Fumaric acid or ''trans''-butenedioic acid is an

organic compound Some chemical authorities define an organic compound as a chemical compound that contains a carbon–hydrogen or carbon–carbon bond; others consider an organic compound to be any chemical compound that contains carbon. For example, carbon-co ...

with the formula HO₂CCH=CHCO₂H. A white solid, fumaric acid occurs widely in nature. It has a

fruit In botany, a fruit is the seed-bearing structure in flowering plants (angiosperms) that is formed from the ovary after flowering. Fruits are the means by which angiosperms disseminate their seeds. Edible fruits in particular have long propaga ...

-like

taste The gustatory system or sense of taste is the sensory system that is partially responsible for the perception of taste. Taste is the perception stimulated when a substance in the mouth biochemistry, reacts chemically with taste receptor cells l ...

and has been used as a

food additive Food additives are substances added to food to preserve flavor or enhance taste, appearance, or other sensory qualities. Some additives, such as vinegar ( pickling), salt ( salting), smoke ( smoking) and sugar ( crystallization), have been used f ...

. Its

E number E numbers, short for Europe numbers, are codes for substances used as food additives, including those found naturally in many foods, such as vitamin C, for use within the European Union (EU) and European Free Trade Association (EFTA). Commonly ...

is E297. The

salts In chemistry, a salt or ionic compound is a chemical compound consisting of an assembly of positively charged ions ( cations) and negatively charged ions (anions), which results in a compound with no net electric charge (electrically neutral). ...

and

ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...

s are known as fumarates. Fumarate can also refer to the ion (in solution). Fumaric acid is the ''trans''

isomer In chemistry, isomers are molecules or polyatomic ions with identical molecular formula – that is, the same number of atoms of each element (chemistry), element – but distinct arrangements of atoms in space. ''Isomerism'' refers to the exi ...

of butenedioic acid, while

maleic acid Maleic acid or ''cis''-butenedioic acid is an organic compound that is a dicarboxylic acid, a molecule with two carboxyl groups. Its chemical formula is HO2CCH=CHCO2H. Maleic acid is the ''cis'' Cis–trans isomerism, isomer of butenedioic acid, ...

is the ''cis'' isomer.

Biosynthesis and occurrence

It is produced in

eukaryotic The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...

organisms from

succinate 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 Fuma ...

in complex 2 of the electron transport chain via the

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

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 ...

. Fumaric acid is found in

fumitory ''Fumaria'' (fumitory or fumewort, from Latin ', "smoke of the earth") is a genus of about 60 species of annual flowering plants in the family Papaveraceae. The genus is native to Europe, Africa and Asia, most diverse in the Mediterranean re ...

(''Fumaria officinalis''),

bolete A bolete is a type of mushroom, or fungal fruiting body. It can be identified thanks to a unique cap. On the underside of the cap there is usually a spongy surface with pores, instead of the gills typical of mushrooms. A similar pore surface i ...

mushroom A mushroom or toadstool is the fleshy, spore-bearing Sporocarp (fungi), fruiting body of a fungus, typically produced above ground on soil or another food source. ''Toadstool'' generally refers to a poisonous mushroom. The standard for the n ...

s (specifically ''Boletus fomentarius var. pseudo-igniarius''),

lichen A lichen ( , ) is a hybrid colony (biology), colony of algae or cyanobacteria living symbiotically among hypha, filaments of multiple fungus species, along with yeasts and bacteria embedded in the cortex or "skin", in a mutualism (biology), m ...

, and

Iceland moss ''Cetraria islandica'', also known as true Iceland lichen or Iceland moss, is an Arctic-alpine lichen whose erect or upright, leaflike habit gives it the appearance of a moss, where its name likely comes from. Description It is often of a pale ...

. Fumarate is an intermediate in the

citric acid cycle The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle (tricarboxylic acid cycle)—is a series of chemical reaction, biochemical reactions that release the energy stored in nutrients through acetyl-Co ...

used by

cells Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a d ...

to produce energy in the form of

adenosine triphosphate Adenosine triphosphate (ATP) is a nucleoside triphosphate that provides energy to drive and support many processes in living cell (biology), cells, such as muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all known ...

