Ergothioneine
Encyclopedia
Ergothioneine is a naturally occurring amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

 and is a thiourea derivative of histidine, containing a sulfur
Sulfur
Sulfur or sulphur is the chemical element with atomic number 16. In the periodic table it is represented by the symbol S. It is an abundant, multivalent non-metal. Under normal conditions, sulfur atoms form cyclic octatomic molecules with chemical formula S8. Elemental sulfur is a bright yellow...

 atom in the imidazole
Imidazole
Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents...

 ring. This compound is made in rather few organisms, notably Actinobacteria
Actinobacteria
Actinobacteria are a group of Gram-positive bacteria with high guanine and cytosine content. They can be terrestrial or aquatic. Actinobacteria is one of the dominant phyla of the bacteria....

 and filamentous fungi. Ergothioneine was discovered in 1909 and named after the ergot
Ergot
Ergot or ergot fungi refers to a group of fungi of the genus Claviceps. The most prominent member of this group is Claviceps purpurea. This fungus grows on rye and related plants, and produces alkaloids that can cause ergotism in humans and other mammals who consume grains contaminated with its...

 fungus from which it was first purified, with its structure being determined later, in 1911. This amino acid has antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...

 properties, but its chemistry differs from conventional sulfur-containing antioxidants such as glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...

 or lipoic acid
Lipoic acid
Lipoic acid , also known as α-lipoic acid and Alpha Lipoic Acid is an organosulfur compound derived from octanoic acid. LA contains two vicinal sulfur atoms attached via a disulfide bond and is thus considered to be oxidized...

.

Although ergothioneine cannot be made in human cells, it is present in some tissues at high levels as it is absorbed from the diet. In humans ergothioneine is taken up from the gut and concentrated in some tissues by a specific transporter called ETT (gene symbol SLC22A4
SLC22A4
Solute carrier family 22, member 4, also known as SLC22A4, is a human gene; the encoded protein is an ergothioneine transporter.- Function :The encoded protein is an integral protein of the plasma membrane containing 12 transmembrane segments...

). However, even today, one hundred years after its discovery, precisely what ergothioneine does in the human body remains a mystery.

Chemistry

Ergothioneine is a thiourea
Thiourea
Thiourea is an organosulfur compound of with the formula SC2 . It is structurally similar to urea, except that the oxygen atom is replaced by a sulfur atom, but the properties of urea and thiourea differ significantly. Thiourea is a reagent in organic synthesis. "Thioureas" refers to a broad...

 derivative of the betaine of histidine
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...

 and contains a sulfur atom bonded to the 2-position of the imidazole ring. This compound is unusual since the sulfur atom is most stable in solution in the thione form, rather than the sulfhydryl. This makes ergothioneine much less reactive than thiols such as glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...

 towards alkylating agents like maleimide
Maleimide
Maleimide is the chemical compound with the formula H2C22NH . This unsaturated imide is an important building block in organic synthesis. The name is a contraction of maleic acid and imide, the -CNHC- functional group...

s, and also prevents the compound from oxidizing
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....

 in air. However, ergothioneine can be slowly oxidized over several days to the disulfide
Disulfide
In chemistry, a disulfide usually refers to the structural unit composed of a linked pair of sulfur atoms. Disulfide usually refer to a chemical compound that contains a disulfide bond, such as diphenyl disulfide, C6H5S-SC6H5....

 form in acidic solutions. If ergothioneine does become oxidized, the disulfide is a very strong oxidizing agent, so this will in turn rapidly oxidize other thiols in the cell such as glutathione.

Metabolism and sources

Ergothioneine has been found in bacteria, plants and animals, sometimes at millimolar levels. Foods rich in ergothioneine include liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

, kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

, black beans, red beans and oat bran, with the highest levels in bolete
Bolete
A bolete is a type of fungal fruiting body characterized by the presence of a pileus that is clearly differentiated from the stipe, with a spongy surface of pores on the underside of the pileus...

 and oyster mushroom
Oyster mushroom
Pleurotus ostreatus, the oyster mushroom, is a common edible mushroom. It was first cultivated in Germany as a subsistence measure during World War I and is now grown commercially around the world for food. However, the first documented cultivation was by Kaufert There is some question about the...

s. Levels can be variable, even within species and some tissues can contain much more than others. In the human body, the largest amounts of ergothioneine are found in erythrocytes, eye lens
Lens (anatomy)
The crystalline lens is a transparent, biconvex structure in the eye that, along with the cornea, helps to refract light to be focused on the retina. The lens, by changing shape, functions to change the focal distance of the eye so that it can focus on objects at various distances, thus allowing a...

 and semen
Semen
Semen is an organic fluid, also known as seminal fluid, that may contain spermatozoa. It is secreted by the gonads and other sexual organs of male or hermaphroditic animals and can fertilize female ova...

, and it is also present in the skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...

.

