Citric acid cycle

Citric acid cycle

Overview

The citric acid cycle — also known as the tricarboxylic acid cycle (TCA cycle), the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reaction
Chemical reaction
A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...

s which is used by all aerobic
Aerobic organism
An aerobic organism or aerobe is an organism that can survive and grow in an oxygenated environment.Faculitative anaerobes grow and survive in an oxygenated environment and so do aerotolerant anaerobes.-Glucose:...

 living organisms to generate energy through the oxidization
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....

 of acetate
Acetate
An acetate is a derivative of acetic acid. This term includes salts and esters, as well as the anion found in solution. Most of the approximately 5 billion kilograms of acetic acid produced annually in industry are used in the production of acetates, which usually take the form of polymers. In...

 derived from carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...

s, fat
Fat
Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...

s and protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s into carbon dioxide
Carbon dioxide
Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...

 and water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...

. In addition, the cycle provides precursors
Precursor (chemistry)
In chemistry, a precursor is a compound that participates in the chemical reaction that produces another compound. In biochemistry, the term "precursor" is used more specifically to refer to a chemical compound preceding another in a metabolic pathway....

 for the biosynthesis of compounds including certain amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

s as well as the reducing agent
Reducing agent
A reducing agent is the element or compound in a reduction-oxidation reaction that donates an electron to another species; however, since the reducer loses an electron we say it is "oxidized"...

 NADH
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...

 that is used in numerous biochemical reactions.
Discussion
Ask a question about 'Citric acid cycle'
Start a new discussion about 'Citric acid cycle'
Answer questions from other users
Full Discussion Forum
 
Unanswered Questions
Encyclopedia

The citric acid cycle — also known as the tricarboxylic acid cycle (TCA cycle), the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reaction
Chemical reaction
A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...

s which is used by all aerobic
Aerobic organism
An aerobic organism or aerobe is an organism that can survive and grow in an oxygenated environment.Faculitative anaerobes grow and survive in an oxygenated environment and so do aerotolerant anaerobes.-Glucose:...

 living organisms to generate energy through the oxidization
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....

 of acetate
Acetate
An acetate is a derivative of acetic acid. This term includes salts and esters, as well as the anion found in solution. Most of the approximately 5 billion kilograms of acetic acid produced annually in industry are used in the production of acetates, which usually take the form of polymers. In...

 derived from carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...

s, fat
Fat
Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...

s and protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s into carbon dioxide
Carbon dioxide
Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...

 and water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...

. In addition, the cycle provides precursors
Precursor (chemistry)
In chemistry, a precursor is a compound that participates in the chemical reaction that produces another compound. In biochemistry, the term "precursor" is used more specifically to refer to a chemical compound preceding another in a metabolic pathway....

 for the biosynthesis of compounds including certain amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

s as well as the reducing agent
Reducing agent
A reducing agent is the element or compound in a reduction-oxidation reaction that donates an electron to another species; however, since the reducer loses an electron we say it is "oxidized"...

 NADH
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...

 that is used in numerous biochemical reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest established components of cellular metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...

 and may have originated abiogenically
Abiogenesis
Abiogenesis or biopoesis is the study of how biological life arises from inorganic matter through natural processes, and the method by which life on Earth arose...

.

The name of this metabolic pathway is derived from citric acid
Citric acid
Citric acid is a weak organic acid. It is a natural preservative/conservative and is also used to add an acidic, or sour, taste to foods and soft drinks...

 (a type of tricarboxylic acid
Tricarboxylic acid
A tricarboxylic acid is an organic carboxylic acid whose chemical structure contains three carboxyl functional groups . The best-known example of a tricarboxylic acid is citric acid.-Examples:*Citric acid*Isocitric acid*Aconitic acid...

) which is first consumed and then regenerated by this sequence of reactions to complete the cycle. In addition, the cycle consumes acetate in the form of acetyl-CoA
Acetyl-CoA
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 to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...

, reduces NAD+
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...

 to NADH, and produces carbon dioxide. The NADH generated by the TCA cycle is fed into the oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...

 pathway. The net result of these two closely linked pathways is the oxidation of nutrients to produce energy in the form of ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...

