View source for Oxaloacetic acid

{{short description|Organic compound}}
{{Use dmy dates|date=September 2023}}
{{chembox
| Watchedfields = changed
| verifiedrevid = 476996415
| Name = Oxaloacetic acid
| ImageFile_Ref = {{chemboximage|correct|??}}
| ImageFile = Oxaloacetic acid.svg
| ImageSize = 170px
| ImageName = Skeletal structure
| ImageFile1 = Oxaloacetic-acid-3D-balls.png
| ImageName1 = Ball-and-stick model
| PIN = 2-Oxobutanedioic acid
| OtherNames = Oxaloacetic acid<br />Oxalacetic acid<br />2-Oxosuccinic acid<br />Ketosuccinic acid
|Section1={{Chembox Identifiers
| IUPHAR_ligand = 5236
| PubChem = 970
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C4H4O5/c5-2(4(8)9)1-3(6)7/h1H2,(H,6,7)(H,8,9)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = KHPXUQMNIQBQEV-UHFFFAOYSA-N
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 328-42-7
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 2F399MM81J
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = C00036
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 945
| EINECS = 206-329-8
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 30744
| SMILES = O=C(O)C(=O)CC(=O)O
}}
|Section2={{Chembox Properties
| Formula = C<sub>4</sub>H<sub>4</sub>O<sub>5</sub>
| MolarMass = 132.07 g/mol
| MeltingPtC = 161
| Density = 1.6 g/cm<sup>3</sup>
  }}
|Section4={{Chembox Thermochemistry
| DeltaHf = −943.21 kJ/mol
| DeltaHc = −1205.58 kJ/mol
  }}
}}

'''Oxaloacetic acid''' (also known as '''oxalacetic acid''' or '''OAA''') is a crystalline [[organic compound]] with the [[chemical formula]] HO<sub>2</sub>CC(O)CH<sub>2</sub>CO<sub>2</sub>H.  Oxaloacetic acid, in the form of its [[conjugate base]] '''oxaloacetate''', is a [[metabolic intermediate]] in many processes that occur in animals. It takes part in [[gluconeogenesis]], the [[urea cycle]], the [[glyoxylate cycle]], [[amino acid synthesis]], [[fatty acid synthesis]] and the [[citric acid cycle]].<ref name=Lehn/>

==Properties==
Oxaloacetic acid undergoes successive [[deprotonation]]s to give the [[dianion]]:
:HO<sub>2</sub>CC(O)CH<sub>2</sub>CO<sub>2</sub>H   {{eqm}}  <sup>−</sup>O<sub>2</sub>CC(O)CH<sub>2</sub>CO<sub>2</sub>H  +  H<sup>+</sup>,  pK<sub>a</sub> = 2.22
:<sup>−</sup>O<sub>2</sub>CC(O)CH<sub>2</sub>CO<sub>2</sub>H   {{eqm}}  <sup>−</sup>O<sub>2</sub>CC(O)CH<sub>2</sub>CO<sub>2</sub><sup>−</sup>  +  H<sup>+</sup>,  pK<sub>a</sub> = 3.89

At high [[pH]], the enolizable proton is ionized:
:<sup>−</sup>O<sub>2</sub>CC(O)CH<sub>2</sub>CO<sub>2</sub><sup>−</sup>   {{eqm}}  <sup>−</sup>O<sub>2</sub>CC(O<sup>−</sup>)CHCO<sub>2</sub><sup>−</sup>  +  H<sup>+</sup>,  pK<sub>a</sub> = 13.03

The [[enol]] forms of oxaloacetic acid are particularly stable.  [[Keto-enol tautomerization]] is catalyzed by the enzyme [[oxaloacetate tautomerase]]. ''trans''-Enol-oxaloacetate also appears when [[tartrate]] is the substrate for [[fumarase]].<ref>{{Citation|title=Biochemical Similarities and Differences between the Catalytic [4Fe-4S] Cluster Containing Fumarases FumA and FumB from ''Escherichia coli''|last1=van Vugt-Lussenburg|first1=BMA|date=February 26, 2021|publication-date=February 6, 2013|last2=van der Weel|first2=L|last3=Hagen|first3=WR|last4=Hagedoorn|first4=P-L|journal=PLOS ONE|volume=8|issue=2|article-number=e55549|doi=10.1371/journal.pone.0055549|pmid=23405168|pmc=3565967|doi-access=free}}</ref>

[[File:Oxaloacetate tautomerase.svg|center|thumb|450px|[[Oxaloacetate tautomerase]] catalyzed creation of enol-oxaloacetate. ''[[E–Z notation|(Z)]]'' isoform is shown.]]

==Biosynthesis==
Oxaloacetate forms in several ways in nature. A principal route is upon [[oxidation]] of [[Malic acid|<small>L</small>-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.<ref>{{cite journal
 |author1=M.V. Panchenko |author2=A.D. Vinogradov | title =  Direct demonstration of enol-oxaloacetate as an immediate product of malate oxidation by the mammalian succinate dehydrogenase
 | year =  1991
 | volume=  286
 | issue =  1–2
 | pages = 76–78
 | doi = 10.1016/0014-5793(91)80944-X
 | journal = FEBS Letters  |pmid=1864383 | doi-access =free
 |bibcode=1991FEBSL.286...76P }}</ref> <br /> 
It also arises from the condensation of [[pyruvate]] with carbonic acid, driven by the hydrolysis of [[Adenosine triphosphate|ATP]]:
:CH<sub>3</sub>C(O)CO<sub>2</sub><sup>−</sup> + HCO<sub>3</sub><sup>−</sup>  +  ATP   →   <sup>−</sup>O<sub>2</sub>CCH<sub>2</sub>C(O)CO<sub>2</sub><sup>−</sup>  +  ADP  +  Pi
Occurring in the [[Leaf#Mesophyll|mesophyll]] of plants, this process proceeds via [[phosphoenolpyruvate]], catalysed by [[phosphoenolpyruvate carboxylase]].  <br />Oxaloacetate can also arise from [[transamination|trans-]] or de- amination of [[aspartic acid]].

