolysis.[9] Pyruvate undergoes oxidative decarboxylation in which it loses its carboxyl group (as carbon dioxide) to form acetyl CoA, giving off 33.5kJ/mol.The oxidative conversion of pyruvate into acetyl-CoA is referred to as the pyruvate dehydrogenase reaction. It is catalyzed by the pyruvate dehydrogenase complex. Other conversions between pyruvate and acetyl-CoA are possible. For example, pyruvate formate lyase disproportionates pyruvate into acetyl-CoA and formic acid.
    Pyruvate dehydrogenase complex reaction
  • Under low glucose level, the production of Acetyl CoA is linked to beta oxidation of fatty acids. Fatty acids are first converted to acyl-CoA. Acyl-CoA is then degraded in a 4-step cycle of dehydrogenation, hydration, oxidation and thiolysis catalyzed by four respective enzymes namely Acyl CoA Dehydrogenase, Enoyl CoA Hydratase, 3-hydroxyacyl CoA dehydrogenase, and Thiolase. The cycle produces a new Acyl-CoA with two less carbons and Acetyl CoA as byproduct.[10]
Metabolism4.jpg

Functions[edit]

Intermediates In Various Pathways[edit]

Two acetyl-CoA molecules condense to form acetoacetyl-CoA, which gives rise to the formation of acetoacetate and beta-hydroxybutyrate.[11] Acetoacetate, beta-hydroxybutyrate, and their spontaneous breakdown product, acetone,[13] are frequently, but confusingly, known as ketone bodies (as they are not "bodies" at all, but water-soluble chemical substances). The ketone bodies are released by the liver into the blood. All cells with mitochondria can take ketone bodies up from the blood and reconvert them into acetyl-CoA, which can then be used as fuel in their citric acid cycles, as no other tissue can divert its oxaloacetate into the gluconeogenic pathway in the way that the liver does. Unlike free fatty acids, ketone bodies can cross the blood-brain barrier and are therefore available as fuel for the cells of the central nervous system, acting as a substitute for glucose, on which these cells normally survive.[11] The occurrence of high levels of ketone bodies in the blood during starvation, a low carbohydrate diet, prolonged heavy exercise, and uncontrolled type-1 diabetes mellitus is known as ketosis, and in its extreme form in out-of-control type-1 diabetes mellitus, as ketoacidosis.

    • On the other hand, when the insulin concentration in the blood is high, and that of glucagon is low (i.e. after meals), the acetyl-CoA produced by glycolysis condenses as normal with oxaloacetate to form citrate in the mitochondrion. However, instead of continuing through the citric acid cycle to be converted to carbon dioxide and water, the citrate is removed from the mitochondrion into the cytoplasm.[11] There it is cleaved by ATP citrate lyase into acetyl-CoA and oxaloacetate. The oxaloacetate is returned to mitochondrion as malate (and then converted back into oxaloacetate to transfer more acetyl-CoA out of the mitochondrion).[14] This cytosolic acetyl-CoA can then be used to synthesize fatty acids through carboxylation by acetyl CoA carboxylase into malonyl CoA, the first committed step in the synthesis of fatty acids.[14][15] This conversion occurs primarily in the liver, adipose tissue and lactating mammary glands, where the fatty acids are combined with glycerol to form triglycerides, the major fuel reservoir of most animals. Fatty acids are also components of the phospholipids that make up the bulk of the lipid bilayers of all the cellular membranes.[11]
    • In plants, de novo fatty acid synthesis occurs in the plastids. Many seeds accumulate large reservoirs of seed oils to support germination and early growth of the seedling before it is a net photosynthetic organism.
    • The cytosolic acetyl-CoA can also condense with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) which is the rate limiting step controlling the synthesis of cholesterol.[11] Cholesterol can be used as is, as a structural component of cellular membranes, or it can be used to synthesize the steroid hormones, bile salts, and vitamin D.[11][15]
    • Acetyl-CoA can be carboxylated in the cytosol by acetyl-CoA carboxylase, giving rise to malonyl-CoA, a substrate required for synthesis of flavonoids and related polyketides, for elongation of fatty acids to produce waxes, cuticle, and seed oils in members of the Brassica family, and for malonation of proteins and other phytochemicals.[16] In plants, these include sesquiterpenes, brassinosteroids (hormones), and membrane sterols.
  • Steroid synthesis:
    • Acetyl CoA participates in Mevalonate pathway by partaking in the synthesis of hydroxymethyl glutaryl-CoA
  • Acetylcholine synthesis:
  • Melatonin synthesis

Acetylation[edit]

Allosteric regulator[edit]

Interactive pathway map[edit]

Click on genes, proteins and metabolites below to visit Gene Wiki pages and related Wikipedia articles. The pathway can be downloaded and edited at WikiPathways.