.

In eukaryotic cells, the citric acid cycle occurs in the matrix of the mitochondrion
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...

. Bacteria also use the TCA cycle to generate energy, but since they lack mitochondria, the reaction sequence is performed in the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....

.

The components and reactions of the citric acid cycle were established in the 1930s by seminal work from the Nobel laureates Albert Szent-Györgyi
Albert Szent-Györgyi
Albert Szent-Györgyi de Nagyrápolt was a Hungarian physiologist who won the Nobel Prize in Physiology or Medicine in 1937. He is credited with discovering vitamin C and the components and reactions of the citric acid cycle...

 and Hans Adolf Krebs
Hans Adolf Krebs
Sir Hans Adolf Krebs was a German-born British physician and biochemist. Krebs is best known for his identification of two important metabolic cycles: the urea cycle and the citric acid cycle...

.

Evolution


Components of the TCA cycle were derived from anaerobic bacteria and the TCA cycle itself may have evolved more than once. Theoretically there are several alternatives to the TCA cycle, however the TCA cycle appears to be the most efficient. If several alternatives independently evolved, they all undoubtedly rapidly converged
Convergent evolution
Convergent evolution describes the acquisition of the same biological trait in unrelated lineages.The wing is a classic example of convergent evolution in action. Although their last common ancestor did not have wings, both birds and bats do, and are capable of powered flight. The wings are...

 to the TCA cycle.

Overview


The citric acid cycle is a key component of the metabolic pathway by which all aerobic organism
Aerobic organism
An aerobic organism or aerobe is an organism that can survive and grow in an oxygenated environment.Faculitative anaerobes grow and survive in an oxygenated environment and so do aerotolerant anaerobes.-Glucose:...

s generate energy. Through catabolism
Catabolism
Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, lipids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides, and amino...

 of sugars, fats, and proteins, a two carbon organic product acetate in the form of acetyl-CoA
Acetyl-CoA
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 to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...

 is produced. Acetyl-CoA along with two equivalents
Equivalent (chemistry)
The equivalent , sometimes termed the molar equivalent, is a unit of amount of substance used in chemistry and the biological sciences.The equivalent is formally defined as the amount of a substance which will either:...

 of water (H2O) are consumed by the citric acid cycle producing two equivalents of carbon dioxide (CO2) and one equivalent of HS-CoA
Coenzyme A
Coenzyme A 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 sequenced genomes encode enzymes that use coenzyme A as a substrate, and around 4% of cellular enzymes use it as a substrate...

. In addition, one complete turn of the cycle converts three equivalents of nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...

 (NAD+) into three equivalents of reduced NAD+ (NADH), one equivalent of ubiquinone (Q) of into one equivalent of reduced ubiquinone (QH2), and one equivalent each of guanosine diphosphate
Guanosine diphosphate
Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside guanosine. GDP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase guanine....

 (GDP) and inorganic phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...

 (Pi) into one equivalent of guanosine triphosphate
Guanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...

 (GTP). The NADH and QH2 that is generated by the citric acid cycle is in turn used by the oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...

 pathway to generate energy rich adenosine triphosphate
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...

 (ATP).

One of the primary sources of acetyl-CoA are sugars that are broken down by glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...

 to produce pyruvate
Pyruvic acid
Pyruvic acid is an organic acid, a ketone, as well as the simplest of the alpha-keto acids. The carboxylate ion of pyruvic acid, CH3COCOO−, is known as pyruvate, and is a key intersection in several metabolic pathways....

 that in turn is decarboxylated by the enzyme pyruvate dehydrogenase
Pyruvate dehydrogenase
Pyruvate dehydrogenase complex is a complex of three enzymes that transform pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. 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...

 generating acetyl-CoA according to the following reaction scheme:
  • CH3C(=O)C(=O)O
    Pyruvic acid
    Pyruvic acid is an organic acid, a ketone, as well as the simplest of the alpha-keto acids. The carboxylate ion of pyruvic acid, CH3COCOO−, is known as pyruvate, and is a key intersection in several metabolic pathways....

