Glyoxylic acid: Difference between revisions

|Watchedfields = changed

|verifiedrevid = 443847685

|Name = Glyoxylic acid

|ImageFile_Ref = {{chemboximage|correct|??}}

|ImageFile = Glyoxylic acid.png

|ImageSize = 150px

|ImageAlt = Skeletal formula of glyoxylic acid

|ImageFile1 = Glyoxylic acid 3D spacefill.png

|ImageSize1 = 160px

|ImageAlt1 = Space-filling model of glyoxylic acid

|PIN = Oxoacetic acid<ref name=iupac2013>{{cite book | title = Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book) | publisher = [[Royal Society of Chemistry|The Royal Society of Chemistry]] | date = 2014 | location = Cambridge | page = 748 | doi = 10.1039/9781849733069-FP001 | isbn = 978-0-85404-182-4| chapter = Front Matter }}</ref>

|SystematicName = Oxoethanoic acid

|OtherNames = Glyoxylic acid<ref name=iupac2013/><br />2-Oxoacetic acid<br />Formylformic acid

|Section1={{Chembox Identifiers

|CASNo_Ref = {{cascite|correct|CAS}}

|CASNo = 298-12-4

|PubChem = 760

|Beilstein = 741891

|ChEBI_Ref = {{ebicite|correct|EBI}}

|ChEBI = 16891

|ChEMBL_Ref = {{ebicite|correct|EBI}}

|ChEMBL = 1162545

|ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

|ChemSpiderID = 740

|DrugBank_Ref = {{drugbankcite|correct|drugbank}}

|DrugBank = DB04343

|EINECS = 206-058-5

|Gmelin = 25752

|KEGG_Ref = {{keggcite|correct|kegg}}

|KEGG = C00048

|UNII_Ref = {{fdacite|correct|FDA}}

|UNII = JQ39C92HH6

|InChI = 1/C2H2O3/c3-1-2(4)5/h1H,(H,4,5)

|InChIKey = HHLFWLYXYJOTON-UHFFFAOYAU

|StdInChI_Ref = {{stdinchicite|correct|chemspider}}

|StdInChI = 1S/C2H2O3/c3-1-2(4)5/h1H,(H,4,5)

|StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

|StdInChIKey = HHLFWLYXYJOTON-UHFFFAOYSA-N

|SMILES = C(=O)C(=O)O

|Section2={{Chembox Properties

|C=2 | H=2 | O=3

|MeltingPtC = 80

|MeltingPt_ref = <ref name=Merck>''[[Merck Index]], 11th Edition, '''4394'''</ref>

|BoilingPtC = 111

|Density = 1.384 g/mL

|pKa = 3.18,<ref>Dissociation Constants Of Organic Acids and Bases (600 compounds), http://zirchrom.com/organic.htm.</ref> 3.32 <ref>pKa Data Compiled by R. Williams, {{cite web |url=http://research.chem.psu.edu/brpgroup/pKa_compilation.pdf |title=Archived copy |access-date=2010-06-02 |url-status=dead |archive-url=https://web.archive.org/web/20100602043012/http://research.chem.psu.edu/brpgroup/pKa_compilation.pdf |archive-date=2010-06-02 }}.</ref>

}}

|Section3={{Chembox Related

|OtherAnions = [[glyoxylate]]

|OtherFunction_label = [[carboxylic acid]]s

|OtherFunction = [[formic acid]]<br />[[acetic acid]]<br />[[glycolic acid]]<br />[[oxalic acid]]<br />[[propionic acid]]<br />[[pyruvic acid]]

|OtherCompounds = [[acetaldehyde]]<br />[[glyoxal]]<br />[[glycolaldehyde]]

'''Glyoxylic acid''' or '''oxoacetic acid''' is an [[organic compound]]. Together with [[acetic acid]], [[glycolic acid]], and [[oxalic acid]], glyoxylic acid is one of the C₂ [[carboxylic acid]]s. It is a colourless solid that occurs naturally and is useful industrially.

