|Jmol 3D model||Interactive image
|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).
|what is ?)(|
Acetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for energy production. The structure of 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 by a "high energy" thioester bond to the sulfhydryl substituent of the β-mercaptoethylamine group. It is this thioester bond that makes acetyl-CoA one of the "high energy" compounds. Hydrolysis of the thioester bond is exergonic (-31.5 kJ). Acetyl-CoA is produced 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 molecules per acetyl group that enters the cycle.
Acetyl-CoA is also an important component in the biogenic synthesis of the neurotransmitter acetylcholine. Choline, in combination with acetyl-CoA, is catalyzed by the enzyme choline acetyltransferase to produce acetylcholine and a Coenzyme A byproduct.
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.
Pyruvate dehydrogenase and pyruvate formate lyase reactions
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.
The two components of acetyl-CoA—the acetyl, supplied via acetate, and Coenzyme-A groups—can be linked directly, catalyzed by the enzyme acetyl—CoA synthetase. This process is involved in metabolism of carbon sugars. As a starting point for the citric acid cycle, the acetyl—CoA synthetase route is less common than the exergonic pyruvate dehydrogenase route which gives off 33.5kJ/mol. Acetyl-CoA is also proposed to be synthesized through the ATP citrate lyase route.
Fatty acid metabolism
Acetyl-CoA is produced by the breakdown of both carbohydrates (by glycolysis) and fats (by beta-oxidation). It then enters the citric acid cycle in the mitochondrion by combining with oxaloacetate to form citrate. This conversion results in the complete conversion of the acetyl group of acetyl-CoA to CO2 and water. The energy released in this process is captured in the form of 12 high energy pyrophosphate bonds (1 GTP and 11 ATP molecules) per acetyl group (or acetic acid molecule) oxidized. Conversion to CO2 is the fate of acetyl-CoA derived from glycolysis or β-oxidation of fatty acids, except under certain circumstances in the liver. In the liver oxaloacetate is wholly or partially diverted into the gluconeogenic pathway during fasting, starvation, a low carbohydrate diet, prolonged strenuous exercise, and in uncontrolled type 1 diabetes mellitus. Under these circumstances oxaloacetate is reduced to malate, which is then removed from the mitochondrion to be converted into glucose in the cytoplasm of the liver cells, from where it is released into the blood. In the liver, therefore, oxaloacetate is unavailable for condensation with the acetyl-CoA produced by the β-oxidation of fatty acids when significant gluconeogenesis has been stimulated (and glycolysis has been inhibited) by low (or absent) insulin and high glucagon concentrations in the blood. Under these circumstances two acetyl-CoA molecules condense to form acetoacetyl-CoA, which then gives rise to the formation of acetoacetate and beta-hydroxybutyrate. Acetoacetate, beta-hydroxybutyrate, and their spontaneous breakdown product, acetone, 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. 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. 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). 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. 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.
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. 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.
- Acetyl-CoA is also the source of the acetyl group incorporated onto certain lysine residues of histone and nonhistone proteins in the posttranslational modification acetylation, a reaction catalyzed by acetyltransferases.
- In plants and animals, cytosolic acetyl-CoA is synthesized by ATP citrate lyase. When glucose is abundant in the blood of animals, it is converted via glycolysis in the cytosol to pyruvate, and then to acetyl-CoA in the mitochondrion. The excess of acetyl-CoA results in production of excess citrate, which is exported into the cytosol to give rise to cytosolic acetyl-CoA.
- 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.
- In plants, these include sesquiterpenes, brassinosteroids (hormones), and membrane sterols.
Interactive pathway map
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- 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.
- Oxidation of fatty acids
- Koeslag, J.H.; Noakes, T.D.; Sloan, A.W. (1980). "Post-exercise ketosis". Journal of Physiology. 301: 79–90.
- Ketone body metabolism, University of Waterloo
- 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
- 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.
- Fatland, B. L.; Ke, J; Anderson, MD; Mentzen, WI; Cui, LW; Allred, CC; Johnston, JL; Nikolau, BJ; Wurtele, ES (2002). "Molecular Characterization of a Heteromeric ATP-Citrate Lyase That Generates Cytosolic Acetyl-Coenzyme a in Arabidopsis". Plant Physiology. 130 (2): 740–56. doi:10.1104/pp.008110. PMC . PMID 12376641.
- 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.