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Revision as of 18:04, 9 January 2012 editBeetstra (talk | contribs)Edit filter managers, Administrators172,052 edits Saving copy of the {{chembox}} taken from revid 468364894 of page Succinic_acid for the Chem/Drugbox validation project (updated: '').		Latest revision as of 05:58, 2 January 2025 edit Arthurfragoso (talk | contribs)Extended confirmed users, Template editors4,591 edits Fixes image on dark mode
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			{{short description|Dicarboxylic acid}}
	{{ambox | text = This page contains a copy of the infobox ({{tl|chembox}}) taken from revid of page ] with values updated to verified values.}}
	{{chembox		{{chembox
	| Verifiedfields = changed
	| Watchedfields = changed		| Watchedfields = changed
	| verifiedrevid = 418123096		| verifiedrevid = 470471892
	| Name = Succinic acid		| Name = Succinic acid
	| ImageFile_Ref = {{chemboximage|correct|??}}		| ImageFile_Ref = {{chemboximage|correct|??}}
	| ImageFile = Bernsteinsäure2.svg		| ImageFile = Bernsteinsäure2.svg
			| ImageClass = skin-invert
	| ImageFile1 = Succinic-acid-3D-balls.png
			| ImageFile1 = Succinic acid molecule ball from xtal.png
	| IUPACName = Butanedioic acid
			| ImageFile2 = Sample of succinic acid.jpg
	| OtherNames = ethane-1,2-dicarboxylic acid
			| ImageSize2 = 200px
	| Section1 = {{Chembox Identifiers
			| PIN = Butanedioic acid<ref name=iupac2013>{{cite book | title = Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book) | publisher = ] | date = 2014 | location = Cambridge | page = 747 | doi = 10.1039/9781849733069-00648 | isbn = 978-0-85404-182-4| chapter = CHAPTER P-6. Applications to Specific Classes of Compounds }}</ref>
	| PubChem = 1110
			| OtherNames = Succinic acid<ref name=iupac2013 /><br />1,4-Butanedioic acid
			|Section1={{Chembox Identifiers
			| IUPHAR_ligand = 3637
			| PubChem = 1110
	| UNII_Ref = {{fdacite|correct|FDA}}		| UNII_Ref = {{fdacite|correct|FDA}}
	| UNII = AB6MNQ6J6L		| UNII = AB6MNQ6J6L
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	| CASNo_Ref = {{cascite|correct|CAS}}		| CASNo_Ref = {{cascite|correct|CAS}}
	| CASNo = 110-15-6		| CASNo = 110-15-6
	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}		| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| ChemSpiderID = 1078		| ChemSpiderID = 1078
	| DrugBank_Ref = {{drugbankcite|changed|drugbank}}		| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
	| DrugBank = DB00139		| DrugBank = DB00139
	| ChEBI_Ref = {{ebicite|changed|EBI}}		| ChEBI_Ref = {{ebicite|correct|EBI}}
	| ChEBI = 15741		| ChEBI = 15741
	| SMILES = C(CC(=O)O)C(=O)O		| SMILES = C(CC(=O)O)C(=O)O
	}}		}}
	| Section2 = {{Chembox Properties		|Section2={{Chembox Properties
	| C = 4		| C=4 | H=6 | O=4
			| Density = 1.56 g/cm<sup>3</sup><ref name=GESTIS/>
	| H = 6
	| O = 4		| MeltingPtC = 184 - 190
			| MeltingPt_ref = <ref name=GESTIS>{{GESTIS|ZVG=37700}}</ref><ref>{{Cite journal|last1=Chikhalia|first1=V.|last2=Forbes|first2=R.T.|last3=Storey|first3=R.A.|last4=Ticehurst|first4=M.|date=January 2006|title=The effect of crystal morphology and mill type on milling induced crystal disorder |journal=European Journal of Pharmaceutical Sciences|volume=27|issue=1|pages=19–26|doi=10.1016/j.ejps.2005.08.013|pmid=16246535|issn=0928-0987}}</ref>
	| Density = 1.56 g/cm<sup>3</sup><ref name=GESTIS/>
	| MeltingPtC = 184		| BoilingPtC = 235
	| Melting_notes = <ref name=GESTIS>{{GESTIS|ZVG=37700}}</ref>		| BoilingPt_ref = <ref name=GESTIS/>
			| Solubility = 80 g/L (20 °C)<ref name=GESTIS/> or 100 mg/mL<ref name="SigmaAl">{{cite web | url=https://www.sigmaaldrich.com/content/dam/sigma-aldrich/docs/Sigma-Aldrich/Product_Information_Sheet/398055pis.pdf | title=Product Information Sheet: Succinic Acid | publisher=Sigma Aldrich | access-date=7 November 2015 | archive-date=7 November 2017 | archive-url=https://web.archive.org/web/20171107151056/https://www.sigmaaldrich.com/content/dam/sigma-aldrich/docs/Sigma-Aldrich/Product_Information_Sheet/398055pis.pdf | url-status=dead }}</ref>
	| BoilingPtC = 235
	| Boiling_notes = <ref name=GESTIS/>		| Solubility1 = 158 mg/mL<ref name="SigmaAl"/>
			| Solvent1 = Methanol
	| Solubility = 58 g/L (20 °C)<ref name=GESTIS/>
			| Solubility2 = 54 mg/mL<ref name="SigmaAl"/>
	| pKa = p''K''<sub>a1</sub> = 4.2<br />p''K''<sub>a2</sub> = 5.6
			| Solvent2 = Ethanol
			| Solubility3 = 27 mg/mL<ref name="SigmaAl"/>
			| Solvent3 = Acetone
			| Solubility4 = 50 mg/mL<ref name="SigmaAl"/>
			| Solvent4 = Glycerol
			| Solubility5 = 8.8 mg/mL<ref name="SigmaAl"/>
			| Solvent5 = Ether
			| pKa = p''K''<sub>a1</sub> = 4.2<br />p''K''<sub>a2</sub> = 5.6
			| MagSus = -57.9·10<sup>−6</sup> cm<sup>3</sup>/mol
	}}		}}
	| Section3 = {{Chembox Hazards		|Section3={{Chembox Hazards
	| MainHazards =		| MainHazards =
			| FlashPtC = 206
	| FlashPt = {{convert|206|C|F}}<ref name=GESTIS/>
			| FlashPt_ref = <ref name=GESTIS/>
	| Autoignition = }}
			| AutoignitionPt = }}
	| Section4 = {{Chembox Related
			|Section4={{Chembox Related
	| OtherAnions = ]
	| Function = ]s		| OtherAnions = ]
			| OtherFunction_label = ]s
	| OtherFunctn = ]<br />]<br />]<br />]<br />]<br />]<br />]<br />]
			| OtherFunction = ]<br />]<br />]<br />]<br />]<br />]<br />]<br />]
	}}		}}
	}}		}}
			'''Succinic acid''' ({{IPAc-en|s|ə|k|ˈ|s|ɪ|n|ᵻ|k}}) is a ] with the ] (CH<sub>2</sub>)<sub>2</sub>(CO<sub>2</sub>H)<sub>2</sub>.<ref name=Toxnet/> In living organisms, succinic acid takes the form of an ], '''succinate''', which has multiple biological roles as a ] being converted into ] by the enzyme ] in complex 2 of the ] which is involved in making ], and as a signaling molecule reflecting the cellular metabolic state.<ref name=Tretter2016rev/>
			Succinate is generated in ] via the ]. Succinate can exit the mitochondrial matrix and function in the cytoplasm as well as the extracellular space, changing gene expression patterns, modulating ] landscape or demonstrating ]-like signaling.<ref name="Tretter2016rev" /> As such, succinate links cellular ], especially ATP formation, to the regulation of cellular function.
