[
]
Chemical reactions
Succinic acid can be dehydrogenated to fumaric acid
Fumaric acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297.
The salts and esters are known as fu ...
or be converted to diesters, such as diethylsuccinate (CH2CO2CH2CH3)2. This diethyl ester is a substrate in the Stobbe condensation
The Claisen condensation is a carbon–carbon bond forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base, resulting in a β-keto ester or a β-diketone. It is named after Ra ...
. Dehydration of succinic acid gives succinic anhydride
Succinic anhydride, is an organic compound with the molecular formula (CH2CO)2O. This colorless solid is the acid anhydride of succinic acid.
Preparation
In the laboratory, this material can be prepared by dehydration of succinic acid. Such dehy ...
. Succinate can be used to derive 1,4-butanediol, maleic anhydride, succinimide, 2-pyrrolidinone and tetrahydrofuran
Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water-miscible organic liquid with low viscosity. It is ma ...
.
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
Precursor or Precursors may refer to:
* Precursor (religion), a forerunner, predecessor
** The Precursor, John the Baptist
Science and technology
* Precursor (bird), a hypothesized genus of fossil birds that was composed of fossilized parts of u ...
to some polyester
Polyester is a category of polymers that contain the ester functional group in every repeat unit of their main chain. As a specific material, it most commonly refers to a type called polyethylene terephthalate (PET). Polyesters include natural ...
s and a component of some alkyd resin
An alkyd is a polyester resin modified by the addition of fatty acids and other components. Alkyds are derived from polyols and organic acids including dicarboxylic acids or carboxylic acid anhydride and triglyceride oils. The term ''alkyd'' is a ...
s.[ ]1,4-Butanediol
1,4-Butanediol, colloquially known as BD or BDO, is a primary alcohol, and an organic compound, with the formula HOCH2CH2CH2CH2OH. It is a colorless viscous liquid. It is one of four stable isomers of butanediol.
Synthesis
In industrial sy ...
(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
In chemistry, acylation (or alkanoylation) is the chemical reaction in which an acyl group () is added to a compound. The compound providing the acyl group is called the acylating agent.
Because they form a strong electrophile when treated with ...
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
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
. 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
An excipient is a substance formulated alongside the active ingredient of a medication, included for the purpose of long-term stabilization, bulking up solid formulations that contain potent active ingredients in small amounts (thus often referred ...
in pharmaceutical products, it is also used to control acidity 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
The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...
, a primary metabolic pathway used to produce chemical energy in the presence of O2. Succinate is generated from succinyl-CoA
Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a thioester of succinic acid and coenzyme A.
Sources
It is an important intermediate in the citric acid cycle, where it is synthesized from α-ketoglutarate by α-ketoglutarate d ...
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
Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates i ...
(SDH), succinate is subsequently oxidized to fumarate
Fumaric acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297.
The salts and esters are known as f ...
:[
Succinate + FAD → Fumarate + FADH2
SDH also participates in the mitochondrial ]electron transport chain
An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...
, 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
Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10.
It is a 1,4-benzoq ...
via the intermediate electron carriers FAD
A fad or trend is any form of collective behavior that develops within a culture, a generation or social group in which a group of people enthusiastically follow an impulse for a short period.
Fads are objects or behaviors that achieve short- ...
and three 2Fe-2S clusters. Succinate thus serves as a direct electron donor to the electron transport chain, and itself is converted into fumarate.
Reductive branch of the TCA cycle
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 oxaloacetate
Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes ...
, malate
Malic acid is an organic compound with the molecular formula . It is a dicarboxylic acid that is made by all living organisms, contributes to the sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric forms (L ...
and fumarate
Fumaric acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297.
The salts and esters are known as f ...
. This pathway is exploited in metabolic engineering to net generate succinate for human use.[ Additionally, succinic acid produced during the fermentation of sugar provides a combination of saltiness, bitterness and acidity to fermented alcohols.
Accumulation of fumarate can drive the reverse activity of SDH, thus enhancing succinate generation. Under pathological and physiological conditions, the ]malate-aspartate shuttle
The malate-aspartate shuttle (sometimes simply the malate shuttle) is a biochemical system for translocating electrons produced during glycolysis across the semipermeable inner membrane of the mitochondrion for oxidative phosphorylation in eukaryo ...
or the purine nucleotide shuttle can increase mitochondrial fumarate, which is then readily converted to succinate.[
]
Glyoxylate cycle
Succinate is also a product of the glyoxylate cycle
The glyoxylate cycle, a variation of the tricarboxylic acid cycle, is an anabolic pathway occurring in plants, bacteria, protists, and fungi. The glyoxylate cycle centers on the conversion of acetyl-CoA to succinate for the synthesis of carbohydrat ...