The structure of glyoxylic acid is shown as having an [[aldehyde]] [[functional group]]. The aldehyde is only a minor component of the form most prevalent in some situations. Instead, glyoxalic acid often exists as a hydrate or a cyclic [[dimer (chemistry)|dimer]]. For example, in the presence of water, the [[carbonyl]] rapidly converts to a [[geminal diol]] (described as the "monohydrate"). The [[equilibrium constant]] (''K'') is 300 for the formation of '''dihydroxyacetic acid''' at room temperature:<ref>{{cite journal |last1= Sørensen |first1= P. E. |last2= Bruhn |first2= K. |last3= Lindeløv |first3= F. |title= Kinetics and equilibria for the reversible hydration of the aldehyde group in glyoxylic acid. |journal= Acta Chem. Scand. |year= 1974 |volume= 28 |pages= 162–168 |doi= 10.3891/acta.chem.scand.28a-0162 |doi-access= free }}</ref> Dihydroxyacetic acid has been characterized by [[X-ray crystallography]].<ref>{{cite journal |doi=10.1107/S1600536807025792 |title=Quinoxaline–dihydroxyacetic acid (1/1) |year=2007 |last1=Czapik |first1=Agnieszka |last2=Gdaniec |first2=Maria |journal=Acta Crystallographica Section E: Structure Reports Online |volume=63 |issue=7 |pages=o3081 }}</ref>

:[[File:Glyoxylic acid hydration.png|300px]]

In aqueous solution, this monohydrate exists in equilibrium with a hemi[[acylal]] dimer form:<ref name=Ull>Georges Mattioda and Yani Christidis “Glyoxylic Acid” Ullmann's Encyclopedia of Industrial Chemistry, 2002, Wiley-VCH, Weinheim. {{doi|10.1002/14356007.a12_495}}</ref>

:[[File:Glyoxylic acid hydrate dimerization.png|300px]]

In isolation, the aldehyde structure has as a major [[Conformational isomerism|conformer]] a cyclic [[hydrogen-bond]]ed structure with the aldehyde carbonyl in close proximity to the [[carboxyl]] hydrogen:<ref>{{cite journal |journal= Journal of Molecular Spectroscopy |volume= 104 |issue= 1 |year= 1984 |pages= 25–39 |title= Vibrational spectra of glyoxylic acid monomers |first1= Richard L. |last1= Redington |first2= Chin-Kang Jim |last2= Liang |doi= 10.1016/0022-2852(84)90242-X |bibcode= 1984JMoSp.104...25R }}</ref>

:[[File:Glyoxylic acid H-bonded.png|100px]]

The [[Henry's law]] constant of glyoxylic acid is K_H = 1.09 × 10⁴ × exp[(40.0 × 10³/R) × (1/T − 1/298)].<ref>{{cite journal|last=Ip|first=H. S. Simon|author2=Huang, X. H. Hilda |author3=Yu, Jian Zhen |title=Effective Henry's law constants of glyoxal, glyoxylic acid, and glycolic acid|journal=Geophysical Research Letters|volume=36|issue=1|pages=L01802|doi=10.1029/2008GL036212|bibcode=2009GeoRL..36.1802I|year=2009|s2cid=129747490 |url=http://repository.ust.hk/ir/bitstream/1783.1-6115/1/HLCpaper2ndrevision.pdf}}</ref>

==Preparations==

{{Anchor|Glyoxylate}}

The [[conjugate base]] of glyoxylic acid is known as '''glyoxylate''' and is the form that the compound exists in solution at neutral pH. Glyoxylate is the byproduct of the [[amidation]] process in biosynthesis of several amidated [[peptide]]s.

For the historical record, glyoxylic acid was prepared from oxalic acid [[Electrosynthesis|electrosynthetically]]:<ref>{{cite journal|author1=Tafel, Julius |author2=Friedrichs, Gustav|title=Elektrolytische Reduction von Carbonsäuren und Carbonsäureestern in schwefelsaurer Lösung|journal=Berichte der Deutschen Chemischen Gesellschaft|year=1904|volume=37|issue=3|pages=3187–3191|doi=10.1002/cber.190403703116|url=https://zenodo.org/record/1426114}}</ref><ref>{{cite book|last=Cohen|first=Julius|title=Practical Organic Chemistry 2nd Ed.|year=1920|publisher=Macmillan and Co. Limited|location=London|pages=102–104|url=http://www.sciencemadness.org/library/books/practical_organic_chemistry.pdf}}</ref> in organic synthesis, [[lead dioxide]] cathodes were applied for preparing glyoxylic acid from [[oxalic acid]] in a sulfuric acid electrolyte.<ref>{{cite book|url=https://books.google.com/books?id=ArsfQZig_9AC&pg=PA573|page=574|title=Materials Handbook: A Concise Desktop Reference|author=François Cardarelli|publisher=Springer|year=2008|isbn=978-1-84628-668-1}}</ref>

