A report on Citric acid cycle and Flavin adenine dinucleotide

Overview of the citric acid cycle
Reaction of FAD to form FADH2
Structural diagram of acetyl-CoA: The portion in blue, on the left, is the acetyl group; the portion in black is coenzyme A.
Approximate absorption spectrum for FAD
Mechanism 1. Hydride transfer occurs by addition of H+ and 2 e−
Mechanism 2. Hydride transfer by abstraction of hydride from NADH
Mechanism 3. Radical formation by electron abstraction
Mechanism 4. The loss of hydride to electron deficient R group
Mechanism 5. Use of nucleophilic addition to break R1-R2 bond
Mechanism 6. Carbon radical reacts with O2 and acid to form H2O2
Riboflavin
FADH{{sub|2}}

The overall yield of energy-containing compounds from the citric acid cycle is three NADH, one FADH2, and one GTP.

- Citric acid cycle

Warburg's work with linking nicotinamide to hydride transfers and the discovery of flavins paved the way for many scientists in the 40s and 50s to discover copious amounts of redox biochemistry and link them together in pathways such as the citric acid cycle and ATP synthesis.

- Flavin adenine dinucleotide
Overview of the citric acid cycle

10 related topics with Alpha

Overall
Interactive animation of the structure of ATP

Adenosine triphosphate

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Organic compound and hydrotrope that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis.

Organic compound and hydrotrope that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis.

Interactive animation of the structure of ATP
The cycles of synthesis and degradation of ATP; 2 and 1 represent input and output of energy, respectively.
This image shows a 360-degree rotation of a single, gas-phase magnesium-ATP chelate with a charge of −2. The anion was optimized at the UB3LYP/6-311++G(d,p) theoretical level and the atomic connectivity modified by the human optimizer to reflect the probable electronic structure.
An example of the Rossmann fold, a structural domain of a decarboxylase enzyme from the bacterium Staphylococcus epidermidis with a bound flavin mononucleotide cofactor.

ATP can be produced by a number of distinct cellular processes; the three main pathways in eukaryotes are (1) glycolysis, (2) the citric acid cycle/oxidative phosphorylation, and (3) beta-oxidation.

NADH and FADH2 are recycled (to NAD+ and FAD, respectively) by oxidative phosphorylation, generating additional ATP.

Two mitochondria from mammalian lung tissue displaying their matrix and membranes as shown by electron microscopy

Mitochondrion

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Double-membrane-bound organelle found in most eukaryotic organisms.

Double-membrane-bound organelle found in most eukaryotic organisms.

Two mitochondria from mammalian lung tissue displaying their matrix and membranes as shown by electron microscopy
Simplified structure of a mitochondrion.
Cross-sectional image of cristae in a rat liver mitochondrion to demonstrate the likely 3D structure and relationship to the inner membrane
Electron transport chain in the mitochondrial intermembrane space
Transmission electron micrograph of a chondrocyte, stained for calcium, showing its nucleus (N) and mitochondria (M).
Typical mitochondrial network (green) in two human cells (HeLa cells)
Model of the yeast multimeric tethering complex, ERMES
Evolution of MROs
The circular 16,569 bp human mitochondrial genome encoding 37 genes, i.e., 28 on the H-strand and 9 on the L-strand.

Of the enzymes, the major functions include oxidation of pyruvate and fatty acids, and the citric acid cycle.

The citric acid cycle oxidizes the acetyl-CoA to carbon dioxide, and, in the process, produces reduced cofactors (three molecules of NADH and one molecule of FADH2) that are a source of electrons for the electron transport chain, and a molecule of GTP (which is readily converted to an ATP).

The electron transport chain in the mitochondrion is the site of oxidative phosphorylation in eukaryotes. The NADH and succinate generated in the citric acid cycle are oxidized, which releases the energy of oxygen to power ATP synthase.

Electron transport chain

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Series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples this electron transfer with the transfer of protons (H+ ions) across a membrane.

Series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples this electron transfer with the transfer of protons (H+ ions) across a membrane.