			Dysregulation of succinate synthesis, and therefore ATP synthesis, happens in some genetic mitochondrial diseases, such as ], and ], and degradation can lead to pathological conditions, such as ] transformation, ] and tissue injury.<ref name="Tretter2016rev" /><ref name="Mills2014rev">{{Cite journal|last1=Mills|first1=Evanna|last2=O'Neill|first2=Luke A.J.|title=Succinate: a metabolic signal in inflammation|journal=Trends in Cell Biology|volume=24|issue=5|pages=313–320|doi=10.1016/j.tcb.2013.11.008|pmid=24361092|date=May 2014|hdl=2262/67833|hdl-access=free}}</ref><ref name="Chouchani|2014primary" />
			Succinic acid is marketed as food additive ]. The name derives from Latin ''succinum'', meaning ].
			==Physical properties==
			Succinic acid is a white, odorless solid with a highly acidic taste.<ref name=Toxnet/> In an ], succinic acid readily ]izes to form its conjugate base, succinate ({{IPAc-en|ˈ|s|ʌ|k|s|ᵻ|n|eɪ|t}}). As a ], succinic acid undergoes two successive deprotonation reactions:
			:(CH<sub>2</sub>)<sub>2</sub>(CO<sub>2</sub>H)<sub>2</sub> → (CH<sub>2</sub>)<sub>2</sub>(CO<sub>2</sub>H)(CO<sub>2</sub>)<sup>−</sup> + H<sup>+</sup>
			:(CH<sub>2</sub>)<sub>2</sub>(CO<sub>2</sub>H)(CO<sub>2</sub>)<sup>−</sup> → (CH<sub>2</sub>)<sub>2</sub>(CO<sub>2</sub>)<sub>2</sub><sup>2−</sup> + H<sup>+</sup>
			The ] of these processes are 4.3 and 5.6, respectively. Both anions are colorless and can be isolated as the salts, e.g., Na(CH<sub>2</sub>)<sub>2</sub>(CO<sub>2</sub>H)(CO<sub>2</sub>) and Na<sub>2</sub>(CH<sub>2</sub>)<sub>2</sub>(CO<sub>2</sub>)<sub>2</sub>. In living organisms, primarily succinate, not succinic acid, is found.<ref name=Toxnet>{{cite web|title=Succinic Acid|url=https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+791|publisher=Toxnet National Library of Medicine HSDB Database|access-date=28 May 2017|date=2005-01-31}}</ref>
			As a ] group it is called a succinyl ({{IPAc-en|ˈ|s|ʌ|k|s|ᵻ|n|əl}}) group.<ref>{{Cite web|url=https://www.merriam-webster.com/dictionary/succinyl|title=Definition of SUCCINYL|website=www.merriam-webster.com|access-date=2017-03-09}}</ref>
			Like most simple mono- and dicarboxylic acids, it is not harmful but can be an irritant to skin and eyes.<ref name=Toxnet/>
			== Commercial production ==
			Historically, succinic acid was obtained from ] by distillation and has thus been known as spirit of amber ({{Langx|la|spiritus succini}}<ref>{{Cite book |last=London |first=Royal College of Physicians of |url=https://books.google.com/books?id=5UZjvBA0KNIC&pg=PA401 |title=Pharmacopœia Londinensis. Or, the New London dispensatory ... Translated into English ... As also, the Praxis of Chymistry ... The second edition corrected and amended ... by William Salmon |date=1682 |publisher=Th. Dawks, Th. Basset, Jo. Wright and Ri. Chiswell |language=en}}</ref>). Common industrial routes include ] of ], oxidation of ], and ] of ]. Succinate is also produced from ] via ].<ref name="Ullmann">{{Ullmann |author=Boy Cornils|author2=Peter Lappe|title=Dicarboxylic Acids, Aliphatic|doi=10.1002/14356007.a08_523}}</ref> Global production is estimated at 16,000 to 30,000 tons a year, with an annual growth rate of 10%.<ref>{{cite web|url = http://www.nnfcc.co.uk/publications/nnfcc-renewable-chemicals-factsheet-succinic-acid |title = NNFCC Renewable Chemicals Factsheet: Succinic Acid|date= 3 February 2010|archive-url =https://web.archive.org/web/20110720182449/http://www.nnfcc.co.uk/publications/nnfcc-renewable-chemicals-factsheet-succinic-acid|archive-date = 20 July 2011}}</ref>
			Genetically engineered '']'' and '']'' are proposed for the commercial production via fermentation of ].<ref name=Thakker2012rev/><ref>{{Cite journal|last1=Otero|first1=José Manuel|last2=Cimini|first2=Donatella|last3=Patil|first3=Kiran R.|last4=Poulsen|first4=Simon G.|last5=Olsson|first5=Lisbeth|last6=Nielsen|first6=Jens|date=2013-01-21|title=Industrial Systems Biology of Saccharomyces cerevisiae Enables Novel Succinic Acid Cell Factory|journal=PLOS ONE|volume=8|issue=1|pages=e54144|doi=10.1371/journal.pone.0054144|issn=1932-6203|pmc=3549990|pmid=23349810|bibcode=2013PLoSO...854144O|doi-access=free}}</ref>
			==Chemical reactions==
			Succinic acid can be dehydrogenated to ] or be converted to diesters, such as diethylsuccinate (CH<sub>2</sub>CO<sub>2</sub>CH<sub>2</sub>CH<sub>3</sub>)<sub>2</sub>. This diethyl ester is a substrate in the ]. Dehydration of succinic acid gives ].<ref>{{cite journal|first1=Louis F.|last1=Fieser|first2=E. L.|last2=Martin|year=1932|title=Succinic Anhydride|journal=Organic Syntheses|volume=12|pages=66|doi=10.15227/orgsyn.012.0066}}</ref> Succinate can be used to derive 1,4-butanediol, maleic anhydride, succinimide, 2-pyrrolidinone and ].<ref name=Thakker2012rev>{{Cite journal|last1=Thakker|first1=Chandresh|last2=Martínez|first2=Irene|last3=San|first3=Ka-Yiu|last4=Bennett|first4=George N.|date=2017-03-07|title=Succinate production in Escherichia coli|journal=Biotechnology Journal|volume=7|issue=2|pages=213–224|doi=10.1002/biot.201100061|pmc=3517001|pmid=21932253}}</ref>
			==Applications==
