Acetyl-CoA

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Acetyl-CoA
Acetyl-CoA-2D colored.svg
Acetyl-CoA-3D-balls.png
Acetyl-CoA-3D-vdW.png
Names
Preferred IUPAC name
O1-{(3R)-4-[(3-{[2-(Acetylsulfanyl)ethyl]amino}-3-oxopropyl)amino]-3-hydroxy-2,2-dimethyl-4-oxobutyl} O3-{[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxy-3-(phosphonooxy)oxolan-2-yl]methyl} dihydrogen diphosphate
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.000.719 OOjs UI icon edit-ltr-progressive.svg
KEGG
MeSH Acetyl+Coenzyme+A
PubChem CID
UNII
  • InChI=1S/C23H38N7O17P3S/c1-12(31)51-7-6-25-14(32)4-5-26-21(35)18(34)23(2,3)9-44-50(41,42)47-49(39,40)43-8-13-17(46-48(36,37)38)16(33)22(45-13)30-11-29-15-19(24)27-10-28-20(15)30/h10-11,13,16-18,22,33-34H,4-9H2,1-3H3,(H,25,32)(H,26,35)(H,39,40)(H,41,42)(H2,24,27,28)(H2,36,37,38)/t13-,16-,17-,18+,22-/m1/s1 Yes check.svgY
    Key: ZSLZBFCDCINBPY-ZSJPKINUSA-N Yes check.svgY
  • InChI=1/C23H38N7O17P3S/c1-12(31)51-7-6-25-14(32)4-5-26-21(35)18(34)23(2,3)9-44-50(41,42)47-49(39,40)43-8-13-17(46-48(36,37)38)16(33)22(45-13)30-11-29-15-19(24)27-10-28-20(15)30/h10-11,13,16-18,22,33-34H,4-9H2,1-3H3,(H,25,32)(H,26,35)(H,39,40)(H,41,42)(H2,24,27,28)(H2,36,37,38)/t13-,16-,17-,18+,22-/m1/s1
    Key: ZSLZBFCDCINBPY-ZSJPKINUBJ
  • O=C(SCCNC(=O)CCNC(=O)[C@H](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)C
  • CC(=O)SCCNC(=O)CCNC(=O)[C@@H](C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)n2cnc3c2ncnc3N)O)OP(=O)(O)O)O
Properties
C23H38N7O17P3S
Molar mass 809.57 g·mol−1
UV-vismax)260 nm; 232 nm [1]
Absorbance ε260 = 16.4 mM−1 cm−1 (adenosine) [1]
ε232 = 8.7 mM−1 cm−1 (thioester) [1]
Δε232 on thioester hydrolysis = −4.5 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).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. [2] Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for energy production.

Contents

Coenzyme A (CoASH or CoA) consists of a β-mercaptoethylamine group linked to pantothenic acid (vitamin B5) through an amide linkage [3] 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 is 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 or 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. [4]

Role

Acetyl-CoA is a metabolic intermediate that is involved in many metabolic pathways in an organism. It is produced during the breakdown of glucose, fatty acids, and amino acids, and is used in the synthesis of many other biomolecules, including cholesterol, fatty acids, and ketone bodies. Acetyl-CoA is also a key molecule in the citric acid cycle, which is a series of chemical reactions that occur in the mitochondria of cells and is responsible for generating energy in the form of ATP. [5] [6]

In addition, acetyl-CoA is a precursor for the biosynthesis of various acetyl-chemicals, acting as an intermediate to transfer an acetyl group during the biosynthesis of those acetyl-chemicals. Acetyl-CoA is also involved in the regulation of various cellular mechanisms by providing acetyl groups to target amino acid residues for post-translational acetylation reactions of proteins.

Biosynthesis

The acetylation of CoA is determined by the carbon sources. [7] [8]

Extramitochondrial

At high glucose levels, glycolysis takes place rapidly, thus increasing the amount of citrate produced from the citric acid cycle. This citrate is then exported to other organelles outside the mitochondria to be broken into acetyl-CoA and oxaloacetate by the enzyme ATP citrate lyase (ACL). This principal reaction is coupled with the hydrolysis of ATP. [9] [10]

At low glucose levels CoA is acetylated using acetate by acetyl-CoA synthetase (ACS), also coupled with ATP hydrolysis. [11] Ethanol also serves as a carbon source for acetylation of CoA utilizing the enzyme alcohol dehydrogenase. [12] Degradation of branched-chain ketogenic amino acids such as valine, leucine, and isoleucine occurs. These amino acids are converted to α-ketoacids by transamination and eventually to isovaleryl-CoA through oxidative decarboxylation by an α-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. [13] [ page needed ]

Intramitochondrial

Pyruvate dehydrogenase complex reaction Pyruvate dehydrogenase complex reaction.svg
Pyruvate dehydrogenase complex reaction