:[[image:GlyoxalicAcidElectrosyn.png|380px]]

Hot [[nitric acid]] can [[organic oxidation|oxidize]] [[glyoxal]] to glyoxylic; however this reaction is highly exothermic and prone to thermal runaway. In addition, oxalic acid is the main side product.

Also, [[ozonolysis]] of [[maleic acid]] is effective.<ref name=Ull/>

== Biological role ==

Glyoxylate is an intermediate of the [[glyoxylate cycle]], which enables [[organism]]s, such as bacteria,<ref name="Holms">{{cite journal|year=1987|title=Control of flux through the citric acid cycle and the glyoxylate bypass in Escherichia coli|journal=Biochem Soc Symp.|volume=54|pages=17–31|pmid=3332993|author=Holms WH}}</ref> fungi, and plants <ref name="Escher and Widmer F">{{cite journal|year=1997|title=Lipid mobilization and gluconeogenesis in plants: do glyoxylate cycle enzyme activities constitute a real cycle? A hypothesis|journal=Biol. Chem.|volume=378|issue=8|pages=803–813|pmid=9377475|vauthors=Escher CL, Widmer F}}</ref> to convert [[fatty acid]]s into [[carbohydrate]]s. The glyoxylate cycle is also important for induction of plant defense mechanisms in response to fungi.<ref>{{Cite journal| doi = 10.1016/j.fgb.2013.06.008| pmid = 23850601| issn = 1087-1845| volume = 58–59| pages = 33–41| last1 = Dubey| first1 = Mukesh K.| last2 = Broberg| first2 = Anders| last3 = Sooriyaarachchi| first3 = Sanjeewani| last4 = Ubhayasekera| first4 = Wimal| last5 = Jensen| first5 = Dan Funck| last6 = Karlsson| first6 = Magnus| title = The glyoxylate cycle is involved in pleotropic phenotypes, antagonism and induction of plant defence responses in the fungal biocontrol agent Trichoderma atroviride| journal = Fungal Genetics and Biology|date=September 2013}}</ref> The glyoxylate cycle is initiated through the activity of isocitrate lyase, which converts isocitrate into glyoxylate and succinate. Research is being done to co-opt the pathway for a variety of uses such as the biosynthesis of succinate.<ref>{{Cite journal| doi = 10.1016/j.ymben.2013.07.004| pmid = 23876414| issn = 1096-7176| volume = 20| pages = 9–19| last1 = Zhu| first1 = Li-Wen| last2 = Li| first2 = Xiao-Hong| last3 = Zhang| first3 = Lei| last4 = Li| first4 = Hong-Mei| last5 = Liu| first5 = Jian-Hua| last6 = Yuan| first6 = Zhan-Peng| last7 = Chen| first7 = Tao| last8 = Tang| first8 = Ya-Jie| title = Activation of glyoxylate pathway without the activation of its related gene in succinate-producing engineered Escherichia coli| journal = Metabolic Engineering|date=November 2013}}</ref>

=== In humans ===

Glyoxylate is produced via two pathways: through the oxidation of glycolate in peroxisomes or through the catabolism of hydroxyproline in mitochondria.<ref name=":0">{{Cite journal| doi = 10.1007/s00109-012-0930-z| pmid = 22729392| issn = 0946-2716| volume = 90| issue = 12| pages = 1497–1504| last1 = Belostotsky| first1 = Ruth| last2 = Pitt| first2 = James Jonathon| last3 = Frishberg| first3 = Yaacov| title = Primary hyperoxaluria type III—a model for studying perturbations in glyoxylate metabolism| journal = Journal of Molecular Medicine| date = 2012-12-01| hdl = 11343/220107| s2cid = 11549218| hdl-access = free}}</ref> In the peroxisomes, glyoxylate is converted into glycine by AGT1 or into oxalate by glycolate oxidase. In the mitochondria, glyoxylate is converted into glycine by AGT2 or into glycolate by glyoxylate reductase. A small amount of glyoxylate is converted into oxalate by cytoplasmic lactate dehydrogenase.<ref name=":1">{{Cite journal| doi = 10.1016/j.jhep.2010.07.036| pmid = 21093948| issn = 0168-8278| volume = 54| issue = 3| pages = 513–520| last1 = Schnedler| first1 = Nina| last2 = Burckhardt| first2 = Gerhard| last3 = Burckhardt| first3 = Birgitta C.| title = Glyoxylate is a substrate of the sulfate-oxalate exchanger, sat-1, and increases its expression in HepG2 cells| journal = Journal of Hepatology|date=March 2011}}</ref>

