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The citric acid cycle (CAC) – also known as the TCA cycle (tricarboxylic acid cycle) or the Krebs cycle – is a series of
chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substance A chemical substance is a form of matter In classical physics and general chemistry, matter is any substance that has mass and t ...

chemical reaction
s to release stored energy through the
oxidation Redox (reduction–oxidation, pronunciation: or ) is a type of chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substance A chemical substance is a form of matter ...

oxidation
of
acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reaction Biochemistry or biological chemistry, is the study of chemical processes within and relating to living organism In biology, an organism (from ...

acetyl-CoA
derived from
carbohydrate A carbohydrate () is a biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a ...
s,
fat In nutrition Nutrition is the biochemical Biochemistry or biological chemistry, is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided ...

fat
s, and
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
s. The Krebs cycle is used by
organisms In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological me ...

organisms
that respire (as opposed to organisms that
ferment Fermentation is a metabolism, metabolic process that produces chemical changes in organic Substrate (chemistry), substrates through the action of enzymes. In biochemistry, it is narrowly defined as the extraction of energy from carbohydrates in ...

ferment
) to generate energy, either by
anaerobic respiration Anaerobic respiration is respiration Respiration may refer to: Biology * Cellular respiration, the process in which nutrients are converted into useful energy in a cell ** Anaerobic respiration, cellular respiration without oxygen ** Maintenan ...
or
aerobic respiration Aerobic means "requiring air File:Atmosphere gas proportions.svg, Composition of Earth's atmosphere by volume, excluding water vapor. Lower pie represents trace gases that together compose about 0.043391% of the atmosphere (0.04402961% at Apr ...
. In addition, the cycle provides precursors of certain
amino acids Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, a ...

amino acids
, as well as the
reducing agent A reducing agent (also called a reductant, reducer, or electron donor) is an element or compound that loses or "donates" an electron The electron is a subatomic particle (denoted by the symbol or ) whose electric charge is negative one ele ...
NADH Nicotinamide adenine dinucleotide (NAD) is a Cofactor (biochemistry), coenzyme central to metabolism. Found in all living cell (biology), cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate ...
, 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 Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life Life is a characteristic that distinguishes physical entities A bubble of exhaled gas in water In common usage and classical mechanics, a phys ...

metabolism
and may have originated abiogenically. Even though it is branded as a 'cycle', it is not necessary for
metabolite In biochemistry Biochemistry or biological chemistry, is the study of es within and relating to living s. A sub-discipline of both and , biochemistry may be divided into three fields: , and . Over the last decades of the 20th century, bio ...
s to follow only one specific route; at least three alternative segments of the citric acid cycle have been recognized. The name of this metabolic pathway is derived from the
citric acid Citric acid is an organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, ...

citric acid
(a
tricarboxylic acid A tricarboxylic acid is an organic chemistry, organic carboxylic acid whose chemical structure contains three carboxyl group, carboxyl functional groups (-COOH). The best-known example of a tricarboxylic acid is citric acid. Uses Citric acid cy ...
, often called citrate, as the ionized form predominates at biological pH) that is consumed and then regenerated by this sequence of reactions to complete the cycle. The cycle consumes acetate (in the form of
acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reaction Biochemistry or biological chemistry, is the study of chemical processes within and relating to living organism In biology, an organism (from ...

acetyl-CoA
) and
water Water (chemical formula H2O) is an Inorganic compound, inorganic, transparent, tasteless, odorless, and Color of water, nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known li ...

water
, reduces NAD+ to NADH, releasing carbon dioxide. The NADH generated by the citric acid cycle is fed into the
oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell (biology), c ...

oxidative phosphorylation
(electron transport) pathway. The net result of these two closely linked pathways is the oxidation of
nutrient A nutrient is a substance Substance may refer to: * Substance (Jainism), a term in Jain ontology to denote the base or owner of attributes * Chemical substance, a material with a definite chemical composition * Matter, anything that has mass and t ...
s to produce usable chemical energy in the form of
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals * American Technical Publishers * ', a Danish pension * Armenia Tree Project * Association for Transpersonal Psychology * ATP architects engineers office * ATP ...

ATP
. In
eukaryotic Eukaryotes () are organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interact ...
cells, the citric acid cycle occurs in the matrix of the
mitochondrion A mitochondrion (; ) is a double-membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Biological membranes include cell membranes ...

mitochondrion
. In
prokaryotic A prokaryote () is a single-celled organism A unicellular organism, also known as a single-celled organism, is an organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individual conti ...
cells, such as bacteria, which lack mitochondria, the citric acid cycle reaction sequence is performed in the cytosol with the proton gradient for being across the cell's surface (
plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane A biological membrane, biomembrane or cell membrane is a selectively permeable membra ...

plasma membrane
) rather than the inner membrane of the
mitochondrion A mitochondrion (; ) is a double-membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Biological membranes include cell membranes ...

mitochondrion
. The overall yield of energy-containing compounds from the TCA cycle is three NADH, one , and one GTP.


