Succinic acid

Succinic acid is a white, odorless solid with a highly acidic taste. 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 (). 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. 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. or as a counter ion. Drugs involving succinate include metoprolol succinate, sumatriptan succinate, doxylamine succinate or solifenacin succinate. == 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: Reductive branch of the TCA cycle Succinate can alternatively be formed by reverse activity of SDH. Under anaerobic conditions certain bacteria such as Actinobacillus succinogenes, A. succiniciproducens and M. succiniciproducens, run the TCA cycle in reverse and convert glucose to succinate through the intermediates of oxaloacetate, malate and fumarate. This pathway is exploited in metabolic engineering to net generate succinate for human use. Accumulation of fumarate can drive the reverse activity of SDH, thus enhancing succinate generation. Under pathological and physiological conditions, the malate-aspartate shuttle or the purine nucleotide shuttle can increase mitochondrial fumarate, which is then readily converted to succinate. GABA shunt Succinate is the re-entry point for the gamma-aminobutyric acid (GABA) shunt into the TCA cycle, a closed cycle which synthesizes and recycles GABA. The GABA shunt serves as an alternate route to convert alpha-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 by GABA transaminase to succinic semialdehyde. Finally, succinic semialdehyde is oxidized by succinic 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. == Cellular metabolism ==

Metabolic intermediate Succinate is produced and concentrated in the mitochondria and its primary biological function is that of a metabolic intermediate. while plasma concentration are only 2–20 μM. ROS production The activity of succinate dehydrogenase (SDH), which interconverts succinate into fumarate participates in mitochondrial reactive oxygen species (ROS) production by directing electron flow in the electron transport chain. Under conditions of succinate accumulation, rapid oxidation of succinate by SDH can drive reverse electron transport (RET). If mitochondrial 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 at mitochondrial respiratory complex 1, the complex normally preceding SDH in the electron transport chain, leads to ROS production and creates a pro-oxidant microenvironment. == Additional biologic functions ==

In addition to its metabolic roles, succinate serves as an intracellular and extracellular signaling molecule. Extra-mitochondrial succinate alters the epigenetic landscape by inhibiting the family of 2-oxogluterate-dependent dioxygenases. In the second step of mitochondrial export, succinate readily crosses the outer mitochondrial membrane through porins, nonspecific protein channels that facilitate the diffusion of molecules less than 1.5 kDa.) receptor on the cells that express this receptor. Most studies have reported that the GPR91 protein consists of 330 amino acids although a few studies have detected a 334 amino acid product of GPR91 gene. 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. that, depending on the cell type bearing it, interacts with multiple G proteins subtypes including Gs, Gi and Gq. This enables GPR91 to regulate a multitude of signaling outcomes. Effect on adipocytes In adipocytes, the succinate-activated GPR91 signaling cascade inhibits lipolysis. Therapies targeting succinate to reduce cardiovascular risk and hypertension are currently under investigation. 2-oxoglutarate-dependent dioxygenases require an iron cofactor to catalyze hydroxylations, desaturations and ring closures. Simultaneous to substrate oxidation, they convert 2-oxoglutarate, also known as alpha-ketoglutarate, into succinate and CO2. 2-oxoglutarate-dependent dioxygenases bind substrates in a sequential, ordered manner. Pathologically elevated levels of succinate lead to hypermethylation, epigenetic silencing and changes in neuroendocrine differentiation, potentially driving cancer formation. 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. Hydroxylation of two prolyl residues in HIF1α facilitates ubiquitin ligation, thus marking it for proteolytic destruction by the ubiquitin/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, 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 vascularization and angiogenesis, energy metabolism, cell survival, and tumor invasion. == Role in human health ==

Inflammation Metabolic signaling involving succinate can be involved in inflammation via stabilization of HIF1-alpha or GPR91 signaling in innate immune cells. Through these mechanisms, succinate accumulation has been shown to regulate production of inflammatory cytokines. Other inflammatory cytokines produced by activated macrophages such as tumor necrosis factor or interleukin 6 are not directly affected by succinate and HIF1. 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 increase glutamine and GABA transporters. Loss-of-function mutations in the genes encoding succinate dehydrogenase, frequently found in hereditary paraganglioma and pheochromocytoma, cause pathological increase in succinate. SDH mutations have also been identified in gastrointestinal stromal tumors, renal tumors, thyroid tumors, testicular seminomas and neuroblastomas. The other two oncometabolites, fumarate and 2-hydroxyglutarate have similar structures to succinate and function through parallel HIF-inducing oncogenic mechanisms. As of 2016 the inhibition of succinate-mediated ROS production was under investigation as a therapeutic drug target. ==See also==