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| Names | |
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| Preferred IUPAC name Butanedioic acid[1] | |
| Other names Succinic acid[1] 1,4-Butanedioic acid | |
| Identifiers | |
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3D model (JSmol) | |
| ChEBI | |
| ChEMBL | |
| ChemSpider |
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| DrugBank |
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| ECHA InfoCard | 100.003.402 |
| E number | E363(antioxidants, ...) |
| UNII | |
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| Properties | |
| C4H6O4 | |
| Molar mass | 118.088 g·mol−1 |
| Density | 1.56 g/cm3[2] |
| Melting point | 184–190 °C (363–374 °F; 457–463 K)[2][4] |
| Boiling point | 235 °C (455 °F; 508 K)[2] |
| 80 g/L (20 °C)[2] or 100 mg/mL[3] | |
| Solubility inMethanol | 158 mg/mL[3] |
| Solubility inEthanol | 54 mg/mL[3] |
| Solubility inAcetone | 27 mg/mL[3] |
| Solubility inGlycerol | 50 mg/mL[3] |
| Solubility inEther | 8.8 mg/mL[3] |
| Acidity (pKa) | pKa1 = 4.2 pKa2 = 5.6 |
| −57.9·10−6 cm3/mol | |
| Hazards | |
| Flash point | 206 °C (403 °F; 479 K)[2] |
| Related compounds | |
Otheranions | sodium succinate |
Relatedcarboxylic acids | propionic acid malonic acid butyric acid malic acid tartaric acid fumaric acid valeric acid glutaric acid |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Succinic acid (/səkˈsɪnɪk/) is adicarboxylic acid with thechemical formula (CH2)2(CO2H)2.[5] In living organisms, succinic acid takes the form of ananion,succinate, which has multiple biological roles as ametabolic intermediate being converted intofumarate by the enzymesuccinate dehydrogenase in complex 2 of theelectron transport chain which is involved in makingATP, and as a signaling molecule reflecting the cellular metabolic state.[6]
Succinate is generated inmitochondria via thetricarboxylic acid (TCA) cycle. Succinate can exit the mitochondrial matrix and function in the cytoplasm as well as the extracellular space, changing gene expression patterns, modulatingepigenetic landscape or demonstratinghormone-like signaling.[6] As such, succinate links cellularmetabolism, especially ATP formation, to the regulation of cellular function.
Dysregulation of succinate synthesis, and therefore ATP synthesis, happens in some genetic mitochondrial diseases, such asLeigh syndrome, andMelas syndrome, and degradation can lead to pathological conditions, such asmalignant transformation,inflammation and tissue injury.[6][7][8]
Succinic acid is marketed as food additiveE363. The name derives from Latinsuccinum, meaningamber.
Succinic acid is a white, odorless solid with a highly acidic taste.[5] In anaqueous solution, succinic acid readilyionizes to form its conjugate base, succinate (/ˈsʌksɪneɪt/). As adiprotic acid, succinic acid undergoes two successive deprotonation reactions:
ThepKa of these processes are 4.3 and 5.6, respectively. Both anions are colorless and can be isolated as the salts, e.g., Na(CH2)2(CO2H)(CO2) and Na2(CH2)2(CO2)2. In living organisms, primarily succinate, not succinic acid, is found.[5]
As aradical group it is called a succinyl (/ˈsʌksɪnəl/) group.[9]
Like most simple mono- and dicarboxylic acids, it is not harmful but can be an irritant to skin and eyes.[5]
Historically, succinic acid was obtained fromamber by distillation and has thus been known as spirit of amber (Latin:spiritus succini[10]). Common industrial routes includehydrogenation ofmaleic acid, oxidation of1,4-butanediol, andcarbonylation ofethylene glycol. Succinate is also produced frombutane viamaleic anhydride.[11] Global production is estimated at 16,000 to 30,000 tons a year, with an annual growth rate of 10%.[12]
Genetically engineeredEscherichia coli andSaccharomyces cerevisiae are proposed for the commercial production via fermentation ofglucose.[13][14]
Succinic acid can be dehydrogenated tofumaric acid or be converted to diesters, such as diethylsuccinate (CH2CO2CH2CH3)2. This diethyl ester is a substrate in theStobbe condensation. Dehydration of succinic acid givessuccinic anhydride.[15] Succinate can be used to derive 1,4-butanediol, maleic anhydride, succinimide, 2-pyrrolidinone andtetrahydrofuran.[13]
In 2004, succinate was placed on the US Department of Energy's list of top 12 platform chemicals from biomass.[16]
Succinic acid is aprecursor to somepolyesters and a component of somealkyd resins.[11]1,4-Butanediol (BDO) can be synthesized using succinic acid as a precursor.[17] The automotive and electronics industries heavily rely on BDO to produce connectors, insulators, wheel covers, gearshift knobs and reinforcing beams.[18] Succinic acid also serves as the bases of certain biodegradable polymers, which are of interest in tissue engineering applications.[19]
Acylation with succinic acid is calledsuccination.Oversuccination occurs when more than one succinate adds to a substrate.[citation needed]