Discovery

Several of the components and reactions of the citric acid cycle were established in the 1930s by the research of
Albert Szent-Györgyi Albert Szent-Györgyi de Nagyrápolt (September 16, 1893 – October 22, 1986) was a Hungarian biochemist Biochemists are scientists who are trained in biochemistry Biochemistry or biological chemistry, is the study of chemical proces ...
, who received the
Nobel Prize in Physiology or Medicine The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly , native_name_lang = , image = Nobel Assembly at Karolinska Institutet.jpeg , size = , motto = , formation = 190113 March 1978(as a forma ...
in 1937 specifically for his discoveries pertaining to
fumaric acid Fumaric acid is an organic compound , CH4; is among the simplest organic compounds. In chemistry Chemistry is the scientific discipline involved with Chemical element, elements and chemical compound, compounds composed of atoms, molecules a ...

fumaric acid
, a key component of the cycle. He made this discovery by studying pigeon breast muscle. Because this tissue maintains its oxidative capacity well after breaking down in the Latapie mill and releasing in aqueous solutions, breast muscle of the pigeon was very well qualified for the study of oxidative reactions. The citric acid cycle itself was finally identified in 1937 by
Hans Adolf Krebs Sir Hans Adolf Krebs (; 25 August 1900 – 22 November 1981) was a German-born British biologist Francesco Redi, the founder of biology, is recognized to be one of the greatest biologists of all time A biologist is a professional who has s ...

Hans Adolf Krebs
and William Arthur Johnson while at the
University of Sheffield , mottoeng = To discover the causes of things , established = – University of SheffieldPredecessor institutions: – Sheffield Medical School , mottoeng = Art is long, life is short , established = 1828 – Sheffield School ...
, for which the former received the
Nobel Prize for Physiology or Medicine The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly , native_name_lang = , image = Nobel Assembly at Karolinska Institutet.jpeg , size = , motto = , formation = 190113 March 1978(as a formal ...
in 1953, and for whom the cycle is sometimes named the "Krebs cycle".


Overview

The citric acid cycle is a key
metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell (biology), cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence ...
that connects
carbohydrate A carbohydrate () is a biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a ...
,
fat In nutrition Nutrition is the biochemical Biochemistry or biological chemistry, is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided ...

fat
, and
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life Life is a characteristic that distinguishes physical entities A bubble of exhaled gas in water In common usage and classical mechanics, a phys ...

metabolism
. The
reaction Reaction may refer to a process or to a response to an action, event, or exposure: Physics and chemistry *Chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformat ...

reaction
s of the cycle are carried out by eight
enzymes Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates int ...
that completely oxidize
acetate An acetate is a salt formed by the combination of acetic acid with a base (e.g. alkaline, earthy, metallic, nonmetal image:Simple Periodic Table Chart-en.svg, upright=1.75, Nonmetals (and metalloids) in the periodic table: Metalloids are i ...

acetate
(a two carbon molecule), in the form of acetyl-CoA, into two molecules each of carbon dioxide and water. Through
catabolism Catabolism () is the set of metabolic Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life Life is a characteristic that distinguishes physical entities that have biological processes, such as Cell ...

catabolism
of sugars, fats, and proteins, the two-carbon organic product acetyl-CoA is produced which enters the citric acid cycle. The reactions of the cycle also convert three equivalents of
nicotinamide adenine dinucleotide Nicotinamide adenine dinucleotide (NAD) is a coenzyme A cofactor is a non-protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino acid residue (biochemistry), residues. Proteins p ...
(NAD+) into three equivalents of reduced NAD+ (NADH), one equivalent of
flavin adenine dinucleotide In biochemistry Biochemistry or biological chemistry, is the study of chemical process In a scientific Science () is a systematic enterprise that Scientific method, builds and organizes knowledge in the form of Testability, testable ...

flavin adenine dinucleotide
(FAD) into one equivalent of , and one equivalent each of
guanosine diphosphate Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers deoxyribonucleic acid (DNA) and ribonucl ...
(GDP) and inorganic
phosphate In chemistry, a phosphate is an anion, salt (chemistry), salt, functional group or ester derived from a phosphoric acids and phosphates, phosphoric acid. It most commonly means orthophosphate, a derivative of phosphoric acid, orthophosphoric a ...

phosphate
(Pi) into one equivalent of
guanosine triphosphate Guanosine-5'-triphosphate (GTP) is a purine Purine is a heterocyclic 125px, Pyridine, a heterocyclic compound A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different chemical element, elemen ...
(GTP). The NADH and FADH2 generated by the citric acid cycle are, in turn, used by the
oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell (biology), c ...

oxidative phosphorylation
pathway to generate energy-rich ATP. One of the primary sources of acetyl-CoA is from the breakdown of sugars by
glycolysis Glycolysis is the metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of on ...

glycolysis
which yield
pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid A carboxylic acid is an organic acid that contains a carboxyl group (C(=O)OH) attached to an R-group. The general formula of a carboxylic acid is R ...

pyruvate
that in turn is decarboxylated by the
pyruvate dehydrogenase complex Pyruvate dehydrogenase complex (PDC) is a complex of three enzymes that converts 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 ...
generating acetyl-CoA according to the following reaction scheme: The product of this reaction, acetyl-CoA, is the starting point for the citric acid cycle.
Acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reaction Biochemistry or biological chemistry, is the study of chemical processes within and relating to living organism In biology, an organism (from ...
may also be obtained from the oxidation of
fatty acids In chemistry Chemistry is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts A fact is an occurrence in ...
. Below is a schematic outline of the cycle: * The
citric acid Citric acid is an organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, ...