(ATP) from

food Food is any substance consumed by an organism for Nutrient, nutritional support. Food is usually of plant, animal, or Fungus, fungal origin and contains essential nutrients such as carbohydrates, fats, protein (nutrient), proteins, vitamins, ...

. It is formed by the

oxidation Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

by the enzyme

. Fumarate is then converted by the enzyme

fumarase Fumarase (or fumarate hydratase) is an enzyme () that catalyzes the reversible Hydration reaction, hydration/Dehydration reaction, dehydration of fumarate to malate. Fumarase comes in two forms: mitochondrial and cytosolic. The mitochondrial iso ...

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 ( ...

. Human skin naturally produces fumaric acid when exposed to

sunlight Sunlight is the portion of the electromagnetic radiation which is emitted by the Sun (i.e. solar radiation) and received by the Earth, in particular the visible spectrum, visible light perceptible to the human eye as well as invisible infrare ...

. Fumarate is also a product of the

urea cycle The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic. The urea cycle converts highl ...

Uses

Food

Fumaric acid has been used as a food acidulant since 1946. It is approved for use as a food additive in the EU, USA and Australia and New Zealand. As a

, it is used as an

acidity regulator Acidity regulators, or pH control agents, are food additives used to change or maintain pH ( acidity or basicity). They can be organic or mineral acids, bases, neutralizing agents, or buffering agents. Typical agents include the following ac ...

and can be denoted by the

E297. It is generally used in beverages and

baking powder Baking powder is a dry chemical leavening agent, a mixture of a carbonate or bicarbonate and a weak acid. The base and acid are prevented from reacting prematurely by the inclusion of a buffer such as cornstarch. Baking powder is used to increas ...

s for which requirements are placed on purity. Fumaric acid is used in the making of

wheat tortilla A flour tortilla (, ) or wheat tortilla is a type of soft, thin flatbread made from finely ground wheat flour. Made with flour- and water-based dough, it is pressed and cooked, similar to corn tortillas. The simplest recipes use only flour, wat ...

s as a food preservative and as the acid in leavening. It is generally used as a substitute for

tartaric acid Tartaric acid is a white, crystalline organic acid that occurs naturally in many fruits, most notably in grapes but also in tamarinds, bananas, avocados, and citrus. Its salt (chemistry), salt, potassium bitartrate, commonly known as cream of ta ...

and occasionally in place of

citric acid Citric acid is an organic compound with the formula . It is a Transparency and translucency, colorless Weak acid, weak organic acid. It occurs naturally in Citrus, citrus fruits. In biochemistry, it is an intermediate in the citric acid cycle, ...

, at a rate of 1 g of fumaric acid to every ~1.5 g of citric acid, in order to add

sourness The gustatory system or sense of taste is the sensory system that is partially responsible for the perception of taste. Taste is the perception stimulated when a substance in the mouth reacts chemically with taste receptor cells located on t ...

, similarly to the way

malic acid 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 ( ...

is used. As well as being a component of some artificial vinegar flavors, such as "Salt and Vinegar" flavored potato chips, it is also used as a coagulant in stove-top pudding mixes. The European Commission Scientific Committee on Animal Nutrition, part of DG Health, found in 2014 that fumaric acid is "practically non-toxic" but high doses are probably

nephrotoxic Nephrotoxicity is toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on kidney function. There are various forms, and some drugs may affect kidney function in more than one way. Nephrotoxin ...

after long-term use.European Commission:

Medicine

Fumaric acid was developed as a medicine to treat the autoimmune condition

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...

in the 1950s in Germany as a tablet containing 3

s, primarily

dimethyl fumarate Dimethyl fumarate (DMF) is the methyl ester of fumaric acid and is named after the earth smoke plant (''Fumaria officinalis''). Dimethyl fumarate combined with three other fumaric acid esters (FAEs) is solely licensed in Germany as an oral thera ...

, and marketed as Fumaderm by

Biogen Biogen Inc. is an American multinational biotechnology company based in Cambridge, Massachusetts, United States specializing in the discovery, development, and delivery of the treatment of neurological diseases to patients worldwide. Biogen ope ...

Idec in Europe. Biogen would later go on to develop the main ester, dimethyl fumarate, as a treatment for

multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...