Although many species contain ergothioneine, only a few can make it, the others absorb it from their diet or, in the case of plants, from their environment. Biosynthesis has been detected in Actinobacteria
Actinobacteria
Actinobacteria are a group of Gram-positive bacteria with high guanine and cytosine content. They can be terrestrial or aquatic. Actinobacteria is one of the dominant phyla of the bacteria....

, such as Mycobacterium smegmatis
Mycobacterium smegmatis
Mycobacterium smegmatis is 3.0 to 5.0 µm long with a bacillus shape, an acid-fast bacterial species in the phylum Actinobacteria. It can be stained by Ziehl-Neelsen method and the auramine-rhodamine fluorescent method. It was first reported in November 1884 by Lustgarten, who found a bacillus...

and filamentous fungi, such as Neurospora crassa
Neurospora crassa
Neurospora crassa is a type of red bread mold of the phylum Ascomycota. The genus name, meaning "nerve spore" refers to the characteristic striations on the spores. The first published account of this fungus was from an infestation of French bakeries in 1843. N...

. Although the exact metabolic pathway
Metabolic pathway
In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...

 is not clear, it is known that the imidazole ring is supplied by histidine
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...

, which is then methylated
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...

 to produce histidine betaine, and then the sulfur atom incorporated from cysteine. Other species of bacteria, such as Bacillus subtilis
Bacillus subtilis
Bacillus subtilis, known also as the hay bacillus or grass bacillus, is a Gram-positive, catalase-positive bacterium commonly found in soil. A member of the genus Bacillus, B. subtilis is rod-shaped, and has the ability to form a tough, protective endospore, allowing the organism to tolerate...

, Escherichia coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...

, Proteus vulgaris
Proteus vulgaris
Proteus vulgaris is a rod-shaped, Gram negative bacterium that inhabits the intestinal tracts of humans and animals. It can be found in soil, water and fecal matter. It is grouped with the enterobacteriaceae and is an opportunistic pathogen of humans...

and Streptococcus
Streptococcus
Streptococcus is a genus of spherical Gram-positive bacteria belonging to the phylum Firmicutes and the lactic acid bacteria group. Cellular division occurs along a single axis in these bacteria, and thus they grow in chains or pairs, hence the name — from Greek στρεπτος streptos, meaning...

, as well as fungi belonging to the groups Ascomycetes and Deuteromycetes, cannot make ergothioneine.

Possible functions

Despite its unusual chemistry, ergothioneine does still have antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...

 properties. It is a good scavenger of hydroxyl radical
Hydroxyl radical
The hydroxyl radical, •OH, is the neutral form of the hydroxide ion . Hydroxyl radicals are highly reactive and consequently short-lived; however, they form an important part of radical chemistry. Most notably hydroxyl radicals are produced from the decomposition of hydroperoxides or, in...

s and hypochlorous acid
Hypochlorous acid
Hypochlorous acid is a weak acid with the chemical formula HClO. It forms when chlorine dissolves in water. It cannot be isolated in pure form due to rapid equilibration with its precursor...

, and can inhibit the production of oxidants by metal ions. On the other hand, since these antioxidant properties were measured in simple cell-free systems, their relevance to the actual function of ergothioneine in the body has been questioned. Another possibility is that ergothioneine is important in protecting cells against the nitrosative stress produced by reactive nitrogen species
Reactive nitrogen species
Reactive nitrogen species are a family of antimicrobial molecules derived from nitric oxide and superoxide produced via the enzymatic activity of inducible nitric oxide synthase 2 and NADPH oxidase respectively...

 such as nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...

. However, it might also be involved in metal ion transport and the regulation of metalloenzymes.

Ergothioneine is transported into human cells by a specific transporter called ETT (gene symbol SLC22A4
SLC22A4
Solute carrier family 22, member 4, also known as SLC22A4, is a human gene; the encoded protein is an ergothioneine transporter.- Function :The encoded protein is an integral protein of the plasma membrane containing 12 transmembrane segments...

). Mutants of this transporter are associated with the autoimmune disorders, rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...

 and Crohn's disease
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...

. Surprisingly, these mutant transporters are not impaired and instead can transport ergothioneine more efficiently than the normal forms of these proteins. This may also relate to the fact that higher blood ergothioneine levels have been associated with rheumatoid arthritis. Since the function of ergothioneine in human metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...

 remains unknown, whether these findings point to a direct role for this amino acid in human disease is unclear.

See also

  • Natural product
    Natural product
    A natural product is a chemical compound or substance produced by a living organism - found in nature that usually has a pharmacological or biological activity for use in pharmaceutical drug discovery and drug design...

  • Oxidative stress
    Oxidative stress
    Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...

  • Reactive oxygen species
    Reactive oxygen species
    Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....

  • Medicinal mushrooms
    Medicinal mushrooms
    Medicinal mushrooms are mushrooms, or mushroom extracts, that are used or studied as possible treatments for diseases. Lentinula edodes , Grifola frondosa , Ganoderma lucidum , and Cordyceps, have a history of medicinal use spanning millennia in parts of Asia...


External links

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