citric acid
cycle begins with the transfer of a two-carbon
acetyl In organic chemistry Organic chemistry is a branch of that studies the structure, properties and reactions of s, which contain in .Clayden, J.; Greeves, N. and Warren, S. (2012) ''Organic Chemistry''. Oxford University Press. pp. 1–15. . ...

acetyl
group from acetyl-CoA 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 A carboxylic acid is an organic acid An organic acid is an organic compound In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: th ...

carboxyl
groups as . 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 Anabolism () is the set of metabolic pathway In biochemistry Biochemistry or biological chemistry, is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be d ...
, they might not be lost, since many citric acid cycle intermediates are also used as precursors for the
biosynthesis Biosynthesis is a multi-step, enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and ...

biosynthesis
of other molecules. * Most of the electrons made available by the oxidative steps of the cycle are transferred to NAD+, forming NADH. For each acetyl group that enters the citric acid cycle, three molecules of NADH are produced. The citric acid cycle includes a series of oxidation reduction reaction in mitochondria. * In addition, electrons from the succinate oxidation step are transferred first to the
FAD A fad is any form of collective behavior that develops within a culture, a generation or social group in which a group of people enthusiastically follow an impulse (psychology), impulse for a short period. Fads are objects or behaviors that ach ...
cofactor of succinate dehydrogenase, reducing it to FADH2, and eventually to
ubiquinone Coenzyme Q, also known as ubiquinone, is a coenzyme A cofactor is a non-protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallog ...

ubiquinone
(Q) in the
mitochondrial membrane A mitochondrion (, plural mitochondria) is a double lipid bilayer, membrane-bound organelle found in most eukaryotic organisms. Some cells in some multicellular organisms lack mitochondria (for example, mature mammalian red blood cells). A numbe ...

mitochondrial membrane
, reducing it to
ubiquinol Ubiquinol is an electron-rich (reduced) form of coenzyme Q10, 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. Co ...

ubiquinol
(QH2) which is a substrate of the
electron transfer chain is the site of oxidative phosphorylation in eukaryote Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus enclosed within a nuclear envelope. Eukaryotes belong to the Domain (biology), domain Eukaryota or Euk ...

electron transfer chain
at the level of
Complex III Complex commonly refers to: * Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe ** Complex system, a system composed of many components which may interact with each ...

Complex III
. * For every NADH and FADH2 that are produced in the citric acid cycle, 2.5 and 1.5 ATP molecules are generated in oxidative
phosphorylation In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior and the changes they undergo during ...

phosphorylation
, respectively. * At the end of each cycle, the four-carbon
oxaloacetate Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound , CH4; is among the simplest organic compounds. In chemistry Chemistry is the scientific discipline involved with Chemical element, elements and chemi ...

oxaloacetate
has been regenerated, and the cycle continues.


Steps

There are ten basic steps in the citric acid cycle, as outlined below. The cycle is continuously supplied with new carbon in the form of
acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reaction Biochemistry or biological chemistry, is the study of chemical processes within and relating to living organism In biology, an organism (from ...

acetyl-CoA
, entering at step 0 in the table. Two
carbon Carbon (from la, carbo "coal") is a with the C and 6. It is lic and —making four s available to form s. It belongs to group 14 of the periodic table. Carbon makes up only about 0.025 percent of Earth's crust. Three occur naturally, ...

carbon
atoms are
oxidized (mild reducing agent) are added to powdered potassium permanganate (strong oxidizing agent), a violent redox reaction accompanied by self-ignition starts. Redox (reduction–oxidation, pronunciation: or ) is a type of chemical reaction A ...

oxidized
to , the energy from these reactions is transferred to other metabolic processes through GTP (or ATP), and as electrons in
NADH Nicotinamide adenine dinucleotide (NAD) is a Cofactor (biochemistry), coenzyme central to metabolism. Found in all living cell (biology), cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate ...
and . The NADH generated in the citric acid cycle may later be oxidized (donate its electrons) to drive in a type of process called
oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell (biology), c ...

oxidative phosphorylation
. is covalently attached to
succinate dehydrogenase Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules up ...

succinate dehydrogenase
, an enzyme which functions both in the CAC and the mitochondrial
electron transport chain An electron transport chain (ETC) is a series of protein complex A protein complex or multiprotein complex is a group of two or more associated polypeptide chain Peptides (from Greek language Greek (modern , romanized: ''Elliniká'', Anc ...

electron transport chain
in oxidative phosphorylation. FADH2, therefore, facilitates transfer of electrons to coenzyme Q, 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 An electron transport chain (ETC) is a series of protein complex A protein complex or multiprotein complex is a group of two or more associated polypeptide chain Peptides (from Greek language Greek (modern , romanized: ''Elliniká'', Anc ...

electron transport chain
. Mitochondria in animals, including humans, possess two
succinyl-CoA Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a thioester of succinic acid Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. The name derives from Latin ''succinum'', meaning amber. In livin ...

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 A protein complex or multiprotein complex is a group of two or more associated polypeptide chain Peptides (from Greek language Greek (modern , romanized: ''Elliniká'', Ancient Greek, ancient , ''Hellēnikḗ'') is an independent branch of ...
within the
mitochondrial matrix 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 mitochondria's DNA, riboso ...
. The GTP that is formed by GDP-forming succinyl-CoA synthetase may be utilized by nucleoside-diphosphate kinase 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 ATP may refer to: Companies and organizations * Association of Tennis Professionals * American Technical Publishers * ', a Danish pension * Armenia Tree Project * Association for Transpersonal Psychology * ATP architects engineers office * ATP ...