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See also[edit]

References[edit]

  1. ^ "Acetyl CoA Crossroads". chemistry.elmhurst.edu. Retrieved 2016-11-08. 
  2. ^ Hynes, Michael J.; Murray, Sandra L. (2010-07-01). "ATP-Citrate Lyase Is Required for Production of Cytosolic Acetyl Coenzyme A and Development in Aspergillus nidulans". Eukaryotic Cell. 9 (7): 1039–1048. doi:10.1128/EC.00080-10. ISSN 1535-9778. PMC 2901662Freely accessible. PMID 20495057. 
  3. ^ Wellen, Kathryn E.; Thompson, Craig B. (2012-04-01). "A two-way street: reciprocal regulation of metabolism and signalling". Nature Reviews Molecular Cell Biology. 13 (4): 270–276. doi:10.1038/nrm3305. ISSN 1471-0072. 
  4. ^ Storey, Kenneth B. (2005-02-25). Functional Metabolism: Regulation and Adaptation. John Wiley & Sons. ISBN 9780471675570. 
  5. ^ "ACLY ATP citrate lyase [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2016-11-06. 
  6. ^ Ragsdale, S. W., "Life with carbon monoxide", CRC Crit Rev Biochem and Mol Biol 2004, 39, 165-195.
  7. ^ Chatterjea (2004-01-01). Textbook of Biochemistry for Dental/Nursing/Pharmacy Students. Jaypee Brothers Publishers. ISBN 9788180612046. 
  8. ^ a b Berg, Jeremy M.; Tymoczko, John L.; Stryer, Lubert; Berg, Jeremy M.; Tymoczko, John L.; Stryer, Lubert (2002-01-01). Biochemistry (5th ed.). W H Freeman. ISBN 0716730510. 
  9. ^ Blackstock, James C. (2014-06-28). Guide to Biochemistry. Butterworth-Heinemann. ISBN 9781483183671. 
  10. ^ Houten, Sander Michel; Wanders, Ronald J. A. (2010-03-02). "A general introduction to the biochemistry of mitochondrial fatty acid β-oxidation". Journal of Inherited Metabolic Disease. 33 (5): 469–477. doi:10.1007/s10545-010-9061-2. ISSN 0141-8955. PMC 2950079Freely accessible. PMID 20195903. 
  11. ^ a b c d e f g Stryer, Lubert (1995). Biochemistry. (Fourth ed.). New York: W.H. Freeman and Company. pp. 510–515, 559–565, 581–613, 614–623, 775–778. ISBN 0 7167 2009 4. 
  12. ^ Oxidation of fatty acids
  13. ^ Ketone body metabolism, University of Waterloo
  14. ^ a b Ferre, P.; F. Foufelle (2007). "SREBP-1c Transcription Factor and Lipid Homeostasis: Clinical Perspective". Hormone Research. 68 (2): 72–82. doi:10.1159/000100426. PMID 17344645. Retrieved 2010-08-30. this process is outlined graphically in page 73 
  15. ^ a b Voet, Donald; Judith G. Voet; Charlotte W. Pratt (2006). Fundamentals of Biochemistry, 2nd Edition. John Wiley and Sons, Inc. pp. 547, 556. ISBN 0-471-21495-7. 
  16. ^ Fatland, B. L. (2005). "Reverse Genetic Characterization of Cytosolic Acetyl-CoA Generation by ATP-Citrate Lyase in Arabidopsis". The Plant Cell Online. 17: 182. doi:10.1105/tpc.104.026211. 
  17. ^ Yi, C. H.; Vakifahmetoglu-Norberg, H.; Yuan, J. (2011-01-01). "Integration of Apoptosis and Metabolism". Cold Spring Harbor Symposia on Quantitative Biology. 76: 375–387. doi:10.1101/sqb.2011.76.010777. ISSN 0091-7451. PMID 22089928. 
  18. ^ Pettit, Flora H.; Pelley, John W.; Reed, Lester J. (1975-07-22). "Regulation of pyruvate dehydrogenase kinase and phosphatase by acetyl-CoA/CoA and NADH/NAD ratios". Biochemical and Biophysical Research Communications. 65 (2): 575–582. doi:10.1016/S0006-291X(75)80185-9. 
  19. ^ Jitrapakdee, Sarawut; Maurice, Martin St.; Rayment, Ivan; Cleland, W. Wallace; Wallace, John C.; Attwood, Paul V. (2008-08-01). "Structure, Mechanism and Regulation of Pyruvate Carboxylase". The Biochemical journal. 413 (3): 369–387. doi:10.1042/BJ20080709. ISSN 0264-6021. PMC 2859305Freely accessible. PMID 18613815. 

External links[edit]