[[File:Glyoxylate_metabolism_in_hepatocytes.jpg|center|thumb|600x600px|Oxalate and glyoxylate metabolism in hepatocytes.

AGT1 and 2, alanine:glyoxylate aminotransferase 1 and 2; GO, glycolate oxidase; GR, glyoxylate reductase; HKGA, 4-hydroxy-2-ketoglutarate lyase; LDH, lactate dehydrogenase

]]

=== In plants ===

In addition to being an intermediate in the [[glyoxylate cycle]], glyoxylate is also an important intermediate in the [[photorespiration]] pathway. Photorespiration is a result of the side reaction of RuBisCO with O₂ instead of CO₂. While at first considered a waste of energy and resources, photorespiration has been shown to be an important method of regenerating carbon and CO₂, removing toxic phosphoglycolate, and initiating defense mechanisms.<ref>{{Cite web| title = photorespiration| access-date = 2017-03-09| url = http://www2.mcdaniel.edu/Biology/botf99/photodark/photorespiration.htm| archive-date = 2006-12-11| archive-url = https://web.archive.org/web/20061211100043/http://www2.mcdaniel.edu/Biology/botf99/photodark/photorespiration.htm| url-status = dead}}</ref><ref name=":2">{{Cite journal| doi = 10.1199/tab.0130| issn = 1543-8120| volume = 8| last1 = Peterhansel| first1 = Christoph| last2 = Horst| first2 = Ina| last3 = Niessen| first3 = Markus| last4 = Blume| first4 = Christian| last5 = Kebeish| first5 = Rashad| last6 = Kürkcüoglu| first6 = Sophia| last7 = Kreuzaler| first7 = Fritz| title = Photorespiration| journal = The Arabidopsis Book| date = 2010-03-23| pmid = 22303256| pmc = 3244903| page=e0130}}</ref> In photorespiration, glyoxylate is converted from glycolate through the activity of glycolate oxidase in the peroxisome. It is then converted into glycine through parallel actions by SGAT and GGAT, which is then transported into the mitochondria.<ref>{{Cite journal| doi = 10.1016/j.jphotobiol.2014.11.009| pmid = 25528301| issn = 1011-1344| volume = 142| pages = 110–117| last1 = Zhang| first1 = Zhisheng| last2 = Mao| first2 = Xingxue| last3 = Ou| first3 = Juanying| last4 = Ye| first4 = Nenghui| last5 = Zhang| first5 = Jianhua| last6 = Peng| first6 = Xinxiang| title = Distinct photorespiratory reactions are preferentially catalyzed by glutamate:glyoxylate and serine:glyoxylate aminotransferases in rice| journal = Journal of Photochemistry and Photobiology B: Biology|date=January 2015}}</ref><ref name=":2" /> It has also been reported that the pyruvate dehydrogenase complex may play a role in glycolate and glyoxylate metabolism.<ref>{{Cite journal| doi = 10.1016/j.phytochem.2013.07.009| pmid = 23916564| issn = 0031-9422| volume = 95| pages = 168–176| last1 = Blume| first1 = Christian| last2 = Behrens| first2 = Christof| last3 = Eubel| first3 = Holger| last4 = Braun| first4 = Hans-Peter| last5 = Peterhansel| first5 = Christoph| title = A possible role for the chloroplast pyruvate dehydrogenase complex in plant glycolate and glyoxylate metabolism| journal = Phytochemistry|date=November 2013| bibcode = 2013PChem..95..168B}}</ref>

[[File:Photorespiration_in_arabidopsis.jpg|center|thumb|600x600px|Basic overview of photorespiration in Arabidopsis.