ATP
), three
NADH Nicotinamide adenine dinucleotide (NAD) is a Cofactor (biochemistry), coenzyme central to metabolism. Found in all living cell (biology), cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate ...
, one and two . Because two acetyl-CoA
molecules A molecule is an electrically Electricity is the set of physical phenomena associated with the presence and motion Image:Leaving Yongsan Station.jpg, 300px, Motion involves a change in position In physics, motion is the phenomenon ...

molecules
are produced from each
glucose Glucose is a simple with the . Glucose is the most abundant , a subcategory of s. Glucose is mainly made by and most during from water and carbon dioxide, using energy from sunlight, where it is used to make in s, the most abundant carbohydr ...

glucose
molecule, two cycles are required per glucose molecule. Therefore, at the end of two cycles, the products are: two GTP, six NADH, two , and four . 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 molecules obtained after complete oxidation of one glucose in glycolysis, citric acid cycle, and
oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell (biology), c ...

oxidative phosphorylation
is estimated to be between 30 and 38.


Efficiency

The theoretical maximum yield of
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals * American Technical Publishers * ', a Danish pension * Armenia Tree Project * Association for Transpersonal Psychology * ATP architects engineers office * ATP ...

ATP
through oxidation of one molecule of glucose in glycolysis, citric acid cycle, and
oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell (biology), c ...

oxidative phosphorylation
is 38 (assuming 3 molar equivalents of ATP per equivalent NADH and 2 ATP per FADH2). In eukaryotes, two equivalents of NADH and four equivalents of ATP are generated in
glycolysis Glycolysis is the metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of on ...

glycolysis
, which takes place in the
cytoplasm In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes ...
. Transport of two of these equivalents of NADH into the mitochondria consumes two equivalents of ATP, thus reducing the net production of ATP to 36. Furthermore, inefficiencies in
oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell (biology), c ...

oxidative phosphorylation
due to leakage of protons across the
mitochondrial membrane A mitochondrion (, plural mitochondria) is a double lipid bilayer, membrane-bound organelle found in most eukaryotic organisms. Some cells in some multicellular organisms lack mitochondria (for example, mature mammalian red blood cells). A numbe ...

mitochondrial membrane
and slippage of the
ATP synthase ATP synthase is a protein that catalyzes the formation of the energy storage molecule adenosine triphosphate (ATP) using adenosine diphosphate (ADP) and inorganic phosphate (Pi). It is classified under ligases as it changes ADP by the formation of ...

ATP synthase
/proton pump commonly reduces the ATP yield from NADH and to less than the theoretical maximum yield. The observed yields are, therefore, closer to ~2.5 ATP per NADH and ~1.5 ATP per FADH2, further reducing the total net production of ATP to approximately 30. An assessment of the total ATP yield with newly revised proton-to-ATP ratios provides an estimate of 29.85 ATP per glucose molecule.


Variation

While the citric acid cycle is in general highly conserved, there is significant variability in the enzymes found in different taxa (note that the diagrams on this page are specific to the mammalian pathway variant). Some differences exist between eukaryotes and prokaryotes. The conversion of D-''threo''-isocitrate to 2-oxoglutarate is catalyzed in eukaryotes by the NAD+-dependen
EC 1.1.1.41
while prokaryotes employ the NADP+-dependen
EC 1.1.1.42
Similarly, the conversion of (''S'')-malate to oxaloacetate is catalyzed in eukaryotes by the NAD+-dependen
EC 1.1.1.37
while most prokaryotes utilize a quinone-dependent enzyme
EC 1.1.5.4
A step with significant variability is the conversion of succinyl-CoA to succinate. Most organisms utiliz
EC 6.2.1.5
succinate–CoA ligase (ADP-forming) (despite its name, the enzyme operates in the pathway in the direction of ATP formation). In mammals a GTP-forming enzyme, succinate–CoA ligase (GDP-forming)
EC 6.2.1.4
also operates. The level of utilization of each isoform is tissue dependent. In some acetate-producing bacteria, such as ''Acetobacter aceti'', an entirely different enzyme catalyzes this conversion 
EC 2.8.3.18
succinyl-CoA:acetate CoA-transferase. This specialized enzyme links the TCA cycle with acetate metabolism in these organisms. Some bacteria, such as ''Helicobacter pylori'', employ yet another enzyme for this conversion – succinyl-CoA:acetoacetate CoA-transferase
EC 2.8.3.5
. Some variability also exists at the previous step – the conversion of 2-oxoglutarate to succinyl-CoA. While most organisms utilize the ubiquitous NAD+-dependent 2-oxoglutarate dehydrogenase, some bacteria utilize a ferredoxin-dependent 2-oxoglutarate
synthase In biochemistry Biochemistry or biological chemistry, is the study of es within and relating to living s. A sub-discipline of both and , biochemistry may be divided into three fields: , and . Over the last decades of the 20th century, bioch ...