     (pyruvate) + HSCoA
    Coenzyme A
    Coenzyme A 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 sequenced genomes encode enzymes that use coenzyme A as a substrate, and around 4% of cellular enzymes use it as a substrate...

     + NAD+
    Nicotinamide adenine dinucleotide
    Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...

     → CH3C(=O)SCoA
    Acetyl-CoA
    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 to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...

     (acetyl-CoA) + NADH + H+ + CO2


The product of this reaction, acetyl-CoA, is the starting point for the citric acid cycle. Below is a schematic outline of the cycle:
  • The citric acid
    Citric acid
    Citric acid is a weak organic acid. It is a natural preservative/conservative and is also used to add an acidic, or sour, taste to foods and soft drinks...

     cycle begins with the transfer of a two-carbon acetyl
    Acetyl
    In organic chemistry, acetyl is a functional group, the acyl with chemical formula COCH3. It is sometimes represented by the symbol Ac . The acetyl group contains a methyl group single-bonded to a carbonyl...

     group from acetyl-CoA
    Acetyl-CoA
    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 to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...

     to the four-carbon acceptor compound (oxaloacetate) to form a six-carbon compound (citrate).
  • The citrate then goes through a series of chemical transformations, losing two carboxyl groups as CO2. The carbons lost as CO2 originate from what was oxaloacetate, not directly from acetyl-CoA. The carbons donated by acetyl-CoA become part of the oxaloacetate carbon backbone after the first turn of the citric acid cycle. Loss of the acetyl-CoA-donated carbons as CO2 requires several turns of the citric acid cycle. However, because of the role of the citric acid cycle in anabolism, they may not be lost, since many TCA cycle intermediates are also used as precursors for the biosynthesis of other molecules.
  • Most of the energy made available by the oxidative steps of the cycle is transferred as energy-rich electrons to NAD+, forming NADH. For each acetyl group that enters the citric acid cycle, three molecules of NADH are produced.
  • Electrons are also transferred to the electron acceptor Q, forming QH2.
  • At the end of each cycle, the four-carbon oxaloacetate has been regenerated, and the cycle continues.

Steps


Two carbon
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...

 atoms are oxidized to CO2
Carbon dioxide
Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...

, the energy from these reactions being transferred to other metabolic processes by GTP
Guanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...

 (or ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...

), and as electrons in NADH and QH2
Ubiquinol
Ubiquinol is an electron-rich form of coenzyme Q10.The natural ubiquinol form of coenzyme Q10 is 2,3-dimethoxy-5-methyl-6-poly prenyl-1,4-benzoquinol, where the polyprenylated side chain is 9-10 units long in mammals...

. The NADH generated in the TCA cycle may later donate its electrons in oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...

 to drive ATP synthesis; FADH2 is covalently attached to succinate dehydrogenase, an enzyme functioning both in the TCA cycle and the mitochondrial electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...

 in oxidative phosphorylation. FADH2, therefore, facilitates transfer of electrons to coenzyme Q
Coenzyme Q
Coenzyme Q10, also known as ubiquinone, ubidecarenone, coenzyme Q, and abbreviated at times to CoQ10 , CoQ, Q10, or Q, is a 1,4-benzoquinone, where Q refers to the quinone chemical group, and 10 refers to the number of isoprenyl chemical subunits in its tail.This oil-soluble, vitamin-like substance...

, which is the final electron acceptor of the reaction catalyzed by the Succinate:ubiquinone oxidoreductase complex, also acting as an intermediate in the electron transport chain.

The citric acid cycle is continuously supplied with new carbon in the form of acetyl-CoA, entering at step 1 below.
Substrates Products Enzyme Reaction type Comment
1 Oxaloacetate
Oxaloacetic acid
Oxaloacetic acid is an organic compound with the chemical formula C4H4O5 or HOOC---COOH. It also has other names ....