			In 2004, succinate was placed on the US Department of Energy's list of top 12 platform chemicals from biomass.<ref>{{cite web|url=https://www1.eere.energy.gov/bioenergy/pdfs/35523.pdf |archive-url=https://web.archive.org/web/20131021015804/http://www1.eere.energy.gov/bioenergy/pdfs/35523.pdf |archive-date=2013-10-21 |url-status=live|title=Top Value Added Chemicals from Biomass, Volume 1: Results of Screening for Potential Candidates from Sugars and Synthesis Gas|date=November 1, 2004|publisher=U.S. Department of Energy|access-date=2013-11-12}}</ref>
			===Precursor to polymers, resins, and solvents===
			Succinic acid is a ] to some ]s and a component of some ]s.<ref name=Ullmann/> ] (BDO) can be synthesized using succinic acid as a precursor.<ref>{{Citation | title = Ashford's Dictionary of Industrial Chemicals | edition = 3rd | year = 2011 | isbn = 978-0-9522674-3-0 | page = 1517| last1 = Ashford | first1 = Robert D. | publisher = Wavelength }}</ref> The automotive and electronics industries heavily rely on BDO to produce connectors, insulators, wheel covers, gearshift knobs and reinforcing beams.<ref>{{cite web|url=http://www.grandviewresearch.com/industry-analysis/1-4-butanediol-market |work=Grand View Research |title=1,4-Butanediol (BDO) Market Analysis By Application (Tetrahydrofuran, Polybutylene Teraphthalate, Gamma-Butyrolactone & Polyurethanes), And Segment Forecasts To 2020 |date=September 2015 |access-date=2015-11-18}}</ref> Succinic acid also serves as the bases of certain biodegradable polymers, which are of interest in tissue engineering applications.<ref>{{Cite journal|last1=Barrett|first1=Devin G.|last2=Yousaf|first2=Muhammad N.|date=2009-10-12|title=Design and Applications of Biodegradable Polyester Tissue Scaffolds Based on Endogenous Monomers Found in Human Metabolism|journal=Molecules|volume=14|issue=10|pages=4022–4050|doi=10.3390/molecules14104022|pmid=19924045|pmc=6255442|doi-access=free}}</ref>
			] with succinic acid is called ''succination''. ''Oversuccination'' occurs when more than one succinate adds to a substrate.{{Citation needed|date=January 2021}}
			===Food and dietary supplement===
			As a ] and ], succinic acid is ] by the ].<ref>{{cite web|website = FDA GRAS Database|url = https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/SCOGS/ucm261458.htm|title = Succinic acid in the FDA SCOGS Database|date = 31 October 2015|access-date = 9 March 2020|archive-date = 31 October 2017|archive-url = https://wayback.archive-it.org/7993/20171031060940/https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/SCOGS/ucm261458.htm|url-status = bot: unknown}}</ref> Succinic acid is used primarily as an ]<ref>{{cite journal | doi = 10.1007/s002530051431 | title = Biotechnology of succinic acid production and markets for derived industrial products | year = 1999 | last1 = Zeikus | first1 = J. G. | last2 = Jain | first2 = M. K. | last3 = Elankovan | first3 = P. | journal = Applied Microbiology and Biotechnology | volume = 51 | issue = 5 | pages = 545| s2cid = 38868987 }}</ref> in the food and beverage industry. It is also available as a flavoring agent, contributing a somewhat sour and astringent component to umami taste.<ref name= Thakker2012rev/> As an ] in pharmaceutical products, it is also used to control acidity<ref>{{cite web |url=http://drugtopics.modernmedicine.com/drugtopics/Drugtopics.com+Exclusives/Overview-of-pharmaceutical-excipients-used-in-tabl/ArticleStandard/Article/detail/561047|title=Overview of pharmaceutical excipients used in tablets and capsules |date=24 October 2008|publisher=Modern Medicine Network|access-date=7 November 2015|url-status=dead|archive-url= https://web.archive.org/web/20120219203453/http://drugtopics.modernmedicine.com/drugtopics/Drugtopics.com+Exclusives/Overview-of-pharmaceutical-excipients-used-in-tabl/ArticleStandard/Article/detail/561047|archive-date=19 February 2012}}</ref> or as a counter ion.<ref name=Thakker2012rev/> Drugs involving succinate include ], ], ] or ].{{Citation needed|date=January 2021}}
			== Biosynthesis ==
			=== Tricarboxylic acid (TCA) cycle ===
			{{see also|Tricarboxylic acid cycle|Succinate dehydrogenase}}
			Succinate is a key intermediate in the ], a primary metabolic pathway used to produce chemical energy in the presence of O<sub>2</sub>. Succinate is generated from ] by the enzyme ] in a ]/]-producing step:<ref name=BiochemText5th/>{{rp|Section 17.1}}
			Succinyl-CoA + NDP + Pi → Succinate + CoA + NTP
			Catalyzed by the enzyme ] (SDH), succinate is subsequently oxidized to ]:<ref name=BiochemText5th/>{{rp|Section 17.1}}
			Succinate + FAD → Fumarate + FADH<sub>2</sub>
			SDH also participates in the mitochondrial ], where it is known as ]. This enzyme complex is a 4 subunit membrane-bound lipoprotein which couples the oxidation of succinate to the reduction of ] via the intermediate electron carriers ] and three 2Fe-2S clusters. Succinate thus serves as a direct electron donor to the electron transport chain, and itself is converted into fumarate.<ref name=Drose2013rev>{{Cite journal|last=Dröse|first=Stefan|date=2013-05-01|title=Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning|journal=Biochimica et Biophysica Acta (BBA) - Bioenergetics|series=Respiratory complex II: Role in cellular physiology and disease|volume=1827|issue=5|pages=578–587|doi=10.1016/j.bbabio.2013.01.004|pmid=23333272 |doi-access=}}</ref>