EC 1.2.7.3
. Other organisms, including obligately autotrophic and methanotrophic bacteria and archaea, bypass succinyl-CoA entirely, and convert 2-oxoglutarate to succinate via succinate semialdehyde, usin
EC 4.1.1.71
2-oxoglutarate decarboxylase, an
EC 1.2.1.79
succinate-semialdehyde dehydrogenase. In
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumor A benign tumor is a mass of cells Cell most often refers to: * Cell (biolo ...

cancer
, there are substantial metabolic derangements that occur to ensure the proliferation of tumor cells, and consequently metabolites can accumulate which serve to facilitate
tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with ...
, dubbed onco
metabolites In biochemistry, a metabolite is an intermediate or end product of metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main purposes of metabo ...

metabolites
. Among the best characterized oncometabolites is 2-hydroxyglutarate which is produced through a
heterozygous Zygosity (the noun, zygote, is from the Greek zygotos "yoked," from zygon "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an or ...

heterozygous
gain-of-function mutation (specifically a neomorphic one) in
isocitrate dehydrogenase Isocitrate dehydrogenase (IDH) () and () is an enzyme Enzymes () are protein Proteins are large s and s that comprise one or more long chains of . Proteins perform a vast array of functions within organisms, including , , , providin ...

isocitrate dehydrogenase
(IDH) (which under normal circumstances catalyzes the
oxidation Redox (reduction–oxidation, pronunciation: or ) is a type of chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substance A chemical substance is a form of matter ...

oxidation
of
isocitrate Isocitric acid is a structural isomer In chemistry Chemistry is the scientific discipline involved with Chemical element, elements and chemical compound, compounds composed of atoms, molecules and ions: their composition, structure, propertie ...
to
oxalosuccinate 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. Oxalosuccinic acid/oxalosuccinate is an unstable 6-carbon intermediate ...
, which then spontaneously to
alpha-ketoglutarate α-Ketoglutaric acid (2-oxoglutaric acid) is one of two ketone In chemistry Chemistry is the scientific discipline involved with Chemical element, elements and chemical compound, compounds composed of atoms, molecules and ions: their ...
, as discussed above; in this case an additional reduction step occurs after the formation of alpha-ketoglutarate via
NADPH Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle The Calvin cycle, light-independent reactions, bio syn ...

NADPH
to yield 2-hydroxyglutarate), and hence IDH is considered an
oncogene An oncogene is a gene In biology, a gene (from ''genos'' "...Wilhelm Johannsen coined the word gene to describe the Mendelian_inheritance#History, Mendelian units of heredity..." (Greek language, Greek) meaning ''generation'' or ''birth'' ...

oncogene
. Under physiological conditions, 2-hydroxyglutarate is a minor product of several metabolic pathways as an error but readily converted to alpha-ketoglutarate via hydroxyglutarate dehydrogenase enzymes (
L2HGDH L-2-hydroxyglutarate dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ''L2HGDH'' gene, also known as C14orf160, on chromosome 14. Function This gene encodes L-2-hydroxyglutarate dehydrogenase, a flavin adenine dinucleo ...
and
D2HGDH D-2-hydroxyglutarate dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ''D2HGDH'' gene. This gene encodes D-2hydroxyglutarate dehydrogenase, a mitochondrial enzyme belonging to the FAD-binding oxidoreductase/transferase typ ...
) but does not have a known physiologic role in mammalian cells; of note, in cancer, 2-hydroxyglutarate is likely a terminal metabolite as isotope labelling experiments of colorectal cancer cell lines show that its conversion back to alpha-ketoglutarate is too low to measure. In cancer, 2-hydroxyglutarate serves as a
competitive inhibitor Competitive inhibition is interruption of a chemistry, chemical pathway owing to one chemical substance inhibiting the effect of another by competing with it for molecular binding, binding or chemical bond, bonding. Any metabolism, metabolic or c ...

competitive inhibitor
for a number of enzymes that facilitate reactions via alpha-ketoglutarate in alpha-ketoglutarate-dependent
dioxygenase Dioxygenases are oxidoreductase In biochemistry, an oxidoreductase is an enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are cal ...
s. This mutation results in several important changes to the metabolism of the cell. For one thing, because there is an extra NADPH-catalyzed reduction, this can contribute to depletion of cellular stores of NADPH and also reduce levels of alpha-ketoglutarate available to the cell. In particular, the depletion of NADPH is problematic because NADPH is highly compartmentalized and cannot freely diffuse between the organelles in the cell. It is produced largely via the
pentose phosphate pathway In chemistry, a pentose is a monosaccharide (simple sugar) with five carbon atom, atoms. The chemical formula of all pentoses is , and their molecular weight is 150.13 g/mol.
in the cytoplasm. The depletion of NADPH results in increased
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species Reactive oxygen species (ROS) are highly chemicals formed from O2. Examples of ROS include s, , , , and . The reduction of molecular oxygen ...
within the cell as it is a required cofactor in the production of , and this oxidative stress can result in DNA damage. There are also changes on the genetic and epigenetic level through the function of (KDMs) and ten-eleven translocation (TET) enzymes; ordinarily TETs hydroxylate to prime them for demethylation. However, in the absence of alpha-ketoglutarate this cannot be done and there is hence hypermethylation of the cell's DNA, serving to promote epithelial-mesenchymal transition (EMT) and inhibit cellular differentiation. A similar phenomenon is observed for the Jumonji C family of KDMs which require a hydroxylation to perform demethylation at the epsilon-amino methyl group. Additionally, the inability of prolyl hydroxylases to catalyze reactions results in stabilization of hypoxia-inducible factor alpha, which is necessary to promote degradation of the latter (as under conditions of low oxygen there will not be adequate substrate for hydroxylation). This results in a pseudohypoxic phenotype in the cancer cell that promotes angiogenesis, metabolic reprogramming, cell growth, and Cell migration, migration.