, 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 decarboxylation steps of the TCA cycle via the enzyme isocitrate lyase which cleaves isocitrate
Isocitric acid is a structural isomer of citric acid. Since citric acid and isocitric acid are structural isomers, they share similar physical and chemical properties. Due to these similar properties, it is difficult to separate the isomers. Salt ...
into succinate and glyoxylate
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 acids. It is a colourless solid that occurs naturally and is useful industrially.
Str ...
. Generated succinate is then available for either energy production or biosynthesis.
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
In enzymology, 4-aminobutyrate transaminase (), also called GABA transaminase or 4-aminobutyrate aminotransferase, or GABA-T, is an enzyme that catalyzes the chemical reaction:
:4-aminobutanoate + 2-oxoglutarate \rightleftharpoons succinate sem ...
to succinic semialdehyde. Finally, succinic semialdehyde is oxidized by succinic semialdehyde dehydrogenase
Aflatoxin B1 aldehyde reductase member 2 is an enzyme that in humans is encoded by the ''AKR7A2'' gene.
Function
Aldo-keto reductases, such as AKR7A2, are involved in the detoxification of aldehydes and ketone
In organic chemistry, a keto ...
(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
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
and its primary biological function is that of a metabolic intermediate.[ 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.][ 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.][ In rodents, mitochondrial concentrations are approximately ~0.5 mM] 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
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
(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.[ Alternative, succinate can be released into the extracellular milieu and the blood stream where it is recognized by target receptors.] 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.[ Upon exiting the mitochondria, succinate serves as a signal of metabolic state, communicating to neighboring cells how metabolically active the originating cell population is.][ 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 dicarboxylate transporters, primarily SLC25A10, a succinate-fumarate/malate transporter. In the second step of mitochondrial export, succinate readily crosses the outer mitochondrial membrane through porins
Porins are beta barrel proteins that cross a cellular membrane and act as a pore, through which molecules can diffuse. Unlike other membrane transport proteins, porins are large enough to allow passive diffusion, i.e., they act as channels tha ...
, nonspecific protein channels that facilitate the diffusion of molecules less than 1.5 kDa.[ Transport across the plasma membrane is likely tissue specific. A key candidate transporter is ]INDY
Indy may refer to:
Computing and technology
*Indy (software), used for Internet access to music
*Internet Direct, or "Indy", a software library
*SGI Indy, a computer workstation
Periodicals
*''The Indy'', shorthand for newspapers that include " ...
(I'm not dead yet), a sodium-independent anion exchanger, which moves both dicarboxylate and citrate into the bloodstream.[
]
Extracellular signaling
Extracellular succinate can act as a signaling molecule with hormone-like function, targeting a variety of tissues such as blood cells, adipose tissue, immune cells, the liver, the heart, the retina and primarily the kidney.[ The ]G-protein coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of protein family, evolution ...
, GPR91 also known as SUCNR1
Succinate receptor 1 is a protein that in humans is encoded by the ''SUCNR1'' gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or '' ...
, serves as the detector of extracellular succinate. Arg99, His103, Arg252, and Arg281 near the center of the receptor generate a positively charged binding site for succinate.[ The ligand specificity of GPR91 was rigorously tested using 800 pharmacologically active compounds and 200 carboxylic acid and succinate-like compounds, all of which demonstrated significantly lower binding affinity.][ Overall, the EC50 for succinate-GPR91 is in the 20–50 uM range.][ Depending on the cell type, GPR91 can interact with multiple G proteins, including Gs, Gi and Gq, and enabling a multitude of signaling outcomes.][
]
Effect on adipocytes
In adipocyte
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
s, the succinate-activated GPR91 signaling cascade inhibits lipolysis
Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most important ...
.[
]
Effect on the liver and retina
Succinate signaling often occurs in response to hypoxic conditions. In the liver, succinate serves as a paracrine Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over ...
signal, released by anoxic hepatocyte
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, ...
s, and targets stellate cells via GPR91. This leads to stellate cell activation and fibrogenesis. Thus, succinate is thought to play a role in liver homeostasis
In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
. In the retina, succinate accumulates in retinal ganglion cell
A retinal ganglion cell (RGC) is a type of neuron located near the inner surface (the ganglion cell layer) of the retina of the human eye, eye. It receives visual information from photoreceptor cell, photoreceptors via two intermediate neuron typ ...
s in response to ischemic conditions. Autocrine Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with p ...
succinate signaling promotes retinal neovascularization
Neovascularization is the natural formation of new blood vessels ('' neo-'' + '' vascular'' + '' -ization''), usually in the form of functional microvascular networks, capable of perfusion by red blood cells, that form to serve as collateral circu ...