			{{TCACycle WP78|highlight=Succinic_acid}}
			=== Reductive branch of the TCA cycle ===
			{{See also|Succinic acid fermentation}}
			Succinate can alternatively be formed by reverse activity of SDH. Under anaerobic conditions certain bacteria such as ''A. succinogenes'', ''A. succiniciproducens'' and ''M. succiniciproducens'', run the TCA cycle in reverse and convert glucose to succinate through the intermediates of ], ] and ].<ref name=Cheng2013rev>{{Cite journal|last1=Cheng|first1=Ke-Ke|last2=Wang|first2=Gen-Yu|last3=Zeng|first3=Jing|last4=Zhang|first4=Jian-An|date=2013-04-18|title=Improved Succinate Production by Metabolic Engineering|journal=BioMed Research International|volume=2013|pages=538790|doi=10.1155/2013/538790|issn=2314-6133|pmc=3652112|pmid=23691505|doi-access=free}}</ref> This pathway is exploited in metabolic engineering to net generate succinate for human use.<ref name=Cheng2013rev/> Additionally, succinic acid produced during the fermentation of sugar provides a combination of saltiness, bitterness and acidity to fermented alcohols.<ref>{{Cite book|title=Knowing and Making Wine|last=Peynaud|first=Emile|date=1984}}</ref>
			Accumulation of fumarate can drive the reverse activity of SDH, thus enhancing succinate generation. Under pathological and physiological conditions, the ] or the ] can increase mitochondrial fumarate, which is then readily converted to succinate.<ref name=Haas2016rev/>
			=== Glyoxylate cycle ===
			{{See also|Glyoxylate cycle}}
			Succinate is also a product of the ], which converts two two-carbon acetyl units into the four-carbon succinate. The glyoxylate cycle is utilized by many bacteria, plants and fungi and allows these organisms to subsist on acetate or acetyl CoA yielding compounds. The pathway avoids the ] steps of the TCA cycle via the enzyme ] which cleaves ] into succinate and ]. Generated succinate is then available for either energy production or biosynthesis.<ref name=BiochemText5th>{{cite book|last1=Berg|first1=JM|last2=Tymoczko|first2=JL|last3=Stryer|first3=L|title=Biochemistry|date=2002|publisher=W H Freeman|location=New York|edition=5th|url=https://www.ncbi.nlm.nih.gov/books/NBK22383/}}</ref>{{rp|Section 17.4}}
			=== GABA shunt ===
			Succinate is the re-entry point for the ] (GABA) shunt into the TCA cycle, a closed cycle which synthesizes and recycles GABA.<ref name=BasicNeurochemTextChapter>{{cite book|last1=Olsen|first1=Richard W|last2=DeLorey|first2=Timothy M|editor1-last=Siegel|editor1-first=GJ|editor2-last=Agranoff|editor2-first=BW|editor3-last=Albers|editor3-first=RW |display-editors=etal |title=Basic Neurochemistry: Molecular, Cellular and Medical Aspects|date=1999|publisher=Lippincott-Raven|location=Philadelphia|edition=6th|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK27979/|chapter=GABA Synthesis, Uptake and Release}}</ref> The GABA shunt serves as an alternate route to convert ] into succinate, bypassing the TCA cycle intermediate succinyl-CoA and instead producing the intermediate GABA. Transamination and subsequent decarboxylation of alpha-ketoglutarate leads to the formation of GABA. GABA is then metabolized by ] to ]. Finally, succinic semialdehyde is oxidized by ] (SSADH) to form succinate, re-entering the TCA cycle and closing the loop. Enzymes required for the GABA shunt are expressed in neurons, glial cells, macrophages and pancreatic cells.<ref name=BasicNeurochemTextChapter/>
			]
			== Cellular metabolism ==
			=== Metabolic intermediate ===
			Succinate is produced and concentrated in the ] and its primary biological function is that of a metabolic ].<ref name=Tretter2016rev/><ref name=BiochemText5th/>{{rp|Section 17.1}} All metabolic pathways that are interlinked with the TCA cycle, including the metabolism of carbohydrates, amino acids, fatty acids, cholesterol, and heme, rely on the temporary formation of succinate.<ref name=Tretter2016rev/> The intermediate is made available for biosynthetic processes through multiple pathways, including the reductive branch of the TCA cycle or the glyoxylate cycle, which are able to drive net production of succinate.<ref name=Cheng2013rev/><ref name=BasicNeurochemTextChapter/> In rodents, mitochondrial concentrations are approximately ~0.5 mM<ref name=Tretter2016rev>{{Cite journal|last1=Tretter|first1=Laszlo|last2=Patocs|first2=Attila|last3=Chinopoulos|first3=Christos|date=2016-08-01|title=Succinate, an intermediate in metabolism, signal transduction, ROS, hypoxia, and tumorigenesis|journal=Biochimica et Biophysica Acta (BBA) - Bioenergetics|series=EBEC 2016: 19th European Bioenergetics Conference|volume=1857|issue=8|pages=1086–1101|doi=10.1016/j.bbabio.2016.03.012|pmid=26971832 |doi-access=free}}</ref> while plasma concentration are only 2–20 μM.<ref name=Ariza2012rev>{{Cite journal|last1=Ariza|first1=Ana Carolina|last2=Deen|first2=Peter M. T.|last3=Robben|first3=Joris Hubertus|date=2012-01-01|title=The succinate receptor as a novel therapeutic target for oxidative and metabolic stress-related conditions|journal= Frontiers in Endocrinology|volume=3|pages=22|doi=10.3389/fendo.2012.00022|pmc=3355999|pmid=22649411|doi-access=free}}</ref>
			=== ROS production ===
			{{See also|Reactive Oxygen Species}}