Regulation

Allosteric regulation by metabolites. The regulation of the citric acid cycle is largely determined by product inhibition and substrate availability. If the cycle were permitted to run unchecked, large amounts of Metabolism, metabolic energy could be wasted in overproduction of reduced coenzyme such as NADH and ATP. The major eventual substrate of the cycle is ADP which gets converted to ATP. A reduced amount of ADP causes accumulation of precursor NADH which in turn can inhibit a number of enzymes. NADH, a product of all dehydrogenases in the citric acid cycle with the exception of
succinate dehydrogenase Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules up ...

succinate dehydrogenase
, inhibits pyruvate dehydrogenase,
isocitrate dehydrogenase Isocitrate dehydrogenase (IDH) () and () is an enzyme Enzymes () are protein Proteins are large s and s that comprise one or more long chains of . Proteins perform a vast array of functions within organisms, including , , , providin ...

isocitrate dehydrogenase
, Alpha-ketoglutarate dehydrogenase, α-ketoglutarate dehydrogenase, and also citrate synthase. Acetyl-coA inhibits pyruvate dehydrogenase, while
succinyl-CoA Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a thioester of succinic acid Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. The name derives from Latin ''succinum'', meaning amber. In livin ...

succinyl-CoA
inhibits alpha-ketoglutarate dehydrogenase and citrate synthase. When tested in vitro with TCA enzymes, ATP inhibits citrate synthase and Alpha-ketoglutarate dehydrogenase, 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%. Citrate is used for feedback inhibition, as it inhibits phosphofructokinase, an enzyme involved in
glycolysis Glycolysis is the metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of on ...

glycolysis
that catalyses formation of fructose 1,6-bisphosphate, 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. Regulation by calcium. Calcium is also used as a regulator in the citric acid cycle. Calcium levels in the mitochondrial matrix can reach up to the tens of micromolar levels during cellular activation. It activates pyruvate dehydrogenase phosphatase which in turn activates the
pyruvate dehydrogenase complex Pyruvate dehydrogenase complex (PDC) is a complex of three enzymes that converts 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 ...
. Calcium also activates
isocitrate dehydrogenase Isocitrate dehydrogenase (IDH) () and () is an enzyme Enzymes () are protein Proteins are large s and s that comprise one or more long chains of . Proteins perform a vast array of functions within organisms, including , , , providin ...

isocitrate dehydrogenase
and Alpha-ketoglutarate dehydrogenase, α-ketoglutarate dehydrogenase. This increases the reaction rate of many of the steps in the cycle, and therefore increases flux throughout the pathway. Transcriptional regulation. Recent work has demonstrated an important link between intermediates of the citric acid cycle and the regulation of hypoxia-inducible factors (HIF1A, HIF). HIF plays a role in the regulation of oxygen homeostasis, and is a transcription factor that targets angiogenesis, Vascular remodelling in the embryo, vascular remodeling,
glucose Glucose is a simple with the . Glucose is the most abundant , a subcategory of s. Glucose is mainly made by and most during from water and carbon dioxide, using energy from sunlight, where it is used to make in s, the most abundant carbohydr ...

glucose
utilization, iron transport and apoptosis. HIF is synthesized constitutively, 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 hydroxylase, prolyl 4-hydroxylases. 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 citric acid cycle

Several catabolic pathways converge on the citric acid cycle. Most of these reactions add intermediates to the citric acid cycle, and are therefore known as anaplerotic reactions, from the Greek meaning to "fill up". These increase the amount of acetyl CoA that the cycle is able to carry, increasing the Mitochondrion (band), mitochondrion's capability to carry out respiration if this is otherwise a limiting factor. Processes that remove intermediates from the cycle are termed "cataplerotic" reactions. In this section and in the next, the citric acid cycle intermediates are indicated in ''italics'' to distinguish them from other substrates and end-products. Pyruvate molecules produced by
glycolysis Glycolysis is the metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of on ...

glycolysis
are active transport, actively transported across the inner Mitochondrion, mitochondrial membrane, and into the matrix. Here they can be Redox, oxidized and combined with coenzyme A to form CO2, ''
acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reaction Biochemistry or biological chemistry, is the study of chemical processes within and relating to living organism In biology, an organism (from ...

acetyl-CoA
'', and
NADH Nicotinamide adenine dinucleotide (NAD) is a Cofactor (biochemistry), coenzyme central to metabolism. Found in all living cell (biology), cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate ...
, as in the normal cycle. However, it is also possible for pyruvate to be carboxylated by pyruvate carboxylase to form ''oxaloacetate''. This latter reaction "fills up" the amount of ''oxaloacetate'' in the citric acid cycle, and is therefore an anaplerotic reaction, increasing the cycle's capacity to metabolize ''acetyl-CoA'' when the tissue's energy needs (e.g. in striated muscle tissue, muscle) are suddenly increased by activity. In the citric acid cycle all the intermediates (e.g. ''Citric acid, citrate'', ''iso-citrate'', ''Alpha-Ketoglutaric acid, alpha-ketoglutarate'', ''Succinic acid, succinate'', ''Fumaric acid, fumarate'', ''Malic acid, malate'', and ''
oxaloacetate Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound , CH4; is among the simplest organic compounds. In chemistry Chemistry is the scientific discipline involved with Chemical element, elements and chemi ...

oxaloacetate
'') are regenerated during each turn of the cycle. Adding more of any of these intermediates to the mitochondrion therefore means that that additional amount is retained within the cycle, increasing all the other intermediates as one is converted into the other. Hence the addition of any one of them to the cycle has an anaplerotic effect, and its removal has a cataplerotic effect. These anaplerotic and cataplerotic reactions will, during the course of the cycle, increase or decrease the amount of ''oxaloacetate'' available to combine with ''acetyl-CoA'' to form ''citric acid''. This in turn increases or decreases the rate of
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals * American Technical Publishers * ', a Danish pension * Armenia Tree Project * Association for Transpersonal Psychology * ATP architects engineers office * ATP ...