As afood additive anddietary supplement, succinic acid isgenerally recognized as safe by theU.S. Food and Drug Administration.[20] Succinic acid is used primarily as anacidity regulator[21] in the food and beverage industry. It is also available as a flavoring agent, contributing a somewhat sour and astringent component to umami taste.[13] As anexcipient in pharmaceutical products, it is also used to control acidity[22] or as a counter ion.[13] Drugs involving succinate includemetoprolol succinate,sumatriptan succinate,doxylamine succinate orsolifenacin succinate.[citation needed]
Succinate is a key intermediate in thetricarboxylic acid cycle, a primary metabolic pathway used to produce chemical energy in the presence of O2. Succinate is generated fromsuccinyl-CoA by the enzymesuccinyl-CoA synthetase in aGTP/ATP-producing step:[23]: Section 17.1
Succinyl-CoA + NDP + Pi → Succinate + CoA + NTP
Catalyzed by the enzymesuccinate dehydrogenase (SDH), succinate is subsequently oxidized tofumarate:[23]: Section 17.1
Succinate + FAD → Fumarate + FADH2
SDH also participates in the mitochondrialelectron transport chain, where it is known asrespiratory complex II. This enzyme complex is a 4 subunit membrane-bound lipoprotein which couples the oxidation of succinate to the reduction ofubiquinone via the intermediate electron carriersFAD and three 2Fe-2S clusters. Succinate thus serves as a direct electron donor to the electron transport chain, and itself is converted into fumarate.[24]
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
Succinate can alternatively be formed by reverse activity of SDH. Under anaerobic conditions certain bacteria such asA. succinogenes,A. succiniciproducens andM. succiniciproducens, run the TCA cycle in reverse and convert glucose to succinate through the intermediates ofoxaloacetate,malate andfumarate.[25] This pathway is exploited in metabolic engineering to net generate succinate for human use.[25] Additionally, succinic acid produced during the fermentation of sugar provides a combination of saltiness, bitterness and acidity to fermented alcohols.[26]
Accumulation of fumarate can drive the reverse activity of SDH, thus enhancing succinate generation. Under pathological and physiological conditions, themalate-aspartate shuttle or thepurine nucleotide shuttle can increase mitochondrial fumarate, which is then readily converted to succinate.[27]
Succinate is also a product of theglyoxylate cycle, 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 thedecarboxylation steps of the TCA cycle via the enzymeisocitrate lyase which cleavesisocitrate into succinate andglyoxylate. Generated succinate is then available for either energy production or biosynthesis.[23]: Section 17.4
Succinate is the re-entry point for thegamma-aminobutyric acid (GABA) shunt into the TCA cycle, a closed cycle which synthesizes and recycles GABA.[28] The GABA shunt serves as an alternate route to convertalpha-ketoglutarate 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 byGABA transaminase tosuccinic semialdehyde. Finally, succinic semialdehyde is oxidized bysuccinic semialdehyde dehydrogenase (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.[28]
Succinate is produced and concentrated in themitochondria and its primary biological function is that of a metabolicintermediate.[6][23]: 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.[6] 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.[25][28] In rodents, mitochondrial concentrations are approximately ~0.5 mM[6] while plasma concentration are only 2–20 μM.[29]
The activity of succinate dehydrogenase (SDH), which interconverts succinate into fumarate participates in mitochondrialreactive oxygen species (ROS) production by directing electron flow in the electron transport chain.[6][24] Under conditions of succinate accumulation, rapid oxidation of succinate by SDH can drivereverse electron transport (RET).[30] Ifmitochondrial respiratory complex III is unable to accommodate excess electrons supplied by succinate oxidation, it forces electrons to flow backwards along the electron transport chain. RET atmitochondrial respiratory complex 1, the complex normally preceding SDH in the electron transport chain, leads to ROS production and creates a pro-oxidant microenvironment.[30]
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In addition to its metabolic roles, succinate serves as an intracellular and extracellular signaling molecule.[6][27] Extra-mitochondrial succinate alters the epigenetic landscape by inhibiting the family of2-oxogluterate-dependent dioxygenases.[27] Alternative, succinate can be released into theextracellular milieu and the blood stream where it is recognized by target receptors.[31] 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,hypoxia or energetic misbalance are all linked to an alteration of flux through the TCA cycle and succinate accumulation.[6][27][32] Upon exiting the mitochondria, succinate serves as a signal of metabolic state, communicating to neighboring cells how metabolically active the originating cell population is.[27] As such, succinate links TCA cycle dysfunction or metabolic changes to cell-cell communication and to oxidative stress-related responses.