. In patients with relapsing-remitting multiple sclerosis, the ester dimethyl fumarate (BG-12, Biogen) significantly reduced relapse and disability progression in a phase 3 trial. It activates the

Nrf2 Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the ''NFE2L2'' gene. NRF2 is a basic leucine zipper (bZIP) protein that may regu ...

antioxidant response pathway, the primary cellular defense against the cytotoxic effects of oxidative stress.

Other uses

Fumaric acid is used in the manufacture of

polyester Polyester is a category of polymers that contain one or two ester linkages 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 some natura ...

resin A resin is a solid or highly viscous liquid that can be converted into a polymer. Resins may be biological or synthetic in origin, but are typically harvested from plants. Resins are mixtures of organic compounds, predominantly terpenes. Commo ...

s and

polyhydric alcohol Sugar alcohols (also called polyhydric alcohols, polyalcohols, alditols or glycitols) are organic compounds, typically derived from sugars, containing one hydroxyl group attached to each carbon atom. They are white, water-soluble solids that ca ...

s and as a

mordant A mordant or dye fixative is a substance used to set (i.e., bind) dyes on fabrics. It does this by forming a coordination complex with the dye, which then attaches to the fabric (or tissue). It may be used for dyeing fabrics or for intensifying ...

for dyes. Fumaric acid can be used to make 6-methylcoumarin. When fumaric acid is added to their feed, lambs produce up to 70% less methane during digestion.

Synthesis

Fumaric acid is produced based on

catalytic Catalysis () is the increase in reaction rate, rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst ...

isomerisation In chemistry, isomerization or isomerisation is the process in which a molecule, polyatomic ion or molecular fragment is transformed into an isomer with a different chemical structure. Enolization is an example of isomerization, as is tautomeri ...

in aqueous solutions at low p''H''. It precipitates from the reaction solution. Maleic acid is accessible in large volumes as a

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

product of maleic anhydride, produced by catalytic oxidation of

benzene Benzene is an Organic compound, organic chemical compound with the Chemical formula#Molecular formula, molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar hexagonal Ring (chemistry), ring with one hyd ...

butane Butane () is an alkane with the formula C4H10. Butane exists as two isomers, ''n''-butane with connectivity and iso-butane with the formula . Both isomers are highly flammable, colorless, easily liquefied gases that quickly vaporize at ro ...

Historic and laboratory routes

Fumaric acid was first prepared from

succinic acid 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 fum ...

. A traditional synthesis involves oxidation of

furfural Furfural is an organic compound with the formula C4H3OCHO. It is a colorless liquid, although commercial samples are often brown. It has an aldehyde group attached to the 2-position of furan. It is a product of the dehydration of sugars, as occu ...

(from the processing of

maize Maize (; ''Zea mays''), also known as corn in North American English, is a tall stout grass that produces cereal grain. It was domesticated by indigenous peoples in southern Mexico about 9,000 years ago from wild teosinte. Native American ...

) using

chlorate Chlorate is the common name of the anion, whose chlorine atom is in the +5 oxidation state. The term can also refer to chemical compounds containing this anion, with Chlorate#Compounds (salts), chlorates being the salt (chemistry), salts of chlo ...

in the presence of a

vanadium Vanadium is a chemical element; it has Symbol (chemistry), symbol V and atomic number 23. It is a hard, silvery-grey, malleable transition metal. The elemental metal is rarely found in nature, but once isolated artificially, the formation of an ...

-based

catalyst Catalysis () is the increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...

Reactions

The chemical properties of fumaric acid can be anticipated from its component

functional group In organic chemistry, a functional group is any substituent or moiety (chemistry), moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions r ...

s. This weak acid forms a di

, it undergoes

bromination In chemistry, halogenation is a chemical reaction which introduces one or more halogens into a chemical compound. Halide-containing compounds are pervasive, making this type of transformation important, e.g. in the production of polymers, drugs ...

across the

double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...

, and it is a good dienophile.

Safety

The oral

LD50 In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a given substance. The value of LD50 for a substance is the dose requ ...

is 10g/kg.

References

External links

International Chemical Safety Card 1173
{{Authority control Dicarboxylic acids Food additives Food acidity regulators Urea cycle Citric acid cycle compounds Nephrotoxins E-number additives Alkene derivatives Metabolic intermediates Biomolecules Carboxylic acid-based monomers