 +
Acetyl CoA +
H2O
Citrate
Citric acid
Citric acid is a weak organic acid. It is a natural preservative/conservative and is also used to add an acidic, or sour, taste to foods and soft drinks...

 +
CoA-SH
Coenzyme A
Coenzyme A 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 sequenced genomes encode enzymes that use coenzyme A as a substrate, and around 4% of cellular enzymes use it as a substrate...

Citrate synthase
Citrate synthase
The enzyme citrate synthase exists in nearly all living cells and stands as a pace-making enzyme in the first step of the Citric Acid Cycle . Citrate synthase is localized within eukaryotic cells in the mitochondrial matrix, but is encoded by nuclear DNA rather than mitochondrial...

Aldol condensation
Aldol condensation
An aldol condensation is an organic reaction in which an enol or an enolate ion reacts with a carbonyl compound to form a β-hydroxyaldehyde or β-hydroxyketone, followed by a dehydration to give a conjugated enone....

irreversible,
extends the 4C oxaloacetate to a 6C molecule
2 Citrate
Citrate
A citrate can refer either to the conjugate base of citric acid, , or to the esters of citric acid. An example of the former, a salt is trisodium citrate; an ester is triethyl citrate.-Other citric acid ions:...

cis-Aconitate
Aconitic acid
Aconitic acid is an organic acid. The two isomers are cis-aconitic acid and trans-aconitic acid. The conjugate base of cis-aconitic acid, cis-aconitate is an intermediate in the isomerization of citrate to isocitrate in the citric acid cycle...

 +
H2O
Aconitase
Aconitase
Aconitase is an enzyme that catalyses the stereo-specific isomerization of citrate to isocitrate via cis-aconitate in the tricarboxylic acid cycle, a non-redox-active process.- Function :...

Dehydration
Dehydration reaction
In chemistry and the biological sciences, a dehydration reaction is usually defined as a chemical reaction that involves the loss of water from the reacting molecule. Dehydration reactions are a subset of elimination reactions...

reversible isomerisation
3 cis-Aconitate +
H2O
Isocitrate
Isocitric acid
Isocitric acid is a protonated form of isocitrate, which is a substrate of the citric acid cycle. Isocitrate is formed from citrate with the help of the enzyme aconitase, and is acted upon by isocitrate dehydrogenase...

Hydration
Hydration reaction
In organic chemistry, a hydration reaction is a chemical reaction in which a hydroxyl group and a hydrogen cation are added to the two carbon atoms bonded together in the carbon-carbon double bond which makes up an alkene functional group. The reaction usually runs in a strong acidic, aqueous...

4 Isocitrate +
NAD
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...

+
Oxalosuccinate
Oxalosuccinic acid
Oxalosuccinic acid is a substrate of the citric acid cycle. It is acted upon by isocitrate dehydrogenase. Salts and esters of oxalosuccinic acid are known as oxalosuccinates....

 +
NADH + H +
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...

Isocitrate dehydrogenase
Isocitrate dehydrogenase
Isocitrate dehydrogenase and , also known as IDH, is an enzyme that participates in the citric acid cycle. It catalyzes the third step of the cycle: the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate and CO2 while converting NAD+ to NADH...

Oxidation generates NADH (equivalent of 2.5 ATP)
5 Oxalosuccinate α-Ketoglutarate +
CO2
Decarboxylation
Decarboxylation
Decarboxylation is a chemical reaction that releases carbon dioxide . Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is the first chemical step in photosynthesis, is called carbonation, the addition of CO2 to...

rate-limiting, irreversible stage,
generates a 5C molecule
6 α-Ketoglutarate +
NAD+ +
CoA-SH
Succinyl-CoA
Succinyl-CoA
Succinyl-Coenzyme A, abbreviated as Succinyl-CoA or SucCoA, is a combination of succinic acid and coenzyme A.-Source:It is an important intermediate in the citric acid cycle, where it is synthesized from α-Ketoglutarate by α-ketoglutarate dehydrogenase through decarboxylation...