The electron transport chain in the mitochondrion is the site of oxidative phosphorylation in eukaryotes. The NADH and succinate generated in the citric acid cycle are oxidized, which releases the energy of oxygen to power ATP synthase.
Photosynthetic electron transport chain of the thylakoid membrane.
Depiction of ATP synthase, the site of oxidative phosphorylation to generate ATP.

The energy released by reactions of oxygen and reduced compounds such as cytochrome c and (indirectly) NADH and FADH is used by the electron transport chain to pump protons into the intermembrane space, generating the electrochemical gradient over the inner mitochondrial membrane.

Most eukaryotic cells have mitochondria, which produce ATP from reactions of oxygen with products of the citric acid cycle, fatty acid metabolism, and amino acid metabolism.

Typical eukaryotic cell

Cellular respiration

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Set of metabolic reactions and processes that take place in the cells of organisms to convert chemical energy from nutrients into adenosine triphosphate , and then release waste products.

Set of metabolic reactions and processes that take place in the cells of organisms to convert chemical energy from nutrients into adenosine triphosphate , and then release waste products.

Typical eukaryotic cell
Out of the cytoplasm it goes into the Krebs cycle with the acetyl CoA. It then mixes with CO2 and makes 2 ATP, NADH, and FADH. From there the NADH and FADH go into the NADH reductase, which produces the enzyme. The NADH pulls the enzyme's electrons to send through the electron transport chain. The electron transport chain pulls H+ ions through the chain. From the electron transport chain, the released hydrogen ions make ADP for an result of 32 ATP. O2 provides most of the energy for the process and combines with protons and the electrons to make water. Lastly, ATP leaves through the ATP channel and out of the mitochondria.
Stoichiometry of aerobic respiration and most known fermentation types in eucaryotic cell. Numbers in circles indicate counts of carbon atoms in molecules, C6 is glucose C6H12O6, C1 carbon dioxide CO2. Mitochondrial outer membrane is omitted.

Although carbohydrates, fats, and proteins are consumed as reactants, aerobic respiration is the preferred method of pyruvate breakdown in glycolysis, and requires pyruvate to the mitochondria in order to be fully oxidized by the citric acid cycle.

The products of this process are carbon dioxide and water, and the energy transferred is used to break bonds in ADP to add a third phosphate group to form ATP (adenosine triphosphate), by substrate-level phosphorylation, NADH and FADH2

The electron transport chain in the cell is the site of oxidative phosphorylation. The NADH and succinate generated in the citric acid cycle are oxidized, releasing the energy of O2 to power the ATP synthase.

Oxidative phosphorylation

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Metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine triphosphate (ATP).

Metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine triphosphate (ATP).

The electron transport chain in the cell is the site of oxidative phosphorylation. The NADH and succinate generated in the citric acid cycle are oxidized, releasing the energy of O2 to power the ATP synthase.
Reduction of coenzyme Q from its ubiquinone form (Q) to the reduced ubiquinol form (QH2).
Complex I or NADH-Q oxidoreductase. The abbreviations are discussed in the text. In all diagrams of respiratory complexes in this article, the matrix is at the bottom, with the intermembrane space above.
Complex II: Succinate-Q oxidoreductase.
The two electron transfer steps in complex III: Q-cytochrome c oxidoreductase. After each step, Q (in the upper part of the figure) leaves the enzyme.
Complex IV: cytochrome c oxidase.
Mechanism of ATP synthase. ATP is shown in red, ADP and phosphate in pink and the rotating γ subunit in black.

The energy stored in the chemical bonds of glucose is released by the cell in the citric acid cycle producing carbon dioxide, and the energetic electron donors NADH and FADH.

Solution NMR structure of protein NMA1147 from Neisseria meningitidis. Northeast structural genomics consortium target mr19

Succinate dehydrogenase

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Enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes.

Enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes.

Solution NMR structure of protein NMA1147 from Neisseria meningitidis. Northeast structural genomics consortium target mr19
Image 5: Subunits of succinate dehydrogenase
Image 6: E2 Succinate oxidation mechanism.
Image 7: E1cb Succinate oxidation mechanism.
Image 8: Ubiquinone reduction mechanism.
Image 9: Electron carriers of the SQR complex. FADH2, iron-sulfur centers, heme b, and ubiquinone.