			The activity of succinate dehydrogenase (SDH), which interconverts succinate into fumarate participates in mitochondrial ] (ROS) production by directing electron flow in the electron transport chain.<ref name=Tretter2016rev/><ref name=Drose2013rev/> Under conditions of succinate accumulation, rapid oxidation of succinate by SDH can drive ] (RET).<ref name=Pell2016rev/> If ] is unable to accommodate excess electrons supplied by succinate oxidation, it forces electrons to flow backwards along the electron transport chain. RET at ], the complex normally preceding SDH in the electron transport chain, leads to ROS production and creates a pro-oxidant microenvironment.<ref name=Pell2016rev/>
			== Additional biologic functions ==
			{{primary sources|date=March 2017}}
			In addition to its metabolic roles, succinate serves as an intracellular and extracellular signaling molecule.<ref name=Tretter2016rev/><ref name=Haas2016rev>{{Cite journal|last1=Haas|first1=Robert|last2=Cucchi|first2=Danilo|last3=Smith|first3=Joanne|last4=Pucino|first4=Valentina|last5=Macdougall|first5=Claire Elizabeth|last6=Mauro|first6=Claudio|title=Intermediates of Metabolism: From Bystanders to Signalling Molecules|journal=Trends in Biochemical Sciences|volume=41|issue=5|pages=460–471|doi=10.1016/j.tibs.2016.02.003|pmid=26935843|year=2016|url=http://qmro.qmul.ac.uk/xmlui/handle/123456789/18257}}</ref> Extra-mitochondrial succinate alters the epigenetic landscape by inhibiting the family of ].<ref name=Haas2016rev/> Alternative, succinate can be released into the ] and the blood stream where it is recognized by target receptors.<ref name=Fonseca2016rev /> In general, leakage from the mitochondria requires succinate overproduction or underconsumption and occurs due to reduced, reverse or completely absent activity of SDH or alternative changes in metabolic state. Mutations in SDH, ] or energetic misbalance are all linked to an alteration of flux through the TCA cycle and succinate accumulation.<ref name=Tretter2016rev /><ref name=Haas2016rev/><ref name=Bardella2011rev/> Upon exiting the mitochondria, succinate serves as a signal of metabolic state, communicating to neighboring cells how metabolically active the originating cell population is.<ref name=Haas2016rev/> As such, succinate links TCA cycle dysfunction or metabolic changes to cell-cell communication and to oxidative stress-related responses.
			=== Transporters ===
			Succinate requires specific transporters to move through both the mitochondrial and plasma membrane. Succinate exits the mitochondrial matrix and passes through the inner mitochondrial membrane via ], primarily SLC25A10, a succinate-fumarate/malate transporter.<ref name=Fonseca2016rev>{{Cite journal|last1=de Castro Fonseca|first1=Matheus|last2=Aguiar|first2=Carla J.|last3=da Rocha Franco|first3=Joao Antônio|last4=Gingold|first4=Rafael N.|last5=Leite|first5=M. Fatima|date=2016-01-01|title=GPR91: expanding the frontiers of Krebs cycle intermediates|journal=Cell Communication and Signaling|volume=14|pages=3|doi=10.1186/s12964-016-0126-1|pmc=4709936|pmid=26759054 |doi-access=free }}</ref> In the second step of mitochondrial export, succinate readily crosses the outer mitochondrial membrane through ], nonspecific protein channels that facilitate the diffusion of molecules less than 1.5 kDa.<ref name=Fonseca2016rev/> Transport across the plasma membrane is likely tissue specific. A key candidate transporter is ] (I'm not dead yet), a sodium-independent anion exchanger, which moves both dicarboxylate and citrate into the bloodstream.<ref name=Fonseca2016rev/>
			]
			=== Extracellular signaling ===
			Extracellular succinate can act as a signaling molecule with hormone-like functions in stimulating a variety of cells such as those in the blood, adipose tissues, immune tissues, liver, heart, retina and kidney.<ref name=Fonseca2016rev/> Extracellular succinate works by binding to and thereby activating the GPR91 (also termed ]<ref name="pmid35888775">{{cite journal | vauthors = Detraux D, Renard P | title = Succinate as a New Actor in Pluripotency and Early Development? | journal = Metabolites | volume = 12 | issue = 7 | date = July 2022 | page = 651 | pmid = 35888775 | pmc = 9325148 | doi = 10.3390/metabo12070651 | doi-access = free | url = }}</ref>) ] on the cells that express this receptor. Most studies have reported that the GPR91 protein consists of 330 ]s although a few studies have detected a 334 amino acid product of ''GPR91'' gene.<ref name="pmid26808164">{{cite journal | vauthors = Gilissen J, Jouret F, Pirotte B, Hanson J | title = Insight into SUCNR1 (GPR91) structure and function | journal = Pharmacology & Therapeutics | volume = 159 | issue = | pages = 56–65 | date = March 2016 | pmid = 26808164 | doi = 10.1016/j.pharmthera.2016.01.008 | hdl = 2268/194560 | s2cid = 24982373 | url = https://orbi.uliege.be/bitstream/2268/194560/1/Gilissen%20et%20al%202016.pdf}}</ref> Arg<sup>99</sup>, His<sup>103</sup>, Arg<sup>252</sup>, and Arg<sup>281</sup> near the center of the GPR91 protein generate a positively charged binding site for succinate. GPR91 resides on its target cells' ]s with its binding site facing the extracellular space.<ref name=Gilissen2016rev/> It is a ] sub-type of receptor<ref name=Gilissen2016rev>{{Cite journal|last1=Gilissen|first1=Julie|last2=Jouret|first2=François|last3=Pirotte|first3=Bernard|last4=Hanson|first4=Julien|date=2016-03-01|title=Insight into SUCNR1 (GPR91) structure and function|journal=Pharmacology & Therapeutics|volume=159|pages=56–65|doi=10.1016/j.pharmthera.2016.01.008|pmid=26808164|hdl=2268/194560|s2cid=24982373 |url=http://orbi.ulg.ac.be/handle/2268/194560|hdl-access=free}}</ref> that, depending on the cell type bearing it, interacts with multiple ] subtypes including ], ] and ]. This enables GPR91 to regulate a multitude of signaling outcomes.<ref name=Fonseca2016rev/>