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 viadicarboxylate transporters, primarily SLC25A10, a succinate-fumarate/malate transporter.[31] In the second step of mitochondrial export, succinate readily crosses the outer mitochondrial membrane throughporins, nonspecific protein channels that facilitate the diffusion of molecules less than 1.5 kDa.[31] Transport across the plasma membrane is likely tissue specific. A key candidate transporter isINDY (I'm not dead yet), a sodium-independent anion exchanger, which moves both dicarboxylate and citrate into the bloodstream.[31]
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.[31] Extracellular succinate works by binding to and thereby activating the GPR91 (also termedSUCNR1[33])receptor on the cells that express this receptor. Most studies have reported that the GPR91 protein consists of 330amino acids although a few studies have detected a 334 amino acid product ofGPR91 gene.[34] Arg99, His103, Arg252, and Arg281 near the center of the GPR91 protein generate a positively charged binding site for succinate. GPR91 resides on its target cells'surface membranes with its binding site facing the extracellular space.[35] It is aG protein-coupled receptor sub-type of receptor[35] that, depending on the cell type bearing it, interacts with multipleG proteins subtypes includingGs,Gi andGq. This enables GPR91 to regulate a multitude of signaling outcomes.[31]
Succinate has a high affinity for GPR91, with anEC50 (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 andphysiological responses (seeFunctions regulated by SUCNR1).[36][37]
Inadipocytes, the succinate-activated GPR91 signaling cascade inhibitslipolysis.[31]
Succinate signaling often occurs in response to hypoxic conditions. In the liver, succinate serves as aparacrine signal, released by anoxichepatocytes, and targetsstellate cells via GPR91.[31] This leads to stellate cell activation and fibrogenesis. Thus, succinate is thought to play a role in liverhomeostasis. In the retina, succinate accumulates inretinal ganglion cells in response to ischemic conditions.Autocrine succinate signaling promotes retinalneovascularization, triggering the activation of angiogenic factors such asendothelial growth factor (VEGF).[31][35]
Extracellular succinate regulatescardiomyocyte viability through GPR91 activation; long-term succinate exposure leads to pathological cardiomyocytehypertrophy.[31] Stimulation of GPR91 triggers at least two signaling pathways in the heart: aMEK1/2 andERK1/2 pathway that activates hypertrophic gene expression and aphospholipase C pathway which changes the pattern of Ca2+ uptake and distribution and triggersCaM-dependent hypertrophic gene activation.[31]
SUCNR1 is highly expressed on immaturedendritic cells, where succinate binding stimulateschemotaxis.[35] Furthermore, SUCNR1 synergizes withtoll-like receptors to increase the production ofproinflammatory cytokines such asTNF alpha andinterleukin-1beta.[7][35] Succinate may enhanceadaptive immunity by triggering the activity of antigen-presenting cells that, in turn, activateT-cells.[7]
SUCNR1 is one of the highest expressed G protein-coupled receptors on human platelets, present at levels similar toP2Y12, though the role of succinate signaling inplatelet aggregation is debated. Multiple studies have demonstrated succinate-induced aggregation, but the effect has high inter-individual variability.[29]
Succinate serves as a modulator of blood pressure by stimulating renin release inmacula densa andjuxtaglomerular apparatus cells via GPR91.[38] Therapies targeting succinate to reduce cardiovascular risk and hypertension are currently under investigation.[29]
Accumulation of either fumarate or succinate reduces the activity of2-oxoglutarate-dependent dioxygenases, including histone and DNAdemethylases,prolyl hydroxylases and collagen prolyl-4-hydroxylases, throughcompetitive inhibition.[39] 2-oxoglutarate-dependent dioxygenases require an iron cofactor to catalyze hydroxylations, desaturations and ring closures.[40] Simultaneous to substrate oxidation, they convert2-oxoglutarate, also known as alpha-ketoglutarate, into succinate and CO2. 2-oxoglutarate-dependent dioxygenases bind substrates in asequential, ordered manner.[40] 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.Oxidative decarboxylation then generates a ferryl intermediate coordinated to succinate, which serves to oxidize the bound primary substrate.[40] 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.