 +
NADH + H+ +
CO2
α-Ketoglutarate dehydrogenase Oxidative
decarboxylation
Decarboxylation
Decarboxylation is a chemical reaction that releases carbon dioxide . Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is the first chemical step in photosynthesis, is called carbonation, the addition of CO2 to...

irreversible stage,
generates NADH (equivalent of 2.5 ATP),
regenerates the 4C chain (CoA excluded)
7 Succinyl-CoA
Succinyl-CoA
Succinyl-Coenzyme A, abbreviated as Succinyl-CoA or SucCoA, is a combination of succinic acid and coenzyme A.-Source:It is an important intermediate in the citric acid cycle, where it is synthesized from α-Ketoglutarate by α-ketoglutarate dehydrogenase through decarboxylation...

 +
GDP
Guanosine diphosphate
Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside guanosine. GDP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase guanine....

 + Pi
Succinate
Succinic acid
Succinic acid is a dicarboxylic acid. Succinate plays a biochemical role in the citric acid cycle. The name derives from Latin succinum, meaning amber, from which the acid may be obtained....

  +
CoA-SH +
GTP
Guanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...

Succinyl-CoA synthetase
Succinyl coenzyme A synthetase
Succinyl Coenzyme A Synthetase is an enzyme that catalyzes the reversible reaction of succinyl-CoA to succinate...

substrate-level phosphorylation
Substrate-level phosphorylation
Substrate-level phosphorylation is a type of metabolism that results in the formation and creation of adenosine triphosphate or guanosine triphosphate by the direct transfer and donation of a phosphoryl group to adenosine diphosphate or guanosine diphosphate from a phosphorylated reactive...

or ADP
Adenosine diphosphate
Adenosine diphosphate, abbreviated ADP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside adenosine. ADP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase adenine....

ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...

 instead of GDP→GTP,
generates 1 ATP or equivalent
8 Succinate +
ubiquinone (Q)
Fumarate
Fumaric acid
Fumaric acid or trans-butenedioic acid is the chemical compound with the formula HO2CCH=CHCO2H. This white crystalline compound is one of two isomeric unsaturated dicarboxylic acids, the other being maleic acid. In fumaric acid the carboxylic acid groups are trans and in maleic acid they are cis...

 +
ubiquinol
Ubiquinol
Ubiquinol is an electron-rich form of coenzyme Q10.The natural ubiquinol form of coenzyme Q10 is 2,3-dimethoxy-5-methyl-6-poly prenyl-1,4-benzoquinol, where the polyprenylated side chain is 9-10 units long in mammals...

 (QH2)
Succinate dehydrogenase Oxidation uses FAD
FAD
In biochemistry, flavin adenine dinucleotide is a redox cofactor involved in several important reactions in metabolism. FAD can exist in two different redox states, which it converts between by accepting or donating electrons. The molecule consists of a riboflavin moiety bound to the phosphate...

 as a prosthetic group (FAD→FADH2 in the first step of the reaction) in the enzyme,
generates the equivalent of 1.5 ATP
9 Fumarate +
H2O
L-Malate
Malic acid
Malic acid is an organic compound with the formula HO2CCH2CHOHCO2H. It is a dicarboxylic acid which is made by all living organisms, contributes to the pleasantly sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric forms , though only the L-isomer exists...

Fumarase
Fumarase
Fumarase is an enzyme that catalyzes the reversible hydration/dehydration of Fumarate to malate. Fumarase comes in two forms: mitochondrial and cytosolic...

Hydration
Hydration reaction
In organic chemistry, a hydration reaction is a chemical reaction in which a hydroxyl group and a hydrogen cation are added to the two carbon atoms bonded together in the carbon-carbon double bond which makes up an alkene functional group. The reaction usually runs in a strong acidic, aqueous...

10 L-Malate
Malate
Malate is the ionized form of malic acid. It is an important chemical compound in biochemistry. In the C4 carbon fixation process, malate is a source of CO2 in the Calvin cycle....

 +
NAD+
Oxaloacetate +
NADH + H+
Malate dehydrogenase
Malate dehydrogenase
Malate dehydrogenase is an enzyme in the citric acid cycle that catalyzes the conversion of malate into oxaloacetate and vice versa...