At high glucose levels, acetyl-CoA is produced through glycolysis. [14] Pyruvate undergoes oxidative decarboxylation in which it loses its carboxyl group (as carbon dioxide) to form acetyl-CoA, giving off 33.5 kJ/mol of energy. 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.

b-Oxidation of fatty acids Metabolism4.jpg
β-Oxidation of fatty acids

At low glucose levels, the production of acetyl-CoA is linked to β-oxidation of fatty acids. Fatty acids are first converted to acyl-CoA. Acyl-CoA is then degraded in a four-step cycle of oxidation, 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 fatty acid chain with two fewer carbons and acetyl-CoA as a byproduct. [15]

Functions

Intermediates in various pathways

Interactive pathway map

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

      Related Research Articles

      <span class="mw-page-title-main">Adenosine triphosphate</span> Energy-carrying molecule in living cells

      Adenosine triphosphate (ATP) is a nucleoside triphosphate that provides energy to drive and support many processes in living cells, such as muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all known forms of life, it is often referred to as the "molecular unit of currency" for intracellular energy transfer.

      <span class="mw-page-title-main">Citric acid cycle</span> Interconnected biochemical reactions releasing energy

      The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle —is a series of biochemical reactions to release the energy stored in nutrients through the oxidation of acetyl-CoA derived from carbohydrates, fats, proteins, and alcohol. The chemical energy released is available in the form of ATP. The Krebs cycle is used by organisms that respire to generate energy, either by anaerobic respiration or aerobic respiration. In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest components of metabolism. Even though it is branded as a "cycle", it is not necessary for metabolites to follow only one specific route; at least three alternative segments of the citric acid cycle have been recognized.

      <span class="mw-page-title-main">Glycolysis</span> Series of interconnected biochemical reactions

      Glycolysis is the metabolic pathway that converts glucose into pyruvate and, in most organisms, occurs in the liquid part of cells. The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes.

      <span class="mw-page-title-main">Ketone bodies</span> Chemicals produced during fat metabolism

      Ketone bodies are water-soluble molecules or compounds that contain the ketone groups produced from fatty acids by the liver (ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acetyl-CoA – which then enters the citric acid cycle and is oxidized for energy. These liver-derived ketone groups include acetoacetic acid (acetoacetate), beta-hydroxybutyrate, and acetone, a spontaneous breakdown product of acetoacetate.

      Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO, is an intermediate in several metabolic pathways throughout the cell.

      <span class="mw-page-title-main">Ketosis</span> Using body fats as fuel instead of carbohydrates

      Ketosis is a metabolic state characterized by elevated levels of ketone bodies in the blood or urine. Physiological ketosis is a normal response to low glucose availability. In physiological ketosis, ketones in the blood are elevated above baseline levels, but the body's acid–base homeostasis is maintained. This contrasts with ketoacidosis, an uncontrolled production of ketones that occurs in pathologic states and causes a metabolic acidosis, which is a medical emergency. Ketoacidosis is most commonly the result of complete insulin deficiency in type 1 diabetes or late-stage type 2 diabetes. Ketone levels can be measured in blood, urine or breath and are generally between 0.5 and 3.0 millimolar (mM) in physiological ketosis, while ketoacidosis may cause blood concentrations greater than 10 mM.

      <span class="mw-page-title-main">Cellular respiration</span> Process to convert glucose to ATP in cells

      Cellular respiration is the process by which biological fuels are oxidized in the presence of an inorganic electron acceptor, such as oxygen, to drive the bulk production of adenosine triphosphate (ATP), which contains energy. Cellular respiration may be described as a set of metabolic reactions and processes that take place in the cells of organisms to convert chemical energy from nutrients into ATP, and then release waste products.

      Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.

      <span class="mw-page-title-main">Ketogenesis</span> Chemical synthesis of ketone bodies

      Ketogenesis is the biochemical process through which organisms produce ketone bodies by breaking down fatty acids and ketogenic amino acids. The process supplies energy to certain organs, particularly the brain, heart and skeletal muscle, under specific scenarios including fasting, caloric restriction, sleep, or others.

      The term amphibolism is used to describe a biochemical pathway that involves both catabolism and anabolism. Catabolism is a degradative phase of metabolism in which large molecules are converted into smaller and simpler molecules, which involves two types of reactions. First, hydrolysis reactions, in which catabolism is the breaking apart of molecules into smaller molecules to release energy. Examples of catabolic reactions are digestion and cellular respiration, where sugars and fats are broken down for energy. Breaking down a protein into amino acids, or a triglyceride into fatty acids, or a disaccharide into monosaccharides are all hydrolysis or catabolic reactions. Second, oxidation reactions involve the removal of hydrogens and electrons from an organic molecule. Anabolism is the biosynthesis phase of metabolism in which smaller simple precursors are converted to large and complex molecules of the cell. Anabolism has two classes of reactions. The first are dehydration synthesis reactions; these involve the joining of smaller molecules together to form larger, more complex molecules. These include the formation of carbohydrates, proteins, lipids and nucleic acids. The second are reduction reactions, in which hydrogens and electrons are added to a molecule. Whenever that is done, molecules gain energy.