ATP
production by the mitochondrion, and thus the availability of ATP to the cell. ''Acetyl-CoA'', on the other hand, derived from pyruvate oxidation, or from the beta-oxidation of fatty acids, is the only fuel to enter the citric acid cycle. With each turn of the cycle one molecule of ''acetyl-CoA'' is consumed for every molecule of ''oxaloacetate'' present in the mitochondrial matrix, and is never regenerated. It is the oxidation of the acetate portion of ''acetyl-CoA'' that produces CO2 and water, with the energy of O2 thus released captured in the form of ATP. The three steps of beta-oxidation resemble the steps that occur in the production of oxaloacetate from succinate in the TCA cycle. Acyl-CoA is oxidized to trans-Enoyl-CoA while FAD is reduced to FADH2, which is similar to the oxidation of succinate to fumarate. FollowingTrans-2-enoyl-CoA reductase (NADPH), , trans-Enoyl-CoA is hydrated across the double bond to beta-hydroxyacyl-CoA, just like fumarate is hydrated to malate. Lastly, beta-hydroxyacyl-CoA is oxidized to beta-ketoacyl-CoA while NAD+ is reduced to NADH, which follows the same process as the oxidation of malate to
oxaloacetate Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound , CH4; is among the simplest organic compounds. In chemistry Chemistry is the scientific discipline involved with Chemical element, elements and chemi ...

oxaloacetate
. In the liver, the carboxylation of cytosolic pyruvate into intra-mitochondrial ''oxaloacetate'' is an early step in the gluconeogenesis, gluconeogenic pathway which converts lactic acid, lactate and de-aminated alanine into glucose, under the influence of high levels of glucagon and/or epinephrine in the blood. Here the addition of ''oxaloacetate'' to the mitochondrion does not have a net anaplerotic effect, as another citric acid cycle intermediate (''malate'') is immediately removed from the mitochondrion to be converted into cytosolic oxaloacetate, which is ultimately converted into glucose, in a process that is almost the reverse of
glycolysis Glycolysis is the metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of on ...

glycolysis
. In protein catabolism,
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
s are broken down by proteases into their constituent amino acids. Their carbon skeletons (i.e. the de-aminated amino acids) may either enter the citric acid cycle as intermediates (e.g. ''alpha-ketoglutarate'' derived from glutamate or glutamine), having an anaplerotic effect on the cycle, or, in the case of leucine, isoleucine, lysine, phenylalanine, tryptophan, and tyrosine, they are converted into ''acetyl-CoA'' which can be burned to CO2 and water, or used to form ketone bodies, which too can only be burned in tissues other than the liver where they are formed, or excreted via the urine or breath. These latter amino acids are therefore termed "ketogenic" amino acids, whereas those that enter the citric acid cycle as intermediates can only be cataplerotically removed by entering the gluconeogenic pathway via ''malate'' which is transported out of the mitochondrion to be converted into cytosolic oxaloacetate and ultimately into
glucose Glucose is a simple with the . Glucose is the most abundant , a subcategory of s. Glucose is mainly made by and most during from water and carbon dioxide, using energy from sunlight, where it is used to make in s, the most abundant carbohydr ...

glucose
. These are the so-called "glucogenic" amino acids. De-aminated alanine, cysteine, glycine, serine, and threonine are converted to pyruvate and can consequently either enter the citric acid cycle as ''oxaloacetate'' (an anaplerotic reaction) or as ''acetyl-CoA'' to be disposed of as CO2 and water. In fat catabolism, triglycerides are hydrolysis, hydrolyzed to break them into fatty acids and glycerol. In the liver the glycerol can be converted into glucose via dihydroxyacetone phosphate and glyceraldehyde-3-phosphate by way of gluconeogenesis. In many tissues, especially heart and skeletal muscle tissue,
fatty acids In chemistry Chemistry is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts A fact is an occurrence in ...
are broken down through a process known as beta oxidation, which results in the production of mitochondrial ''acetyl-CoA'', which can be used in the citric acid cycle. Beta oxidation of
fatty acids In chemistry Chemistry is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts A fact is an occurrence in ...
with an odd number of methylene bridges produces propionyl-CoA, which is then converted into ''
succinyl-CoA Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a thioester of succinic acid Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. The name derives from Latin ''succinum'', meaning amber. In livin ...

succinyl-CoA
'' and fed into the citric acid cycle as an anaplerotic intermediate. The total energy gained from the complete breakdown of one (six-carbon) molecule of glucose by
glycolysis Glycolysis is the metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of on ...

glycolysis
, the formation of 2 ''acetyl-CoA'' molecules, their catabolism in the citric acid cycle, and oxidative phosphorylation equals about 30 Adenosine triphosphate, ATP molecules, in Eukaryote, eukaryotes. The number of ATP molecules derived from the beta oxidation of a 6 carbon segment of a fatty acid chain, and the subsequent Redox, oxidation of the resulting 3 molecules of Acetyl-CoA carboxylase, ''acetyl-CoA'' is 40.


