Oxaloacetic Acid
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Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline
organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon- hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. Th ...
with the
chemical formula In chemistry, a chemical formula is a way of presenting information about the chemical proportions of atoms that constitute a particular chemical compound or molecule, using chemical element symbols, numbers, and sometimes also other symbols, ...
HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its
conjugate base A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed when an acid donates a proton () to a base—in other words, it is a base with a hydrogen ion added to it, as in the reverse reaction it loses a ...
oxaloacetate, is a metabolic intermediate in many processes that occur in animals. It takes part in
gluconeogenesis Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non- carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verteb ...
, the
urea cycle The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic. The urea cycle converts hi ...
, the glyoxylate cycle, amino acid synthesis,
fatty acid synthesis In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes called fatty acid synthases. This process takes place in the cytoplasm of the cell. Most of the acetyl-CoA which is ...
and the
citric acid cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and prote ...
.


Properties

Oxaloacetic acid undergoes successive deprotonations to give the dianion: :HO2CC(O)CH2CO2H O2CC(O)CH2CO2H + H+, pKa = 2.22 :O2CC(O)CH2CO2H O2CC(O)CH2CO2 + H+, pKa = 3.89 At high pH, the enolizable proton is ionized: :O2CC(O)CH2CO2 O2CC(O)CHCO2 + H+, pKa = 13.03 The
enol In organic chemistry, alkenols (shortened to enols) are a type of reactive structure or intermediate in organic chemistry that is represented as an alkene (olefin) with a hydroxyl group attached to one end of the alkene double bond (). The te ...
forms of oxaloacetic acid are particularly stable, so much so that the two tautomers have different melting points (152 °C for the ''cis'' isoform and 184 °C for the ''trans'' isoform). This reaction is catalyzed by the enzyme oxaloacetate tautomerase. ''trans''-Enol-oxaloacetate also appears when tartrate is the substrate for fumarase.


Biosynthesis

Oxaloacetate forms in several ways in nature. A principal route is upon
oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...
of L-malate, catalyzed by malate dehydrogenase, in the citric acid cycle. Malate is also oxidized by succinate dehydrogenase in a slow reaction with the initial product being enol-oxaloacetate.
It also arises from the condensation of
pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell. Pyruvic aci ...
with carbonic acid, driven by the hydrolysis of
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...
: :CH3C(O)CO2 + HCO3 + ATP → O2CCH2C(O)CO2 + ADP + Pi Occurring in the mesophyll of plants, this process proceeds via
phosphoenolpyruvate Phosphoenolpyruvate (2-phosphoenolpyruvate, PEP) is the ester derived from the enol of pyruvate and phosphate. It exists as an anion. PEP is an important intermediate in biochemistry. It has the highest-energy phosphate bond found (−61.9 kJ/ ...
, catalysed by
phosphoenolpyruvate carboxylase Phosphoenolpyruvate carboxylase (also known as PEP carboxylase, PEPCase, or PEPC; , PDB ID: 3ZGE) is an enzyme in the family of carboxy-lyases found in plants and some bacteria that catalyzes the addition of bicarbonate (HCO3−) to phosphoenolp ...
.
Oxaloacetate can also arise from
trans- Trans- is a Latin prefix meaning "across", "beyond", or "on the other side of". Used alone, trans may refer to: Arts, entertainment, and media * Trans (festival), a former festival in Belfast, Northern Ireland, United Kingdom * ''Trans'' (film ...
or de- amination of
aspartic acid Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α- amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pr ...
.


Biochemical functions

Oxaloacetate is an intermediate of the
citric acid cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and prote ...
, where it reacts with
acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized fo ...
to form
citrate Citric acid is an organic compound with the chemical formula HOC(CO2H)(CH2CO2H)2. It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry, it is an intermediate in the citric acid cycle, which occurs in t ...
, catalyzed by citrate synthase. It is also involved in
gluconeogenesis Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non- carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verteb ...
, the
urea cycle The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic. The urea cycle converts hi ...
, the glyoxylate cycle, amino acid synthesis, and
fatty acid synthesis In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes called fatty acid synthases. This process takes place in the cytoplasm of the cell. Most of the acetyl-CoA which is ...
. Oxaloacetate is also a potent inhibitor of complex II.


Gluconeogenesis

Gluconeogenesis Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non- carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verteb ...
is a metabolic pathway consisting of a series of eleven enzyme-catalyzed reactions, resulting in the generation of
glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, usi ...
from non-carbohydrates substrates. The beginning of this process takes place in the mitochondrial matrix, where
pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell. Pyruvic aci ...
molecules are found. A pyruvate molecule is carboxylated by a pyruvate carboxylase enzyme, activated by a molecule each of
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...
and water. This reaction results in the formation of oxaloacetate.
NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...
reduces oxaloacetate to
malate Malic acid is an organic compound with the molecular formula . It is a dicarboxylic acid that is made by all living organisms, contributes to the sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric forms ...
. This transformation is needed to transport the molecule out of the mitochondria. Once in the
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
, malate is oxidized to oxaloacetate again using NAD+. Then oxaloacetate remains in the cytosol, where the rest of reactions will take place. Oxaloacetate is later decarboxylated and phosphorylated by phosphoenolpyruvate carboxykinase and becomes
2-phosphoenolpyruvate Phosphoenolpyruvate (2-phosphoenolpyruvate, PEP) is the ester derived from the enol of pyruvate and phosphate. It exists as an anion. PEP is an important intermediate in biochemistry. It has the high-energy phosphate, highest-energy phosphate bo ...
using
guanosine triphosphate Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanosine nucleoside, the only ...
(GTP) as phosphate source. Glucose is obtained after further downstream processing.