Oxidation reversible (in fact, equilibrium favors malate), generates NADH (equivalent of 2.5 ATP)


Mitochondria in animals, including humans, possess two succinyl-CoA synthetases: one that produces GTP from GDP, and another that produces ATP from ADP. Plants have the type that produces ATP (ADP-forming succinyl-CoA synthetase). Several of the enzymes in the cycle may be loosely-associated in a multienzyme protein complex
Protein complex
A multiprotein complex is a group of two or more associated polypeptide chains. If the different polypeptide chains contain different protein domain, the resulting multiprotein complex can have multiple catalytic functions...

 within the mitochondrial matrix
Mitochondrial matrix
In the mitochondrion, the matrix contains soluble enzymes that catalyze the oxidation of pyruvate and other small organic molecules.The mitochondrial matrix also contains the mitochondria's DNA and ribosomes. The word "matrix" stems from the fact that this space is viscous, compared to the...

.

The GTP that is formed by GDP-forming succinyl-CoA synthetase may be utilized by nucleoside-diphosphate kinase
Nucleoside-diphosphate kinase
Nucleoside-diphosphate kinases are enzymes that catalyze the exchange of phosphate groups between different nucleoside diphosphates...

 to form ATP (the catalyzed reaction is GTP + ADP → GDP + ATP).

Products


Products of the first turn of the cycle are: one GTP (or ATP), three NADH, one QH2, two CO2.

Because two acetyl-CoA molecules are produced from each glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

 molecule, two cycles are required per glucose molecule. Therefore, at the end of two cycles, the products are: two GTP, six NADH, two QH2, and four CO2
Description Reactants Products
>-
| The sum of all reactions in the citric acid cycle is:
Acetyl-CoA + 3 NAD+ + Q + GDP + Pi + 2 H2O + + QH2 + GTP + 2 CO2
>-
| Combining the reactions occurring during the pyruvate oxidation with those occurring during the citric acid cycle, the following overall pyruvate oxidation reaction is obtained:
Pyruvate ion + 4 NAD+ + Q + GDP + Pi + 2 H2O + + QH2 + GTP + 3 CO2
>-
| Combining the above reaction with the ones occurring in the course of glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...

, the following overall glucose oxidation reaction (excluding reactions in the respiratory chain) is obtained:
Glucose + 10 NAD+ + 2 Q + 2 ADP + 2 GDP + 4 Pi + 2 H2O → 10 NADH + 10 H+ + 2 QH2 + 2 ATP + 2 GTP + 6 CO2


The above reactions are balanced if Pi represents the H2PO4- ion, ADP and GDP the ADP2- and GDP2- ions, respectively, and ATP and GTP the ATP3- and GTP3- ions, respectively.

The total number of ATP obtained after complete oxidation of one glucose in glycolysis, citric acid cycle, and oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...

 is estimated to be between 30 and 38. A recent assessment of the total ATP yield with the updated proton-to-ATP ratios provides an estimate of 29.85 ATP per glucose molecule.

Regulation


Although pyruvate dehydrogenase is not technically a part of the citric acid cycle, its regulation is included here.

The regulation of the TCA cycle is largely determined by substrate availability and product inhibition. NADH, a product of all dehydrogenases in the TCA cycle with the exception of succinate dehydrogenase, inhibits pyruvate dehydrogenase
Pyruvate dehydrogenase
Pyruvate dehydrogenase complex is a complex of three enzymes that transform pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. 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...

, isocitrate dehydrogenase
Isocitrate dehydrogenase
Isocitrate dehydrogenase and , also known as IDH, is an enzyme that participates in the citric acid cycle. It catalyzes the third step of the cycle: the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate and CO2 while converting NAD+ to NADH...

, α-ketoglutarate dehydrogenase, and also citrate synthase
Citrate synthase
The enzyme citrate synthase exists in nearly all living cells and stands as a pace-making enzyme in the first step of the Citric Acid Cycle . Citrate synthase is localized within eukaryotic cells in the mitochondrial matrix, but is encoded by nuclear DNA rather than mitochondrial...