Succinate and fumarate inhibit theTET (ten-eleven translocation) family of5-methylcytosine DNA modifying enzymes and theJmjC domain-containing histone lysine demethylase (KDM).[41] Pathologically elevated levels of succinate lead to hypermethylation, epigenetic silencing and changes in neuroendocrine differentiation, potentially driving cancer formation.[41][42]
Succinate inhibition ofprolyl hydroxylases (PHDs) stabilizes the transcription factorhypoxia inducible factor (HIF)1α.[6][27][43] PHDs hydroxylate proline in parallel to oxidatively decarboxylating 2-oxyglutarate to succinate and CO2. In humans, three HIF prolyl 4-hydroxylases regulate the stability of HIFs.[43] Hydroxylation of two prolyl residues in HIF1α facilitates ubiquitin ligation, thus marking it for proteolytic destruction by theubiquitin/proteasome 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,[42] 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 invascularization andangiogenesis, energymetabolism, cell survival, and tumor invasion.[6][43]
Metabolic signaling involving succinate can be involved ininflammation via stabilization ofHIF1-alpha or GPR91 signaling in innate immune cells. Through these mechanisms, succinate accumulation has been shown to regulate production of inflammatorycytokines.[7] For dendritic cells, succinate functions as a chemoattractant and increases their antigen-presenting function via receptor stimulated cytokine production.[35] In inflammatorymacrophages, succinate-induced stability of HIF1 results in increased transcription of HIF1-dependent genes, including the pro-inflammatory cytokineinterleukin-1β.[44] Other inflammatory cytokines produced by activated macrophages such astumor necrosis factor orinterleukin 6 are not directly affected by succinate and HIF1.[7] The mechanism by which succinate accumulates in immune cells is not fully understood.[7] Activation of inflammatory macrophages throughtoll-like receptors induces a metabolic shift towards glycolysis.[45] In spite of a general downregulation of the TCA cycle under these conditions, succinate concentration is increased. However,lipopolysaccharides involved in the activation of macrophages increaseglutamine andGABA transporters.[7] Succinate may thus be produced from enhanced glutamine metabolism via alpha-ketoglutarate or the GABA shunt.[citation needed]
Succinate is one of three oncometabolites, metabolic intermediates whose accumulation causes metabolic and non-metabolic dysregulation implicated intumorigenesis.[42][46] Loss-of-function mutations in the genes encodingsuccinate dehydrogenase, frequently found in hereditaryparaganglioma andpheochromocytoma, cause pathological increase in succinate.[32] SDH mutations have also been identified ingastrointestinal stromal tumors,renal tumors,thyroid tumors, testicular seminomas andneuroblastomas.[42] The oncogenic mechanism caused by mutated SHD is thought to relate to succinate's ability to inhibit2-oxogluterate-dependent dioxygenases. Inhibition of KDMs and TET hydroxylases results in epigenetic dysregulation and hypermethylation affecting genes involved incell differentiation.[41] 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.[47] The other two oncometabolites,fumarate and2-hydroxyglutarate have similar structures to succinate and function through parallel HIF-inducing oncogenic mechanisms.[46]
Succinate accumulation under hypoxic conditions has been implicated in thereperfusion injury through increased ROS production.[8][30] During ischemia, succinate accumulates. Upon reperfusion, succinate is rapidly oxidized leading to abrupt and extensive production of ROS.[8] ROS then trigger the cellularapoptotic machinery or induce oxidative damage to proteins, membranes, organelles etc. In animal models, pharmacological inhibition of ischemic succinate accumulation ameliorated ischemia-reperfusion injury.[30] As of 2016 the inhibition of succinate-mediated ROS production was under investigation as a therapeuticdrug target.[30]
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