, triggering the activation of angiogenic factors such as endothelial growth factor
Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
(VEGF).[
]
Effect on the heart
Extracellular succinate regulates cardiomyocyte
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...
viability through GPR91 activation; long-term succinate exposure leads to pathological cardiomyocyte hypertrophy
Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number.Updated by Linda J ...
.[ Stimulation of GPR91 triggers at least two signaling pathways in the heart: a MEK1/2 and ERK1/2 pathway that activates hypertrophic gene expression and a phospholipase C pathway which changes the pattern of Ca2+ uptake and distribution and triggers ]CaM
Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the bin ...
-dependent hypertrophic gene activation.
Effect on immune cells
SUCNR1 is highly expressed on immature dendritic cells, where succinate binding stimulates chemotaxis.[ Furthermore, SUCNR1 synergizes with ]toll-like receptor
Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are Bitopic protein, single-pass membrane-spanning Receptor (biochemistry), receptors usually expressed on sentinel cells such as macrophage ...
s to increase the production of proinflammatory cytokine An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include inte ...
s such as TNF alpha
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
and interleukin-1beta.[ Succinate may enhance ]adaptive immunity
The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...
by triggering the activity of antigen-presenting cells that, in turn, activate T-cells
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
.[
]
Effect on platelets
SUCNR1 is one of the highest expressed G protein-coupled receptors on human platelets, present at levels similar to P2Y12, though the role of succinate signaling in platelet aggregation
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
is debated. Multiple studies have demonstrated succinate-induced aggregation, but the effect has high inter-individual variability.[
]
Effect on the kidneys
Succinate serves as a modulator of blood pressure by stimulating renin release in macula densa
In the kidney, the macula densa is an area of closely packed specialized cells lining the wall of the distal tubule, at the point where the thick ascending limb of the Loop of Henle meets the distal convoluted tubule. The macula densa is the t ...
and juxtaglomerular apparatus cells via GPR91. Therapies targeting succinate to reduce cardiovascular risk and hypertension are currently under investigation.[
]
Intracellular signaling
Accumulation of either fumarate or succinate reduces the activity of 2-oxoglutarate-dependent dioxygenases, including histone and DNA demethylase
Demethylases are enzymes that remove methyl (CH3) groups from nucleic acids, proteins (particularly histones), and other molecules. Demethylases are important epigenetics, epigenetic proteins, as they are responsible for transcriptional regulation ...
s, prolyl hydroxylases and collagen prolyl-4-hydroxylases, through competitive inhibition
Competitive inhibition is interruption of a chemical pathway owing to one chemical substance inhibiting the effect of another by competing with it for binding or bonding. Any metabolic or chemical messenger system can potentially be affected b ...
. 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.[ 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
Oxidative decarboxylation is a decarboxylation reaction caused by oxidation. Most are accompanied by α- Ketoglutarate α- Decarboxylation caused by dehydrogenation of hydroxyl carboxylic acids such as carbonyl carboxylic acid, malic acid, isocitr ...
then generates a ferryl intermediate coordinated to succinate, which serves to oxidize the bound primary substrate.[ 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 TET (ten-eleven translocation) family of 5-methylcytosine DNA modifying enzymes and the JmjC domain-containing histone lysine demethylase (KDM). Pathologically elevated levels of succinate lead to hypermethylation, epigenetic silencing and changes in neuroendocrine differentiation, potentially driving cancer formation.[
]
Gene regulation
Succinate inhibition of prolyl hydroxylase
Procollagen-proline dioxygenase, commonly known as prolyl hydroxylase, is a member of the class of enzymes known as alpha-ketoglutarate-dependent hydroxylases. These enzymes catalyze the incorporation of oxygen into organic substrates through a mec ...
s (PHDs) stabilizes the transcription factor hypoxia inducible factor (HIF)1α. 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
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
and angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
, energy metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
, cell survival, and tumor invasion.[
]
Role in human health
Inflammation
Metabolic signaling involving succinate can be involved in inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
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 cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s.[ For dendritic cells, succinate functions as a chemoattractant and increases their antigen-presenting function via receptor stimulated cytokine production.][ In inflammatory ]macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s, succinate-induced stability of HIF1 results in increased transcription of HIF1-dependent genes, including the pro-inflammatory cytokine interleukin-1β. Other inflammatory cytokines produced by activated macrophages such as tumor necrosis factor
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
or interleukin 6
Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene.