. Acetyl-coA
Acetyl-CoA
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 to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...

 inhibits pyruvate dehydrogenase
Pyruvate dehydrogenase
Pyruvate dehydrogenase complex is a complex of three enzymes that transform pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. 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...

, while succinyl-CoA
Succinyl-CoA
Succinyl-Coenzyme A, abbreviated as Succinyl-CoA or SucCoA, is a combination of succinic acid and coenzyme A.-Source:It is an important intermediate in the citric acid cycle, where it is synthesized from α-Ketoglutarate by α-ketoglutarate dehydrogenase through decarboxylation...

 inhibits succinyl-CoA synthetase and citrate synthase
Citrate synthase
The enzyme citrate synthase exists in nearly all living cells and stands as a pace-making enzyme in the first step of the Citric Acid Cycle . Citrate synthase is localized within eukaryotic cells in the mitochondrial matrix, but is encoded by nuclear DNA rather than mitochondrial...

. When tested in vitro with TCA enzymes, ATP inhibits citrate synthase
Citrate synthase
The enzyme citrate synthase exists in nearly all living cells and stands as a pace-making enzyme in the first step of the Citric Acid Cycle . Citrate synthase is localized within eukaryotic cells in the mitochondrial matrix, but is encoded by nuclear DNA rather than mitochondrial...

 and α-ketoglutarate dehydrogenase; however, ATP levels do not change more than 10% in vivo between rest and vigorous exercise. There is no known allosteric mechanism that can account for large changes in reaction rate from an allosteric effector whose concentration changes less than 10%.

Calcium is used as a regulator. It activates pyruvate dehydrogenase
Pyruvate dehydrogenase
Pyruvate dehydrogenase complex is a complex of three enzymes that transform pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. 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...

, isocitrate dehydrogenase
Isocitrate dehydrogenase
Isocitrate dehydrogenase and , also known as IDH, is an enzyme that participates in the citric acid cycle. It catalyzes the third step of the cycle: the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate and CO2 while converting NAD+ to NADH...

 and α-ketoglutarate dehydrogenase. This increases the reaction rate of many of the steps in the cycle, and therefore increases flux throughout the pathway.

Citrate is used for feedback inhibition, as it inhibits phosphofructokinase
Phosphofructokinase
Phosphofructokinase-1 is the most important regulatory enzyme of glycolysis. It is an allosteric enzyme made of 4 subunits and controlled by many activators and inhibitors...

, an enzyme involved in glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...

 that catalyses formation of fructose 1,6-bisphosphate
Fructose 1,6-bisphosphate
Fructose 1,6-bisphosphate is fructose sugar phosphorylated on carbons 1 and 6 . The β-D-form of this compound is very common in cells...

,a precursor of pyruvate. This prevents a constant high rate of flux when there is an accumulation of citrate and a decrease in substrate for the enzyme.

Recent work has demonstrated an important link between intermediates of the citric acid cycle and the regulation of hypoxia-inducible factors (HIF
HIF1A
Hypoxia-inducible factor 1, alpha subunit , also known as HIF1A, is a protein that in humans is encoded by the HIF1A gene...

). HIF plays a role in the regulation of oxygen homeostasis, and is a transcription factor that targets angiogenesis, vascular remodeling, glucose utilization, iron transport and apoptosis. HIF is synthesized consititutively, and hydroxylation of at least one of two critical proline residues mediates their interaction with the von Hippel Lindau E3 ubiquitin ligase complex, which targets them for rapid degradation. This reaction is catalysed by prolyl 4-hydroxylase
Prolyl hydroxylase
Prolyl hydroxylase is an enzyme involved in the production of collagen, acting to hydroxylate proline to hydroxyproline....

s. Fumarate and succinate have been identified as potent inhibitors of prolyl hydroxylases, thus leading to the stabilisation of HIF.