			Succinate has a high affinity for GPR91, with an ] (i.e., concentration that induces a half maximal response) for stimulating GPR91 in the 20–50 μM range. Succinate's activation of the GPR91 receptor simulates a wide range of cell types and ] responses (see ]).<ref name="pmid34301438">{{cite journal | vauthors = Fernández-Veledo S, Ceperuelo-Mallafré V, Vendrell J | title = Rethinking succinate: an unexpected hormone-like metabolite in energy homeostasis | journal = Trends in Endocrinology and Metabolism | volume = 32 | issue = 9 | pages = 680–692 | date = September 2021 | pmid = 34301438 | doi = 10.1016/j.tem.2021.06.003 | s2cid = 236097682 | url = }}</ref><ref name="pmid33279412">{{cite journal | vauthors = Krzak G, Willis CM, Smith JA, Pluchino S, Peruzzotti-Jametti L | title = Succinate Receptor 1: An Emerging Regulator of Myeloid Cell Function in Inflammation | journal = Trends in Immunology | volume = 42 | issue = 1 | pages = 45–58 | date = January 2021 | pmid = 33279412 | doi = 10.1016/j.it.2020.11.004 | s2cid = 227522279 | url = }}</ref>
			==== Effect on adipocytes ====
			In ]s, the succinate-activated GPR91 signaling cascade inhibits ].<ref name=Fonseca2016rev/>
			==== Effect on the liver and retina ====
			Succinate signaling often occurs in response to hypoxic conditions. In the liver, succinate serves as a ] signal, released by anoxic ]s, and targets ]s via GPR91.<ref name=Fonseca2016rev /> This leads to stellate cell activation and fibrogenesis. Thus, succinate is thought to play a role in liver ]. In the retina, succinate accumulates in ]s in response to ischemic conditions. ] succinate signaling promotes retinal ], triggering the activation of angiogenic factors such as ] (VEGF).<ref name=Fonseca2016rev/><ref name=Gilissen2016rev/>
			==== Effect on the heart ====
			Extracellular succinate regulates ] viability through GPR91 activation; long-term succinate exposure leads to pathological cardiomyocyte ].<ref name=Fonseca2016rev/> Stimulation of GPR91 triggers at least two signaling pathways in the heart: a ] and ] pathway that activates hypertrophic gene expression and a ] pathway which changes the pattern of Ca<sup>2+</sup> uptake and distribution and triggers ]-dependent hypertrophic gene activation.<ref name="Fonseca2016rev" />
			==== Effect on immune cells ====
			SUCNR1 is highly expressed on immature ]s, where succinate binding stimulates ].<ref name=Gilissen2016rev/> Furthermore, SUCNR1 synergizes with ]s to increase the production of ]s such as ] and ].<ref name=Mills2014rev/><ref name=Gilissen2016rev/> Succinate may enhance ] by triggering the activity of antigen-presenting cells that, in turn, activate ].<ref name=Mills2014rev/>
			==== Effect on platelets ====
			SUCNR1 is one of the highest expressed G protein-coupled receptors on human platelets, present at levels similar to ], though the role of succinate signaling in ] is debated. Multiple studies have demonstrated succinate-induced aggregation, but the effect has high inter-individual variability.<ref name=Ariza2012rev/>
			==== Effect on the kidneys ====
			Succinate serves as a modulator of blood pressure by stimulating renin release in ] and ] via GPR91.<ref>{{Cite journal|last1=Peti-Peterdi|first1=János|last2=Gevorgyan|first2=Haykanush|last3=Lam|first3=Lisa|last4=Riquier-Brison|first4=Anne|date=2012-06-23|title=Metabolic control of renin secretion|journal=Pflügers Archiv: European Journal of Physiology|volume=465|issue=1|pages=53–58|doi=10.1007/s00424-012-1130-y|issn=0031-6768|pmc=4574624|pmid=22729752}}</ref> Therapies targeting succinate to reduce cardiovascular risk and hypertension are currently under investigation.<ref name=Ariza2012rev/>
			=== Intracellular signaling ===
			{{See also|Dioxygenase}}
			]
			Accumulation of either fumarate or succinate reduces the activity of ], including histone and DNA ]s, ] and collagen prolyl-4-hydroxylases, through ].<ref>{{Cite journal|last1=Xiao|first1=Mengtao|last2=Yang|first2=Hui|last3=Xu|first3=Wei|last4=Ma|first4=Shenghong|last5=Lin|first5=Huaipeng|last6=Zhu|first6=Honguang|last7=Liu|first7=Lixia|last8=Liu|first8=Ying|last9=Yang|first9=Chen|date=2012-06-15|title=Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors|journal=Genes & Development|volume=26|issue=12|pages=1326–1338|doi=10.1101/gad.191056.112|issn=0890-9369|pmc=3387660|pmid=22677546}}</ref> 2-oxoglutarate-dependent dioxygenases require an iron cofactor to catalyze hydroxylations, desaturations and ring closures.<ref name=Hewitson2005rev>{{Cite journal|last1=Hewitson|first1=K. S.|last2=Granatino|first2=N.|last3=Welford|first3=R. W. D.|last4=McDonough|first4=M. A.