It is the only enzyme that participates in both the citric acid cycle and the electron transport chain.

SdhA contains a covalently attached flavin adenine dinucleotide (FAD) cofactor and the succinate binding site and SdhB contains three iron-sulfur clusters: [2Fe-2S], [4Fe-4S], and [3Fe-4S].

Pyruvate dehydrogenase complex

Pyruvate dehydrogenase complex

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Complex of three enzymes that converts pyruvate into acetyl-CoA by a process called pyruvate decarboxylation.

Complex of three enzymes that converts pyruvate into acetyl-CoA by a process called pyruvate decarboxylation.

Pyruvate dehydrogenase complex
Pymol-generated image of E1 subunit of pyruvate dehydrogenase complex in E. Coli
Pymol-generated E3 subunit of pyruvate dehydrogenase complex in Pseudomonas putida
500px

Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, and this complex links the glycolysis metabolic pathway to the citric acid cycle.

First, FAD oxidizes dihydrolipoate back to its lipoate resting state, producing FADH2.

Schematic demonstrating mitochondrial fatty acid beta-oxidation and effects of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, LCHAD deficiency

Beta oxidation

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Schematic demonstrating mitochondrial fatty acid beta-oxidation and effects of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, LCHAD deficiency
Complete beta oxidation of linoleic acid (an unsaturated fatty acid).

In biochemistry and metabolism, beta-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, which enters the citric acid cycle, and NADH and FADH2, which are co-enzymes used in the electron transport chain.

Biological roles of succinate. Inside the mitochondria, succinate serves as an intermediate in multiple metabolic pathways and contributes to the generation of ROS. Outside the mitochondria, succinate functions as both an intracellular and extracellular signaling molecule. OOA=oxaloacetate; a-KG=alpha ketoglutarate; GLUT= Glutamate; GABA = gamma-aminobutyric acid; SSA=Succinic semialdehyde ; PHD= prolyl hydroxylase; HIF-1a=hypoxia inducible factor 1a; TET= Ten-eleven Translocation Enzymes; JMJD3= Histone demethylase Jumonji D3

Succinic acid

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Dicarboxylic acid with the chemical formula 2(CO2H)2.

Dicarboxylic acid with the chemical formula 2(CO2H)2.

Biological roles of succinate. Inside the mitochondria, succinate serves as an intermediate in multiple metabolic pathways and contributes to the generation of ROS. Outside the mitochondria, succinate functions as both an intracellular and extracellular signaling molecule. OOA=oxaloacetate; a-KG=alpha ketoglutarate; GLUT= Glutamate; GABA = gamma-aminobutyric acid; SSA=Succinic semialdehyde ; PHD= prolyl hydroxylase; HIF-1a=hypoxia inducible factor 1a; TET= Ten-eleven Translocation Enzymes; JMJD3= Histone demethylase Jumonji D3
Amino acid sequence of GPR91. Succinate binds to GPR91, a 7-transmembrane G-protein coupled receptor, located on a variety of cell types. Red amino acids represent those involved in binding succinate. All other amino acids are colored according to their chemical properties (grey=nonpolar, cyan=negative charge, dark blue = positive charge, green=aromatic, dark purple=polar and noncharged, orange/light purple = special cases).
Accumulated succinate inhibits dioxygenases, such as histone and DNA demethylases or prolyl hydroxylases, by competitive inhibition. Thus, succinate modifies the epigenic landscape and regulates gene expression.

Succinate is generated in mitochondria via the tricarboxylic acid cycle (TCA).

This enzyme complex is a 4 subunit membrane-bound lipoprotein which couples the oxidation of succinate to the reduction of ubiquinone via the intermediate electron carriers FAD and three 2Fe-2S clusters.