GGAT, glyoxylate:glutamate aminotransferase; GLYK, glycerate kinase; GO, glycolate oxidase; HPR, hydroxypyruvate reductase; PGLP, phosphoglycolate phosphatase; Rubisco, RuBP carboxylase/oxygenase; SGAT, serine:glyoxylate aminotransferase; SHM, serine hydroxymethyltransferase

]]

== Disease relevance ==

{{primary sources|date=March 2017}}

=== Diabetes ===

Glyoxylate is thought to be a potential early marker for [[Diabetes mellitus type 2|Type II diabetes]].<ref name=":3" /> One of the key conditions of diabetes pathology is the production of [[advanced glycation end-product]]s (AGEs) caused by the [[hyperglycemia]].<ref>{{Cite journal| doi = 10.3389/fendo.2012.00170| issn = 1664-2392| volume = 3| pages = 170| last1 = Nguyen| first1 = Dung V.| last2 = Shaw| first2 = Lynn C.| last3 = Grant| first3 = Maria B.| title = Inflammation in the pathogenesis of microvascular complications in diabetes| journal = Frontiers in Endocrinology| date = 2012-12-21| pmid = 23267348| pmc = 3527746| doi-access = free}}</ref> AGEs can lead to further complications of diabetes, such as tissue damage and cardiovascular disease.<ref>{{Cite journal| doi = 10.1007/s00592-012-0412-3| issn = 0940-5429| volume = 50| issue = 2| pages = 101–110| last1 = Piarulli| first1 = Francesco| last2 = Sartore| first2 = Giovanni| last3 = Lapolla| first3 = Annunziata| title = Glyco-oxidation and cardiovascular complications in type 2 diabetes: a clinical update| journal = Acta Diabetologica|date=April 2013| pmid = 22763581| pmc = 3634985}}</ref> They are generally formed from reactive aldehydes, such as those present on reducing sugars and [[alpha-oxoaldehyde]]s. In a study, glyoxylate levels were found to be significantly increased in patients who were later diagnosed with Type II diabetes.<ref name=":3">{{Cite journal| doi = 10.1155/2014/685204| issn = 2314-6745| volume = 2014| last1 = Nikiforova| first1 = Victoria J.| last2 = Giesbertz| first2 = Pieter| last3 = Wiemer| first3 = Jan| last4 = Bethan| first4 = Bianca| last5 = Looser| first5 = Ralf| last6 = Liebenberg| first6 = Volker| last7 = Ruiz Noppinger| first7 = Patricia| last8 = Daniel| first8 = Hannelore| last9 = Rein| first9 = Dietrich| title = Glyoxylate, a New Marker Metabolite of Type 2 Diabetes| journal = Journal of Diabetes Research| date = 2014| pmid = 25525609| pmc = 4265698| pages=685204| doi-access = free}}</ref> The elevated levels were found sometimes up to three years before the diagnosis, demonstrating the potential role for glyoxylate to be an early predictive marker.

=== Nephrolithiasis ===

Glyoxylate is involved in the development of [[hyperoxaluria]], a key cause of [[Kidney stone disease|nephrolithiasis]] (commonly known as kidney stones). Glyoxylate is both a substrate and inductor of sulfate anion transporter-1 (sat-1), a gene responsible for oxalate transportation, allowing it to increase sat-1 mRNA expression and as a result oxalate efflux from the cell. The increased oxalate release allows the buildup of calcium oxalate in the urine, and thus the eventual formation of kidney stones.<ref name=":1" />

The disruption of glyoxylate metabolism provides an additional mechanism of hyperoxaluria development. Loss of function mutations in the [[HOGA1]] gene leads to a loss of the 4-hydroxy-2-oxoglutarate aldolase, an enzyme in the hydroxyproline to glyoxylate pathway. The glyoxylate resulting from this pathway is normally stored away to prevent oxidation to oxalate in the cytosol. The disrupted pathway, however, causes a buildup of 4-hydroxy-2-oxoglutarate which can also be transported to the cytosol and converted into glyoxylate through a different aldolase. These glyoxylate molecules can be oxidized into oxalate increasing its concentration and causing hyperoxaluria.<ref name=":0" />