|last5=Schofield|first5=C. J.|date=2005-04-15|title=Oxidation by 2-oxoglutarate oxygenases: non-haem iron systems in catalysis and signalling|journal=Philosophical Transactions of the Royal Society of London A: Mathematical, Physical and Engineering Sciences|volume=363|issue=1829|pages=807–828|doi=10.1098/rsta.2004.1540|pmid=15901537|bibcode=2005RSPTA.363..807H|s2cid=8568103}}</ref> Simultaneous to substrate oxidation, they convert ], also known as alpha-ketoglutarate, into succinate and CO<sub>2</sub>. 2-oxoglutarate-dependent dioxygenases bind substrates in a ].<ref name=Hewitson2005rev/> First, 2-oxoglutarate coordinates with an Fe(II) ion bound to a conserved 2-histidinyl–1-aspartyl/glutamyl triad of residues present in the enzymatic center. Subsequently, the primary substrate enters the binding pocket and lastly dioxygen binds to the enzyme-substrate complex. ] then generates a ferryl intermediate coordinated to succinate, which serves to oxidize the bound primary substrate.<ref name=Hewitson2005rev/> Succinate may interfere with the enzymatic process by attaching to the Fe(II) center first, prohibiting the binding of 2-oxoglutarate. Thus, via enzymatic inhibition, increased succinate load can lead to changes in transcription factor activity and genome-wide alterations in histone and DNA methylation.
			==== Epigenetic effects ====
			Succinate and fumarate inhibit the ] (ten-eleven translocation) family of ] DNA modifying enzymes and the ] (KDM).<ref name=Yang2013comment>{{Cite journal|last1=Yang|first1=Ming|last2=Pollard|first2=Patrick J.|title=Succinate: A New Epigenetic Hacker|journal=Cancer Cell|volume=23|issue=6|pages=709–711|doi=10.1016/j.ccr.2013.05.015|pmid=23763995|date=10 June 2013|doi-access=free}}</ref> Pathologically elevated levels of succinate lead to hypermethylation, epigenetic silencing and changes in neuroendocrine differentiation, potentially driving cancer formation.<ref name=Yang2013comment/><ref name=Yang2013rev/>
			==== Gene regulation ====
			Succinate inhibition of ]s (PHDs) stabilizes the transcription factor ].<ref name=Tretter2016rev/><ref name=Haas2016rev/><ref name=Koivunen2007rev>{{cite journal|last1=Koivunen|first1=P|last2=Hirsilä|first2=M|last3=Remes|first3=AM|last4=Hassinen|first4=IE|last5=Kivirikko|first5=KI|last6=Myllyharju|first6=J|title=Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF.|journal=The Journal of Biological Chemistry|date=16 February 2007|volume=282|issue=7|pages=4524–32|doi=10.1074/jbc.M610415200|pmid=17182618|doi-access=free}}</ref> PHDs hydroxylate proline in parallel to oxidatively decarboxylating 2-oxyglutarate to succinate and CO<sub>2</sub>. In humans, three HIF prolyl 4-hydroxylases regulate the stability of HIFs.<ref name=Koivunen2007rev/> Hydroxylation of two prolyl residues in HIF1α facilitates ubiquitin ligation, thus marking it for proteolytic destruction by the ] pathway. Since PHDs have an absolute requirement for molecular oxygen, this process is suppressed in hypoxia allowing HIF1α to escape destruction. High concentrations of succinate will mimic the hypoxia state by suppressing PHDs,<ref name=Yang2013rev/> therefore stabilizing HIF1α and inducing the transcription of HIF1-dependent genes even under normal oxygen conditions. HIF1 is known to induce transcription of more than 60 genes, including genes involved in ] and ], energy ], cell survival, and tumor invasion.<ref name=Tretter2016rev/><ref name=Koivunen2007rev/>
			== Role in human health ==
			=== Inflammation ===
			Metabolic signaling involving succinate can be involved in ] via stabilization of ] or GPR91 signaling in innate immune cells. Through these mechanisms, succinate accumulation has been shown to regulate production of inflammatory ]s.<ref name=Mills2014rev/> For dendritic cells, succinate functions as a chemoattractant and increases their antigen-presenting function via receptor stimulated cytokine production.<ref name=Gilissen2016rev/> In inflammatory ]s, succinate-induced stability of HIF1 results in increased transcription of HIF1-dependent genes, including the pro-inflammatory cytokine ].<ref>{{Cite journal|last1=Tannahill|first1=GM|last2=Curtis|first2=AM|last3=Adamik|first3=J|last4=Palsson-McDermott|first4=EM|last5=McGettrick|first5=AF|last6=Goel|first6=G|last7=Frezza|first7=C|last8=Bernard|first8=NJ|last9=Kelly|first9=B|date=2013-04-11|title=Succinate is a danger signal that induces IL-1β via HIF-1α|journal=Nature|volume=496|issue=7444|pages=238–242|doi=10.1038/nature11986|issn=0028-0836|pmc=4031686|pmid=23535595}}</ref> Other inflammatory cytokines produced by activated macrophages such as ] or ] are not directly affected by succinate and HIF1.<ref name=Mills2014rev /> The mechanism by which succinate accumulates in immune cells is not fully understood.<ref name=Mills2014rev/> Activation of inflammatory macrophages through ]s induces a metabolic shift towards glycolysis.<ref>{{Cite journal|last1=Kelly|first1=Beth|last2=O'Neill|first2=Luke AJ|date=2015-07-01|title=Metabolic reprogramming in macrophages and dendritic cells in innate immunity|journal=Cell Research|volume=25|issue=7|pages=771–784|doi=10.1038/cr.2015.68|issn=1001-0602|pmc=4493277|pmid=26045163}}</ref> In spite of a general downregulation of the TCA cycle under these conditions, succinate concentration is increased. However, ]s involved in the activation of macrophages increase ] and ]s.<ref name=Mills2014rev/> Succinate may thus be produced from enhanced glutamine metabolism via alpha-ketoglutarate or the GABA shunt.{{Citation needed|date=January 2021}}
