497-30-3

Basic information

• Product Name: L-(+)-ERGOTHIONEINE
• Synonyms: L-(+)-ERGOTHIONEINE INNER SALT;ERGOLD;2-MERCAPTOHISTIDINE BETAINE;(S)-ALPHA-CARBOXY-2,3-DIHYDRO-N,N,N-TRIMETHYL-2-THIOXO-1H-IMIDAZOLE-4-ETHANAMINIUM INNER SALT;THIONEINE;(S)-[1-carboxy-2-(2-mercaptoimidazol-4-yl)ethyl]trimethylammonium hydroxide;1H-Imidazole-4-ethanaminium, .alpha.-carboxy-2,3-dihydro-N,N,N-trimethyl-2-thioxo-, inner salt, (.alpha.S)-;3-(2-sulfanylidene-1,3-dihydroimidazol-4-yl)-2-trimethylammonio-propanoate
• CAS NO: 497-30-3
• Molecular Formula: C₉H₁₅N₃O₂S
• Molecular Weight: 229.3
• EINECS: 207-843-5
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds;Heterocycles
• Mol File: 497-30-3.mol
• Article Data: 10

Chemical Properties

• Melting Point: 275-277°C (dec.)
• Appearance: White solid
• Density: 1.2541 (rough estimate)
• Refractive Index: 1.6740 (estimate)
• Storage Temp.: −20°C
• Solubility: Soluble in Water (up to 10 mg/ml)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in water may be stored at -20°C for no more then 1 day.
• CAS DataBase Reference: L-(+)-ERGOTHIONEINE(CAS DataBase Reference)
• NIST Chemistry Reference: L-(+)-ERGOTHIONEINE(497-30-3)
• EPA Substance Registry System: L-(+)-ERGOTHIONEINE(497-30-3)

Safety Data

• WGK Germany: 3
• Hazardous Substances Data: 497-30-3(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Applications:
L-(+)-Ergothioneine is used as a therapeutic agent for its antioxidizing properties, which may have potential in treating various health conditions.
Used in Food Industry:
L-(+)-Ergothioneine is used as a food additive due to its antioxidant properties, which can help extend the shelf life of certain products and maintain their quality.
Used in Cosmetics:
L-(+)-Ergothioneine is used in the cosmetics industry for its antioxidant and anti-inflammatory properties, which can contribute to the development of skincare products with potential benefits for the skin.

benefits

L-(+)-Ergothioneine is a natural antioxidant, which has various physiological functions such as scavenging free radicals, detoxification, maintaining DNA biosynthesis, normal cell growth and cellular immunity.

Biochem/physiol Actions

L-(+)-Ergothioneine (ET) has the maximum concentrations in tissues subjected to oxidative stress, with the highest being in blood, eye lens, bone marrow, semen and liver. It acts as an anti-oxidant and prevents apoptosis, by scavenging reactive oxygen and nitrogen species. The anti-oxidant activity is attributable to sulfhydryl groups. It acts as a substrate for SLC22A4 (solute carrier family 22, member 4) transporter. In alveolar macrophages, it prevents the release of interleukin-8 (IL-8) by tumor necrosis factor (TNF)α. IL-8 is an inflammatory cytokine. It also regulates the oxidative damage in liver and kidneys, and has a protective action against lipid peroxidation. It is also responsible for the conservation of endogenous glutathione and α-tocopherol. ET being an antioxidant, protects against γ and UV radiation. In UV-irradiated human dermal fibroblasts, it scavenges reactive oxygen species (ROS), and suppresses matrix metalloproteinases 1 (MMP1) expression. It might also have anti-ageing effects on skin caused by UV-radiation.

InChI:InChI=1/C9H15N3O2S/c1-12(2,3)7(8(13)14)4-6-5-10-9(15)11-6/h5,7H,4H2,1-3H3,(H2-,10,11,13,14,15)/t7-/m0/s1

Synthetic route

potassium thiocyanate + C8H16N2O3 → ergothioneine (497-30-3)

Conditions	Yield
Stage #1: potassium thiocyanate; C8H16N2O3 In water at 85 - 90℃; Stage #2: With hydrogenchloride In ethanol; water at 30℃; Reagent/catalyst;	1.1 g

ergothioneine (497-30-3) → L-ergothioneine disulfide (33605-54-8)

Conditions	Yield
With formic acid; copper(II) sulfate at 25℃; for 0.5h;

