Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological roles as a metabolic intermediate being converted into fumarate by the enzyme succinate dehydrogenase in complex 2 of the electron transport chain which is involved in making ATP, and as a signaling molecule reflecting the cellular metabolic state. Succinate is generated in mitochondria via the tricarboxylic acid (TCA) cycle. Succinate can exit the mitochondrial matrix and function in the cytoplasm as well as the extracellular space, changing gene expression patterns, modulating epigenetic landscape or demonstrating hormone-like signaling. As such, succinate links cellular metabolism, 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 Leigh syndrome, and Melas syndrome, and degradation can lead to pathological conditions, such as malignant transformation, inflammation and tissue injury. Succinic acid is marketed as food additive E363. The name derives from Latin succinum, meaning amber.
Physical properties Succinic acid is a white, odorless solid with a highly acidic taste. In an aqueous solution, succinic acid readily ionizes to form its conjugate base, succinate (). As a diprotic acid, succinic acid undergoes two successive deprotonation reactions:
(CH2)2(CO2H)2 → (CH2)2(CO2H)(CO2)− + H+ (CH2)2(CO2H)(CO2)− → (CH2)2(CO2)22− + H+ The pKa 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. As a radical group it is called a succinyl () group. Like most simple mono- and dicarboxylic acids, it is not harmful but can be an irritant to skin and eyes.
Commercial production Historically, succinic acid was obtained from amber by distillation and has thus been known as spirit of amber (Latin: spiritus succini). Common industrial routes include hydrogenation of maleic acid, oxidation of 1,4-butanediol, and carbonylation of ethylene glycol. Succinate is also produced from butane via maleic anhydride. Global production is estimated at 16,000 to 30,000 tons a year, with an annual growth rate of 10%. Genetically engineered Escherichia coli and Saccharomyces cerevisiae are proposed for the commercial production via fermentation of glucose.
Chemical reactions Succinic acid can be dehydrogenated to fumaric acid or be converted to diesters, such as diethylsuccinate (CH2CO2CH2CH3)2. This diethyl ester is a substrate in the Stobbe condensation. Dehydration of succinic acid gives succinic anhydride. Succinate can be used to derive 1,4-butanediol, maleic anhydride, succinimide, 2-pyrrolidinone and tetrahydrofuran.
Applications In 2004, succinate was placed on the US Department of Energy's list of top 12 platform chemicals from biomass.
Precursor to polymers, resins, and solvents Succinic acid is a precursor to some polyesters and a component of some alkyd resins. 1,4-Butanediol (BDO) can be synthesized using succinic acid as a precursor. The automotive and electronics industries heavily rely on BDO to produce connectors, insulators, wheel covers, gearshift knobs and reinforcing beams. Succinic acid also serves as the bases of certain biodegradable polymers, which are of interest in tissue engineering applications. Acylation with succinic acid is called succination. Oversuccination occurs when more than one succinate adds to a substrate.
Food and dietary supplement As a food additive and dietary supplement, succinic acid is generally recognized as safe by the U.S. Food and Drug Administration. Succinic acid is used primarily as an acidity regulator in the food and beverage industry. It is also available as a flavoring agent, contributing a somewhat sour and astringent component to umami taste. As an excipient in pharmaceutical products, it is also used to control acidity or as a counter ion.
Pharmaceuticals Drugs that include formulations of their active ingredients as succinate salts include metoprolol succinate, sumatriptan succinate, doxylamine succinate, and solifenacin succinate. The mono-esters of succinic acid are known as hemisuccinate esters. These types of esters are commonly used as prodrugs for pharmacuetical compounds that have low solubility. Conversion to a hemisuccinate ester can improve solubility, facilitating formulation or delivery; subsequent metabolism then releases the active drug. Examples include pregnenolone hemisuccinate, propofol hemisuccinate, hydrocortisone hemisuccinate, oxazepam hemisuccinate, and estradiol hemisuccinate, among others.
Biosynthesis
Tricarboxylic acid (TCA) cycle
Succinate is a key intermediate in the tricarboxylic acid cycle, a primary metabolic pathway used to produce chemical energy in the presence of O2. Succinate is generated from succinyl-CoA by the enzyme succinyl-CoA synthetase in a GTP/ATP-producing step: Succinyl-CoA + NDP + Pi → Succinate + CoA + NTP Catalyzed by the enzyme succinate dehydrogenase (SDH), succinate is subsequently oxidized to fumarate: Succinate + FAD → Fumarate + FADH2 SDH also participates in the mitochondrial electron transport chain, where it is known as respiratory complex II. This enzyme complex is a 4 subunit membrane-bound lipoprotein which couples the oxidation of succinate to the reduction of ubiquinone via the intermediate electron carriers FAD and three 2Fe-2S clusters. Succinate thus serves as a direct electron donor to the electron transport chain, and itself is converted into fumarate. Click on genes, proteins and metabolites below to link to respective articles.
Reductive branch of the TCA cycle
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