			=== Tumorigenesis ===
			Succinate is one of three oncometabolites, metabolic intermediates whose accumulation causes metabolic and non-metabolic dysregulation implicated in ].<ref name=Yang2013rev>{{Cite journal|last1=Yang|first1=Ming|last2=Soga|first2=Tomoyoshi|last3=Pollard|first3=Patrick J.|date=2013-09-03|title=Oncometabolites: linking altered metabolism with cancer|journal=The Journal of Clinical Investigation|volume=123|issue=9|pages=3652–8|doi=10.1172/JCI67228|issn=0021-9738|pmc=3754247|pmid=23999438}}</ref><ref name=Sciacovelli2017rev>{{Cite journal|last1=Sciacovelli|first1=Marco|last2=Frezza|first2=Christian|date=2017-03-06|title=Oncometabolites: Unconventional triggers of oncogenic signalling cascades|journal=Free Radical Biology & Medicine|volume=100|pages=175–181|doi=10.1016/j.freeradbiomed.2016.04.025|issn=0891-5849|pmc=5145802|pmid=27117029}}</ref> Loss-of-function mutations in the genes encoding ], frequently found in hereditary ] and ], cause pathological increase in succinate.<ref name=Bardella2011rev>{{Cite journal|last1=Bardella|first1=Chiara|last2=Pollard|first2=Patrick J.|last3=Tomlinson|first3=Ian|date=2011-11-01|title=SDH mutations in cancer|journal=Biochimica et Biophysica Acta (BBA) - Bioenergetics|volume=1807|issue=11|pages=1432–1443|doi=10.1016/j.bbabio.2011.07.003|pmid=21771581|doi-access=free}}</ref> SDH mutations have also been identified in ]s, ], ], testicular seminomas and ]s.<ref name=Yang2013rev/> The oncogenic mechanism caused by mutated SHD is thought to relate to succinate's ability to inhibit ]. Inhibition of KDMs and TET hydroxylases results in epigenetic dysregulation and hypermethylation affecting genes involved in ].<ref name=Yang2013comment/> Additionally, succinate-promoted activation of HIF-1α generates a pseudo-hypoxic state that can promote tumorneogensis by transcriptional activation of genes involved in proliferation, metabolism and angiogenesis.<ref>{{Cite journal|last1=King|first1=A.|last2=Selak|first2=M. A.|last3=Gottlieb|first3=E.|date=2006-01-01|title=Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer|journal=Oncogene|volume=25|issue=34|pages=4675–4682|doi=10.1038/sj.onc.1209594|pmid=16892081|issn=0950-9232|doi-access=|s2cid=26263513 }}</ref> The other two oncometabolites, ] and ] have similar structures to succinate and function through parallel HIF-inducing oncogenic mechanisms.<ref name=Sciacovelli2017rev/>
			=== Ischemia reperfusion injury ===
			Succinate accumulation under hypoxic conditions has been implicated in the ] through increased ROS production.<ref name=Chouchani|2014primary>{{cite journal|last1=Chouchani|first1=ET|last2=Pell|first2=VR|last3=Gaude|first3=E|last4=Aksentijević|first4=D|last5=Sundier|first5=SY|last6=Robb|first6=EL|last7=Logan|first7=A|last8=Nadtochiy|first8=SM|last9=Ord|first9=EN|last10=Smith|first10=AC|last11=Eyassu|first11=F|last12=Shirley|first12=R|last13=Hu|first13=CH|last14=Dare|first14=AJ|last15=James|first15=AM|last16=Rogatti|first16=S|last17=Hartley|first17=RC|last18=Eaton|first18=S|last19=Costa|first19=AS|last20=Brookes|first20=PS|last21=Davidson|first21=SM|last22=Duchen|first22=MR|last23=Saeb-Parsy|first23=K|last24=Shattock|first24=MJ|last25=Robinson|first25=AJ|last26=Work|first26=LM|last27=Frezza|first27=C|last28=Krieg|first28=T|last29=Murphy|first29=MP|title=Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS.|journal=Nature|date=20 November 2014|volume=515|issue=7527|pages=431–5|doi=10.1038/nature13909|pmid=25383517|pmc=4255242|bibcode=2014Natur.515..431C}}</ref><ref name=Pell2016rev/> During ischemia, succinate accumulates. Upon reperfusion, succinate is rapidly oxidized leading to abrupt and extensive production of ROS.<ref name=Chouchani|2014primary/> ROS then trigger the cellular ] machinery or induce oxidative damage to proteins, membranes, organelles etc. In animal models, pharmacological inhibition of ischemic succinate accumulation ameliorated ischemia-reperfusion injury.<ref name=Pell2016rev>{{Cite journal|last1=Pell|first1=Victoria R.|last2=Chouchani|first2=Edward T.|last3=Frezza|first3=Christian|last4=Murphy|first4=Michael P.|last5=Krieg|first5=Thomas|date=2016-07-15|title=Succinate metabolism: a new therapeutic target for myocardial reperfusion injury|journal=Cardiovascular Research|volume=111|issue=2|pages=134–141|doi=10.1093/cvr/cvw100|pmid= 27194563|url=https://www.repository.cam.ac.uk/handle/1810/284972|doi-access=free}}</ref> As of 2016 the inhibition of succinate-mediated ROS production was under investigation as a therapeutic ].<ref name=Pell2016rev/>
			==See also==
			* ]
			* ], procured by heating succinic acid
			* ]
			* ]
			* ]
			==References==
			{{Reflist|30em}}
			==External links==
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			{{citric acid cycle}}
			{{Navbox linear saturated dicarboxylic acids}}
			{{Authority control}}
			{{DEFAULTSORT:Succinic Acid}}
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