In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smooth ...
are not directly affected by succinate and HIF1. The mechanism by which succinate accumulates in immune cells is not fully understood.[ Activation of inflammatory macrophages through ]toll-like receptor
Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are Bitopic protein, single-pass membrane-spanning Receptor (biochemistry), receptors usually expressed on sentinel cells such as macrophage ...
s induces a metabolic shift towards glycolysis. In spite of a general downregulation of the TCA cycle under these conditions, succinate concentration is increased. However, lipopolysaccharide
Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer m ...
s involved in the activation of macrophages increase glutamine
Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...
and GABA transporter GABA transporters ( Gamma-Aminobutyric acid transporters) belong to the family of neurotransmitters known as sodium symporters, also known as solute carrier 6 ( SLC6). These are large family of neurotransmitter which are Na+ concentration dependen ...
s.[ Succinate may thus be produced from enhanced glutamine metabolism via alpha-ketoglutarate or the GABA shunt.
]
Tumorigenesis
Succinate is one of three oncometabolites, metabolic intermediates whose accumulation causes metabolic and non-metabolic dysregulation implicated in tumorigenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
. Loss-of-function mutations in the genes encoding succinate dehydrogenase
Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates i ...
, frequently found in hereditary paraganglioma
A paraganglioma is a rare neuroendocrine neoplasm that may develop at various body sites (including the head, neck, thorax and abdomen). When the same type of tumor is found in the adrenal gland, they are referred to as a pheochromocytoma. They a ...
and pheochromocytoma
Pheochromocytoma (PHEO or PCC) is a rare tumor of the adrenal medulla composed of chromaffin cells, also known as pheochromocytes. When a tumor composed of the same cells as a pheochromocytoma develops outside the adrenal gland, it is referred t ...
, cause pathological increase in succinate. SDH mutations have also been identified in gastrointestinal stromal tumor
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs arise in the smooth muscle pacemaker interstitial cell of Cajal, or similar cells. They are defined as tumors whose behavior ...
s, renal tumors, thyroid tumors, testicular seminomas and neuroblastoma
Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in th ...
s.[ The oncogenic mechanism caused by mutated SHD is thought to relate to succinate's ability to inhibit 2-oxogluterate-dependent dioxygenases. Inhibition of KDMs and TET hydroxylases results in epigenetic dysregulation and hypermethylation affecting genes involved in cell differentiation.][ 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. The other two oncometabolites, ]fumarate
Fumaric acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297.
The salts and esters are known as f ...
and 2-hydroxyglutarate
α-Hydroxyglutaric acid (2-hydroxyglutaric acid) is an alpha hydroxy acid form of glutaric acid.
In biology
In humans the compound is formed by a hydroxyacid-oxoacid transhydrogenase whereas in bacteria is formed by a 2-hydroxyglutarate synthas ...
have similar structures to succinate and function through parallel HIF-inducing oncogenic mechanisms.[
]
Ischemia reperfusion injury
Succinate accumulation under hypoxic conditions has been implicated in the reperfusion injury
Reperfusion injury, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is the tissue damage caused when blood supply returns to tissue ('' re-'' + ''perfusion'') after a period of ischemia or lack of oxygen (anoxia or hy ...
through increased ROS production.[ During ischemia, succinate accumulates. Upon reperfusion, succinate is rapidly oxidized leading to abrupt and extensive production of ROS.] ROS then trigger the cellular apoptotic
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes incl ...
machinery or induce oxidative damage to proteins, membranes, organelles etc. In animal models, pharmacological inhibition of ischemic succinate accumulation ameliorated ischemia-reperfusion injury. As of 2016 the inhibition of succinate-mediated ROS production was under investigation as a therapeutic drug target
A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...
.[
]
See also
*Flame retardant
The term flame retardants subsumes a diverse group of chemicals that are added to manufactured materials, such as plastics and textiles, and surface finishes and coatings. Flame retardants are activated by the presence of an ignition source a ...
Flame Retardant Finishing of Cotton Fleece Fabric: Part IV-Bifunctional Carboxylic Acids
/ref>
*Oil of amber
Amber is fossilized tree resin that has been appreciated for its color and natural beauty since Neolithic times. Much valued from antiquity to the present as a gemstone, amber is made into a variety of decorative objects."Amber" (2004). In M ...
, procured by heating succinic acid
*Citric acid cycle
The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...
*Metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
*Oncometabolism Oncometabolism is the field of study that focuses on the metabolic changes that occur in cells that make up the tumor microenvironment (TME) and accompany oncogenesis and tumor progression toward a neoplastic state.
Cells with increased growth an ...
References
External links
FDA
Calculator: Water and solute activities in aqueous succinic acid
ScienceDirect: Succinic Acid - Production of organic acids and enzymes / biocatalysts from food waste
PubChem: Compound Summary for Succinic Acid
{{DEFAULTSORT:Succinic Acid
Citric acid cycle compounds
Dicarboxylic acids
Excipients
Succinates
E-number additives