== Reactions and uses ==

Glyoxylic acid is about ten times stronger an acid than [[acetic acid]], with an [[acid dissociation constant]] of 4.7&nbsp;×&nbsp;10⁻⁴ (p''K''_a = 3.32):

:OCHCO₂H {{eqm}} {{chem|OCHCO|2|−}} + H⁺

With concentrated base, glyoxylic acid [[disproportionation|disproportionates]] via a [[Cannizzaro reaction]], forming [[hydroxyacetic acid]] and [[oxalic acid]]:{{citation needed|date=April 2019}}

:2 OCHCO₂H + H₂O → HOCH₂CO₂H + HO₂CCO₂H

Glyoxylic acid gives heterocycles upon [[condensation reaction|condensation]] with [[urea]] and [[1,2-diaminobenzene]].

In general, glyoxylic acid undergoes an [[electrophilic aromatic substitution]] reaction with [[phenols]], a versatile step in the synthesis of several other compounds.

The immediate product with [[phenol]] itself is [[4-Hydroxymandelic acid|4-hydroxymandelic acid]]. This species reacts with ammonia to give hydroxyphenylglycine, a precursor to the drug [[amoxicillin]]. Reduction of the 4-hydroxymandelic acid gives [[4-hydroxyphenylacetic acid]], a precursor to the drug [[atenolol]].

The sequence of reactions, in which glyoxylic acid reacts with [[guaiacol]] the phenolic component followed by oxidation and [[decarboxylation]], provides a route to [[vanillin]] as a net [[formylation]] process.<ref name=Ull/><ref>{{cite journal|author1=Fatiadi, Alexander |author2=Schaffer, Robert|title=An Improved Procedure for Synthesis of <small>DL</small>-4-Hydroxy-3-methoxymandelic Acid (<small>DL</small>-"Vanillyl"-mandelic Acid, VMA)|journal=Journal of Research of the National Bureau of Standards Section A|year=1974|volume=78A|issue=3|pages=411–412|doi=10.6028/jres.078A.024|pmid=32189791|pmc=6742820 |doi-access=free}}</ref><ref>{{cite book|author1=Kamlet, Jonas |author2=Mathieson, Olin|title=Manufacture of vanillin and its homologues U.S. Patent 2,640,083|year=1953|publisher=U.S. Patent Office|url=https://docs.google.com/viewer?url=patentimages.storage.googleapis.com/pdfs/US2640083.pdf|author1-link=Jonas Kamlet}}</ref>

===Hopkins Cole reaction===

Glyoxylic acid is a component of the [[Hopkins–Cole reaction]], used to check for the presence of [[tryptophan]] in proteins.<ref>{{cite book|author=R.A. Joshi|title=Question Bank of Biochemistry|url=https://books.google.com/books?id=Acf9BkEqJWYC&pg=PA64|year=2006|publisher=New Age International|isbn=978-81-224-1736-4|page=64}}</ref>

===Environmental chemistry===

Glyoxylic acid is one of several ketone- and aldehyde-containing carboxylic acids that together are abundant in [[secondary organic aerosol]]s. In the presence of water and sunlight, glyoxylic acid can undergo [[photochemical]] oxidation. Several different reaction pathways can ensue, leading to various other carboxylic acid and aldehyde products.<ref>{{cite journal | title= Aqueous Photochemistry of Glyoxylic Acid |first1= Alexis J. |last1= Eugene |first2= Sha-Sha |last2= Xia |first3= Marcelo I. |last3= Guzman |journal= J. Phys. Chem. A |year= 2016 |volume= 120 |issue= 21 |pages= 3817–3826 |doi= 10.1021/acs.jpca.6b00225 |pmid= 27192089 |bibcode= 2016JPCA..120.3817E |doi-access= free }}</ref>

The compound is not very toxic with an {{LD50}} for rats of 2500&nbsp;mg/kg.

But a recent experiment shows that it is toxic. See https://karger.com/cnd/article/12/2/112/827730/Acute-Kidney-Injury-following-Exposure-to.

== See also ==

* [[Semialdehyde]]

{{Authority control}}

[[Category:Conjugated aldehydes]]

[[Category:Aldehydic acids]]