Urea cycle

The
urea cycle The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic. The urea cycle converts hi ...
is a metabolic pathway that results in the formation of
urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...
using one ammonium molecule from degraded amino acids, another ammonium group from aspartate and one bicarbonate molecule. This route commonly occurs in hepatocytes. The reactions related to the urea cycle produce
NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...
, and NADH can be produced in two different ways. One of these uses oxaloacetate. In the cytosol there are
fumarate Fumaric acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297. The salts and esters are known as f ...
molecules. Fumarate can be transformed into
malate Malic acid is an organic compound with the molecular formula . It is a dicarboxylic acid that is made by all living organisms, contributes to the sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric forms ...
by the actions of the enzyme fumarase. Malate is acted on by malate dehydrogenase to become oxaloacetate, producing a molecule of NADH. After that, oxaloacetate will be recycled to
aspartate Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
, as transaminases prefer these keto acids over the others. This recycling maintains the flow of
nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at seve ...
into the cell.


Glyoxylate cycle

The glyoxylate cycle is a variant of the citric acid cycle. It is an
anabolic Anabolism () is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breaking-d ...
pathway occurring in
plants Plants are predominantly photosynthetic eukaryotes of the kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all current definitions of Plantae exclud ...
and
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...
utilizing the enzymes isocitrate lyase and malate synthase. Some intermediate steps of the cycle are slightly different from the citric acid cycle; nevertheless oxaloacetate has the same function in both processes. This means that oxaloacetate in this cycle also acts as the primary reactant and final product. In fact the oxaloacetate is a net product of the glyoxylate cycle because its loop of the cycle incorporates two molecules of acetyl-CoA.


Fatty acid synthesis

In previous stages acetyl-CoA is transferred from the mitochondria to the cytoplasm where
fatty acid synthase Fatty acid synthase (FAS) is an enzyme that in humans is encoded by the ''FASN'' gene. Fatty acid synthase is a multi-enzyme protein that catalyzes fatty acid synthesis. It is not a single enzyme but a whole enzymatic system composed of two iden ...
resides. The acetyl-CoA is transported as a citrate, which has been previously formed in the mitochondrial matrix from acetyl-coA and oxaloacetate. This reaction usually initiates the citric acid cycle, but when there is no need of energy it is transported to the cytoplasm where it is broken down to cytoplasmatic acetyl -CoA and oxaloacetate. Another part of the cycle requires NADPH for the synthesis of fatty acids. Part of this reducing power is generated when the cytosolic oxaloacetate is returned to the mitochondria as long as the internal mitochondrial layer is non-permeable for oxaloacetate. Firstly the oxaloacetate is reduced to malate using NADH. Then the malate is decarboxylated to pyruvate. Now this pyruvate can easily enter the mitochondria, where it is carboxylated again to oxaloacetate by pyruvate carboxylase. In this way, the transfer of acetyl-CoA that is from the mitochondria into the cytoplasm produces a molecule of NADH. The overall reaction, which is spontaneous, may be summarized as: :HCO3 + ATP + acetyl-CoA → ADP + Pi + malonyl-CoA


Amino acid synthesis

Six essential amino acids and three nonessential are synthesized from oxaloacetate and pyruvate. Aspartate and alanine are formed from oxaloacetate and pyruvate, respectively, by transamination from glutamate. Asparagine is synthesized by amidation of aspartate, with glutamine donating the NH4. These are nonessential amino acids, and their simple biosynthetic pathways occur in all organisms. Methionine, threonine, lysine, isoleucine, valine, and leucine are essential amino acids in humans and most vertebrates. Their biosynthetic pathways in bacteria are complex and interconnected.


Oxalate biosynthesis

Oxaloacetate produces oxalate by hydrolysis. :oxaloacetate + H2O oxalate + acetate This process is catalyzed by the
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
oxaloacetase In enzymology, an oxaloacetase () is an enzyme that catalyzes the chemical reaction: :oxaloacetate + H2O \rightleftharpoons oxalate + acetate Thus, the two substrates of this enzyme are oxaloacetate and H2O, whereas its two products are oxalat ...
. This enzyme is seen in plants, but is not known in the animal kingdom.Xu, Hua-Wei. "Oxalate accumulation and regulations is independent of glycolate oxidase in rice leaves" Journal of Experimental Botany, Vol 57, No. 9 pp. 1899-1908, 2006


Interactive pathway map


See also

*
Dioxosuccinic acid Dioxosuccinic acid or dioxobutanedioic acid is an organic compound with formula C4H2O6 or HO−(C=O)4−OH. Removal of two protons from the molecule would yield the dioxosuccinate anion, or −O−(C=O)4−O−. This is one of the oxocarbon ani ...
* Glycolysis *
Oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine t ...
*
Citric acid cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and prote ...


References

{{Amino acid metabolism intermediates Citric acid cycle compounds Dicarboxylic acids Alpha-keto acids Beta-keto acids