==Biochemical functions==
Oxaloacetate is an intermediate of the [[citric acid cycle]], where it reacts with [[acetyl-CoA]] to form [[citrate]], catalyzed by [[citrate synthase]]. It is also involved in [[gluconeogenesis]], the [[urea cycle]], the [[glyoxylate cycle]], [[amino acid synthesis]], and [[fatty acid synthesis]]. Oxaloacetate is also a potent inhibitor of [[complex II]].

===Gluconeogenesis===
[[Gluconeogenesis]]<ref name=Lehn>{{Lehninger4th}}</ref> is a metabolic pathway consisting of a series of eleven enzyme-catalyzed reactions, resulting in the generation of [[glucose]] from non-carbohydrate substrates. The beginning of this process takes place in the [[mitochondrial matrix]], where [[pyruvate]] molecules are found. A pyruvate molecule is carboxylated by a [[pyruvate carboxylase]] enzyme, activated by a molecule each of [[Adenosine triphosphate|ATP]] and water. This reaction results in the formation of oxaloacetate. [[NADH]] reduces oxaloacetate to [[malate]]. This transformation is needed to transport the molecule out of the [[mitochondria]]. Once in the [[cytosol]], 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]] using [[guanosine triphosphate]] (GTP) as phosphate source. Glucose is obtained after further downstream processing.

===Urea cycle===
The [[urea cycle]] is a metabolic pathway that results in the formation of [[urea]] using one ammonium molecule from degraded amino acids, another ammonium group from aspartate and one bicarbonate molecule.<ref name=Lehn/> This route commonly occurs in [[hepatocytes]]. The reactions related to the urea cycle produce [[NADH]], and NADH can be produced in two different ways. One of these uses '''oxaloacetate'''. In the cytosol there are [[fumarate]] molecules. Fumarate can be transformed into [[malate]] 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]], as [[transaminase]]s prefer these [[keto acid]]s over the others. This recycling maintains the flow of [[nitrogen]] into the cell.
[[Image:Oxaloac-malic.png|thumb|150px|center|Relationship of oxaloacetic acid, malic acid, and aspartic acid]]

===Glyoxylate cycle===<!--plagiarism?-->
The [[glyoxylate cycle]] is a variant of the citric acid cycle.<ref>{{cite web|url=http://www.pearsonhighered.com/mathews/ch14/c14gc.htm|title=Welcome to The Chemistry Place|website=www.pearsonhighered.com|access-date=5 April 2018}}</ref> It is an [[anabolic]] pathway occurring in [[plants]] and [[bacteria]] 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.<ref name=Lehn/> 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===<!--plagiarism?-->
In previous stages acetyl-CoA is transferred from the mitochondria to the cytoplasm where [[fatty acid synthase]] 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 cytoplasmic acetyl-CoA and oxaloacetate.

Another part of the cycle requires NADPH for the synthesis of fatty acids.<ref>{{cite web|title=fatty acids synthesis |website=www.rpi.edu |url=http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/fasynthesis.htm }}</ref> 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:
:HCO<sub>3</sub><sup>–</sup>  +  ATP  +  acetyl-CoA   →   ADP  +  P<sub>i</sub>  +  malonyl-CoA

===Amino acid synthesis===
Six essential amino acids and three nonessential are synthesized from [[Amino acid synthesis#Aspartate|oxaloacetate and pyruvate]].<ref>{{cite web|url=http://faculty.ksu.edu.sa/69436/Documents/lecture-15-aa_from_oxaloacetate_and_pyruvate.pptx |access-date=2013-10-21 |archive-url=https://web.archive.org/web/20131021203457/http://faculty.ksu.edu.sa/69436/Documents/lecture-15-aa_from_oxaloacetate_and_pyruvate.pptx |archive-date=2013-10-21 |title=Animo acids synthesized from oxaloacetate and pyruvate |website=faculty.ksu.edu.sa |format=PPTX}}</ref>  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.
[[File:Oxaloacetate and pyruvate aminoacid synthesis.png|400px|center|Oxaloacetate and pyruvate aminoacid synthesis]]

===Oxalate biosynthesis===
Oxaloacetate produces oxalate by hydrolysis.<ref>[[Geoffrey Michael Gadd|Gadd, Geoffrey M.]] "Fungal production of citric and oxalic acid: importance in metal speciation, physiology and biogeochemical processes" Advances in Microbial Physiology (1999), 41, 47-92.</ref>
:oxaloacetate + H<sub>2</sub>O {{eqm}} oxalate + acetate
This process is catalyzed by the [[enzyme]] [[oxaloacetase]].  This enzyme is seen in plants, but is not known in the animal kingdom.<ref>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</ref>

== Interactive pathway map ==
{|
| width =390|{{GlycolysisGluconeogenesis_WP534|highlight=Oxaloacetic_acid}}
| width =390|{{TCACycle_WP78|highlight=Oxaloacetic_acid}}
|}

==See also==
*[[Dioxosuccinic acid]]
* [[Glycolysis]]
* [[Oxidative phosphorylation]]
* [[Citric acid cycle]]

==References==
{{reflist}}

{{citric acid cycle}}
{{Amino acid metabolism intermediates}}

[[Category:Citric acid cycle compounds]]
[[Category:Dicarboxylic acids]]
[[Category:Alpha-keto acids]]
[[Category:Beta-keto acids]]
[[Category:Metabolic intermediates]]
[[Category:Biomolecules]]