Citric acid cycle intermediates serve as substrates for biosynthetic processes

In this subheading, as in the previous one, the TCA intermediates are identified by ''italics''. Several of the citric acid cycle intermediates are used for the synthesis of important compounds, which will have significant cataplerotic effects on the cycle. ''Acetyl-CoA'' cannot be transported out of the mitochondrion. To obtain cytosolic acetyl-CoA, ''citrate'' is removed from the citric acid cycle and carried across the inner mitochondrial membrane into the cytosol. 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). The cytosolic acetyl-CoA is used for fatty acid synthesis and the Mevalonate pathway, production of cholesterol. Cholesterol can, in turn, be used to synthesize the Steroid#Steroidogenesis, steroid hormones, Bile acids, bile salts, and vitamin D. The carbon skeletons of many Essential amino acid, non-essential amino acids are made from citric acid cycle intermediates. To turn them into amino acids the Keto acid, alpha keto-acids formed from the citric acid cycle intermediates have to acquire their amino groups from glutamate in a transamination reaction, in which Pyridoxine, pyridoxal phosphate is a cofactor. In this reaction the glutamate is converted into alpha-Ketoglutaric acid, ''alpha-ketoglutarate'', which is a citric acid cycle intermediate. The intermediates that can provide the Skeletal formula, carbon skeletons for amino acid synthesis are ''
oxaloacetate Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound , CH4; is among the simplest organic compounds. In chemistry Chemistry is the scientific discipline involved with Chemical element, elements and chemi ...

oxaloacetate
'' which forms aspartate and asparagine; and ''alpha-ketoglutarate'' which forms glutamine, proline, and arginine. Of these amino acids, aspartate and glutamine are used, together with carbon and nitrogen atoms from other sources, to form the purines that are used as the bases in DNA and RNA, as well as in
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals * American Technical Publishers * ', a Danish pension * Armenia Tree Project * Association for Transpersonal Psychology * ATP architects engineers office * ATP ...

ATP
, Adenosine monophosphate, AMP, GTP, Nicotinamide adenine dinucleotide, NAD, Flavin adenine dinucleotide, FAD and Coenzyme A, CoA. The pyrimidines are partly assembled from aspartate (derived from ''oxaloacetate''). The pyrimidines, thymine, cytosine and uracil, form the complementary bases to the purine bases in DNA and RNA, and are also components of Cytidine triphosphate, CTP, Uridine monophosphate, UMP, Uridine diphosphate, UDP and Uridine triphosphate, UTP. The majority of the carbon atoms in the porphyrins come from the citric acid cycle intermediate, ''
succinyl-CoA Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a thioester of succinic acid Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. The name derives from Latin ''succinum'', meaning amber. In livin ...

succinyl-CoA
''. These molecules are an important component of the hemoproteins, such as hemoglobin, myoglobin and various cytochromes. During gluconeogenesis Gluconeogenesis#Pathway, mitochondrial ''oxaloacetate'' is reduced to ''malate'' which is then transported out of the mitochondrion, to be oxidized back to oxaloacetate in the cytosol. Cytosolic oxaloacetate is then Decarboxylation, decarboxylated to phosphoenolpyruvate by phosphoenolpyruvate carboxykinase, which is the rate limiting step in the conversion of nearly all the Glucogenic amino acid, gluconeogenic precursors (such as the glucogenic amino acids and lactate) into glucose by the liver and kidney. Because the citric acid cycle is involved in both catabolic and anabolic processes, it is known as an amphibolic pathway. Evan M.W.Duo


Glucose feeds the TCA cycle via circulating lactate

The Metabolic pathway, metabolic role of Lactic acid, lactate is well recognized as a fuel for Tissue (biology), tissues and Neoplasm, tumors. In the classical Cori cycle, muscles produce lactate which is then taken up by the liver for gluconeogenesis. New studies suggest that lactate can be used as a source of
carbon Carbon (from la, carbo "coal") is a with the C and 6. It is lic and —making four s available to form s. It belongs to group 14 of the periodic table. Carbon makes up only about 0.025 percent of Earth's crust. Three occur naturally, ...

carbon
for the TCA cycle.


Evolution

It is believed that components of the citric acid cycle were derived from anaerobic bacteria, and that the TCA cycle itself may have evolved more than once. Theoretically, several alternatives to the TCA cycle exist; however, the TCA cycle appears to be the most efficient. If several TCA alternatives had evolved independently, they all appear to have convergent evolution, converged to the TCA cycle.


See also

* Calvin cycle * Glyoxylate cycle * Reverse Krebs cycle, Reverse (reductive) Krebs cycle


References


External links


An animation of the citric acid cycle
at Smith College
Citric acid cycle variants
at MetaCyc
Pathways connected to the citric acid cycle
at KEGG, Kyoto Encyclopedia of Genes and Genomes
''metpath'': Interactive representation of the citric acid cycle
{{DEFAULTSORT:Citric Acid Cycle Citric acid cycle, Biochemistry Cellular respiration Exercise physiology Metabolic pathways 1937 in biology