      <span class="mw-page-title-main">Oxaloacetic acid</span> Organic compound

      Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes that occur in animals. It takes part in gluconeogenesis, the urea cycle, the glyoxylate cycle, amino acid synthesis, fatty acid synthesis and the citric acid cycle.

      <span class="mw-page-title-main">Mitochondrial matrix</span> Space within the inner membrane of the mitochondrion

      In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribosomes, soluble enzymes, small organic molecules, nucleotide cofactors, and inorganic ions.[1] The enzymes in the matrix facilitate reactions responsible for the production of ATP, such as the citric acid cycle, oxidative phosphorylation, oxidation of pyruvate, and the beta oxidation of fatty acids.

      Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes that generate energy and (2) anabolic processes where they serve as building blocks for other compounds.

      <span class="mw-page-title-main">Pyruvate carboxylase</span> Enzyme

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      In biochemistry and metabolism, beta oxidation (also β-oxidation) is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl-CoA enters the citric acid cycle, generating NADH and FADH2, which are electron carriers used in the electron transport chain. It is named as such because the beta carbon of the fatty acid chain undergoes oxidation and is converted to a carbonyl group to start the cycle all over again. Beta-oxidation is primarily facilitated by the mitochondrial trifunctional protein, an enzyme complex associated with the inner mitochondrial membrane, although very long chain fatty acids are oxidized in peroxisomes.

      <span class="mw-page-title-main">Glyoxylate cycle</span> Series of interconnected biochemical reactions

      The glyoxylate cycle, a variation of the tricarboxylic acid cycle, is an anabolic pathway occurring in plants, bacteria, protists, and fungi. The glyoxylate cycle centers on the conversion of acetyl-CoA to succinate for the synthesis of carbohydrates. In microorganisms, the glyoxylate cycle allows cells to use two carbons, such as acetate, to satisfy cellular carbon requirements when simple sugars such as glucose or fructose are not available. The cycle is generally assumed to be absent in animals, with the exception of nematodes at the early stages of embryogenesis. In recent years, however, the detection of malate synthase (MS) and isocitrate lyase (ICL), key enzymes involved in the glyoxylate cycle, in some animal tissue has raised questions regarding the evolutionary relationship of enzymes in bacteria and animals and suggests that animals encode alternative enzymes of the cycle that differ in function from known MS and ICL in non-metazoan species.

      In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes called fatty acid synthases. This process takes place in the cytoplasm of the cell. Most of the acetyl-CoA which is converted into fatty acids is derived from carbohydrates via the glycolytic pathway. The glycolytic pathway also provides the glycerol with which three fatty acids can combine to form triglycerides, the final product of the lipogenic process. When only two fatty acids combine with glycerol and the third alcohol group is phosphorylated with a group such as phosphatidylcholine, a phospholipid is formed. Phospholipids form the bulk of the lipid bilayers that make up cell membranes and surrounds the organelles within the cells. In addition to cytosolic fatty acid synthesis, there is also mitochondrial fatty acid synthesis (mtFASII), in which malonyl-CoA is formed from malonic acid with the help of malonyl-CoA synthetase (ACSF3), which then becomes the final product octanoyl-ACP (C8) via further intermediate steps.

      <span class="mw-page-title-main">Bioenergetic systems</span> Metabolic processes for energy production

      Bioenergetic systems are metabolic processes that relate to the flow of energy in living organisms. Those processes convert energy into adenosine triphosphate (ATP), which is the form suitable for muscular activity. There are two main forms of synthesis of ATP: aerobic, which uses oxygen from the bloodstream, and anaerobic, which does not. Bioenergetics is the field of biology that studies bioenergetic systems.

      <span class="mw-page-title-main">Pyruvate decarboxylation</span> Conversion of pyruvate into acetyl-CoA

      Pyruvate decarboxylation or pyruvate oxidation, also known as the link reaction, is the conversion of pyruvate into acetyl-CoA by the enzyme complex pyruvate dehydrogenase complex.

      <span class="mw-page-title-main">Citrate–malate shuttle</span> Series of chemical reactions

      The citrate-malate shuttle is a series of chemical reactions, commonly referred to as a biochemical cycle or system, that transports acetyl-CoA in the mitochondrial matrix across the inner and outer mitochondrial membranes for fatty acid synthesis. Mitochondria are enclosed in a double membrane. As the inner mitochondrial membrane is impermeable to acetyl-CoA, the shuttle system is essential to fatty acid synthesis in the cytosol. It plays an important role in the generation of lipids in the liver.

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