Major metabolic pathways converging on the TCA cycle


Several catabolic pathways converge on the TCA cycle. Reactions that form intermediates of the TCA cycle in order to replenish them (especially during the scarcity of the intermediates) are called anaplerotic reactions
Anaplerotic reactions
Anaplerotic reactions are those that form intermediates of a metabolic pathway. Examples of such are found in the Tricarboxylic acid Cycle...

.

The citric acid cycle is the third step in carbohydrate catabolism
Carbohydrate catabolism
Carbohydrate catabolism is the breakdown of carbohydrates into smaller units. Carbohydrates literally undergo combustion to retrieve the large amounts of energy in their bonds...

 (the breakdown of sugars). Glycolysis breaks glucose (a six-carbon-molecule) down into pyruvate (a three-carbon molecule). In eukaryote
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...

s, pyruvate moves into the mitochondria
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...

. It is converted into acetyl-CoA by decarboxylation and enters the citric acid cycle.

In protein catabolism
Protein catabolism
Protein catabolism is the breakdown of proteins into amino acids and simple derivative compounds, for transport into the cell through the plasma membrane and ultimately for the polymerisation into new proteins via the use of ribonucleic acids and ribosomes...

, protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s are broken down by protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....

s into their constituent amino acids. The carbon backbone of these amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

s can become a source of energy by being converted to acetyl-CoA and entering into the citric acid cycle.

In fat catabolism, triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....

s are hydrolyzed
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...

 to break them into fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...

s and glycerol
Glycerol
Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...

. In the liver the glycerol can be converted into glucose via dihydroxyacetone phosphate and glyceraldehyde-3-phosphate by way of gluconeogenesis
Gluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....

. In many tissues, especially heart tissue, fatty acids are broken down through a process known as beta oxidation
Beta oxidation
Beta oxidation is the process by which fatty acids, in the form of Acyl-CoA molecules, are broken down in mitochondria and/or in peroxisomes to generate Acetyl-CoA, the entry molecule for the Citric Acid cycle....

, which results in acetyl-CoA, which can be used in the citric acid cycle. Beta oxidation of fatty acids with an odd number of methylene groups produces propionyl CoA, which is then converted into succinyl-CoA
Succinyl-CoA
Succinyl-Coenzyme A, abbreviated as Succinyl-CoA or SucCoA, is a combination of succinic acid and coenzyme A.-Source:It is an important intermediate in the citric acid cycle, where it is synthesized from α-Ketoglutarate by α-ketoglutarate dehydrogenase through decarboxylation...

 and fed into the citric acid cycle.

The total energy gained from the complete breakdown of one molecule of glucose by glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...

, the citric acid cycle, and oxidative phosphorylation equals about 30 ATP molecules, in eukaryotes. The citric acid cycle is called an amphibolic
Amphibolic
The term amphibolic is used to describe a biochemical pathway that involves both catabolism and anabolism. The citric acid cycle is a good example. The first reaction of the cycle, in which oxaloacetate condenses with acetate to form citrate is typically anabolic...

 pathway because it participates in both catabolism
Catabolism
Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, lipids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides, and amino...

 and anabolism
Anabolism
Anabolism is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy. One way of categorizing metabolic processes, whether at the cellular, organ or organism level is as 'anabolic' or as 'catabolic', which is the opposite...

.

See also

  • Calvin cycle
    Calvin cycle
    The Calvin cycle or Calvin–Benson-Bassham cycle or reductive pentose phosphate cycle or C3 cycle or CBB cycle is a series of biochemical redox reactions that take place in the stroma of chloroplasts in photosynthetic organisms...

  • Reverse (Reductive) Krebs cycle
    Reverse Krebs cycle
    The reverse Krebs cycle...

  • Glyoxylate cycle
    Glyoxylate cycle
    The glyoxylate cycle, a variation of the Tricarboxylic Acid Cycle, is an anabolic metabolic pathway occurring in plants, bacteria, protists, fungi and several microorganisms, such as E. coli and yeast. The glyoxylate cycle centers on the conversion of acetyl-CoA to succinate for the synthesis of...


External links