A diagrammatic illustration of the process of lipolysis (in a fat cell) induced by high epinephrine and low insulin levels in the blood. Epinephrine binds to a beta-adrenergic receptor in the cell membrane of the adipocyte, which causes cAMP to be generated inside the cell. The cAMP activates a protein kinase, which phosphorylates and thus, in turn, activates a hormone-sensitive lipase in the fat cell. This lipase cleaves free fatty acids from their attachment to glycerol in the fat stored in the fat droplet of the adipocyte. The free fatty acids and glycerol are then released into the blood. However more recent studies have shown that adipose triglyceride lipase has to first convert triacylglycerides to diacylglycerides, and that hormone-sensitive lipase converts the diacylglycerides to monoglycerides and free fatty acids. Monoglycerides are hydrolyzed by monoglyceride lipase. The activity of hormone sensitive lipase is regulated by the circulation hormones insulin, glucagon, norepinephrine, and epinephrine, as shown in the diagram.

Fatty acid metabolism

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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.

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.

A diagrammatic illustration of the process of lipolysis (in a fat cell) induced by high epinephrine and low insulin levels in the blood. Epinephrine binds to a beta-adrenergic receptor in the cell membrane of the adipocyte, which causes cAMP to be generated inside the cell. The cAMP activates a protein kinase, which phosphorylates and thus, in turn, activates a hormone-sensitive lipase in the fat cell. This lipase cleaves free fatty acids from their attachment to glycerol in the fat stored in the fat droplet of the adipocyte. The free fatty acids and glycerol are then released into the blood. However more recent studies have shown that adipose triglyceride lipase has to first convert triacylglycerides to diacylglycerides, and that hormone-sensitive lipase converts the diacylglycerides to monoglycerides and free fatty acids. Monoglycerides are hydrolyzed by monoglyceride lipase. The activity of hormone sensitive lipase is regulated by the circulation hormones insulin, glucagon, norepinephrine, and epinephrine, as shown in the diagram.
A diagrammatic illustration of the transport of free fatty acids in the blood attached to plasma albumin, its diffusion across the cell membrane using a protein transporter, and its activation, using ATP, to form acyl-CoA in the cytosol. The illustration is, for diagrammatic purposes, of a 12 carbon fatty acid. Most fatty acids in human plasma are 16 or 18 carbon atoms long.
A diagrammatic illustration of the transfer of an acyl-CoA molecule across the inner membrane of the mitochondrion by carnitine-acyl-CoA transferase (CAT). The illustrated acyl chain is, for diagrammatic purposes, only 12 carbon atoms long. Most fatty acids in human plasma are 16 or 18 carbon atoms long. CAT is inhibited by high concentrations of malonyl-CoA (the first committed step in fatty acid synthesis) in the cytoplasm. This means that fatty acid synthesis and fatty acid catabolism cannot occur simultaneously in any given cell.
A diagrammatic illustration of the process of the beta-oxidation of an acyl-CoA molecule in the mitochodrial matrix. During this process an acyl-CoA molecule which is 2 carbons shorter than it was at the beginning of the process is formed. Acetyl-CoA, water and 5 ATP molecules are the other products of each beta-oxidative event, until the entire acyl-CoA molecule has been reduced to a set of acetyl-CoA molecules.
Example of an unsaturated fat triglyceride. Left part: glycerol, right part from top to bottom: palmitic acid, oleic acid, alpha-linolenic acid. Chemical formula: C55H98O6
Chemical structure of the diglyceride 1-palmitoyl-2-oleoyl-glycerol
Arachidonic acid
Prostaglandin E1 - Alprostadil
Dietary fats are emulsified in the duodenum by soaps in the form of bile salts and phospholipids, such as phosphatidylcholine. The fat droplets thus formed can be attacked by pancreatic lipase.
Structure of a bile acid (cholic acid), represented in the standard form, a semi-realistic 3D form, and a diagrammatic 3D form
Diagrammatic illustration of mixed micelles formed in the duodenum in the presence of bile acids (e.g. cholic acid) and the digestion products of fats, the fat soluble vitamins and cholesterol.
A schematic diagram of a chylomicron.
Synthesis of saturated fatty acids via Fatty Acid Synthase II in E. coli

When compared to other macronutrient classes (carbohydrates and protein), fatty acids yield the most ATP on an energy per gram basis, when they are completely oxidized to CO2 and water by beta oxidation and the citric acid cycle.

1) Dehydrogenation by acyl-CoA dehydrogenase, yielding 1 FADH2