Upstream product

• 1136531-74-2 C₁₃H₂₃N₃O₂S 
• 127-17-3 2-oxo-propionic acid 
• 107-96-0 3-mercaptopropionic acid 
• 1136531-73-1 (2S)-3-(2-(tert-butylthio)-1H-imidazol-4-yl)-2-(dimethylamino)propanoic acid 
• 1392219-76-9 C₁₃H₂₄N₃O₂S⁽¹⁺⁾*I^(1-) 
• 507-29-9 Hercynine 
• 162138-72-9 methyl (S)-3-<1-(ethoxycarbonyl)-2-<(ethoxycarbonyl)thio>-1H-imidazol-4-yl>-2-(dimethylamino)propionate 
• 162138-71-8 methyl (S)-3-(2-mercapto-1H-imidazol-4-yl)-2-(dimethylamino)propionate 
• 4467-54-3 l-histidine methyl ester dihydrochloride 
• 74-88-4 methyl iodide 
• 162240-57-5 methyl (S)-3-<1-(ethoxycarbonyl)-2-<(ethoxycarbonyl)thio>-1H-imidazol-4-yl>-2-(trimethylammonio)propionate iodide 

Downstream Products

• 507-29-9 Hercynine 
• 534-30-5 α-N,N,N-trimethylhistidine 
• 124-38-9 carbon dioxide 
• 7783-06-4 hydrogen sulfide 
• 7664-41-7 ammonia 
• 154679-07-9 L-glutamate 
• 75-50-3 trimethylamine 

Relevant articles and documents

Synthesis method of ergothioneine

The invention provides a synthesis method and an intermediate of ergothioneine. According to the method, chirality is introduced in a chiral catalysis mode, reaction intermediates can be dissolved inan organic solvent, high-purity ergothioneine can be conveniently obtained at a low cost, reaction conditions are mild, control is easy, environmental pollution is small, and the method can better adapt to industrial production.

In Vitro Reconstitution of the Remaining Steps in Ovothiol A Biosynthesis: C-S Lyase and Methyltransferase Reactions

Ovothiols are thiolhistidine derivatives. The first step of ovothiol biosynthesis is OvoA-catalyzed oxidative coupling between histidine and cysteine. In this report, the remaining steps of ovothiol A biosynthesis were reconstituted in vitro. ETA-14770 (OvoB) was reported as a PLP-dependent sulfoxide lyase, responsible for mercaptohistidine production. OvoA was found to be a bifunctional enzyme, which mediates both oxidative C-S bond formation and methylation of mercaptohistidine to afford ovothiol A. Besides reconstituting the whole biosynthetic pathway, two unique features proposed in the literature were also examined: A potential cysteine-recycling mechanism of the C-S lyase (OvoB) and the selectivity of the ?-N methyltransferase.

Snapshots of C-S Cleavage in Egt2 Reveals Substrate Specificity and Reaction Mechanism

Sulfur incorporation in the biosynthesis of ergothioneine, a histidine thiol derivative, differs from other well-characterized transsulfurations. A combination of a mononuclear non-heme iron enzyme-catalyzed oxidative C-S bond formation and a subsequent pyridoxal 5′-phosphate (PLP)-mediated C-S lyase reaction leads to the net transfer of a sulfur atom from a cysteine to a histidine. In this study, we structurally and mechanistically characterized a PLP-dependent C-S lyase Egt2, which mediates the sulfoxide C-S bond cleavage in ergothioneine biosynthesis. A cation-π interaction between substrate and enzyme accounts for Egt2's preference of sulfoxide over thioether as a substrate. Using mutagenesis and structural biology, we captured three distinct states of the Egt2 C-S lyase reaction cycle, including a labile sulfenic intermediate captured in Egt2 crystals. Chemical trapping and high-resolution mass spectrometry were used to confirm the involvement of the sulfenic acid intermediate in Egt2 catalysis. Irani et al. have determined the structure of Egt2, a C-S lyase at the final step in the ergothioneine biosynthesis pathways. Using X-ray crystallography and various biochemical studies, the reaction mechanism was delineated.

Nα, Nα, Nα-trialkyl histidine derivatives useful for the preparation of ergothioneine compounds

Provided herein are Nα,Nα,Nα-trialkyl histidine derivative compounds and methods of their preparation. Also provided are methods of their use for preparing useful compounds such as ergothioneine.

Bioinformatic and biochemical characterizations of C-S bond formation and cleavage enzymes in the fungus neurospora crassa ergothioneine biosynthetic pathway

Ergothioneine is a histidine thiol derivative. Its mycobacterial biosynthetic pathway has five steps (EgtA-E catalysis) with two novel reactions: a mononuclear nonheme iron enzyme (EgtB) catalyzed oxidative C-S bond formation and a PLP-mediated C-S lyase (EgtE) reaction. Our bioinformatic and biochemical analyses indicate that the fungus Neurospora crassa has a more concise ergothioneine biosynthetic pathway because its nonheme iron enzyme, Egt1, makes use of cysteine instead of γ-Glu-Cys as the substrate. Such a change of substrate preference eliminates the competition between ergothioneine and glutathione biosyntheses. In addition, we have identi fied the N. crassa C-S lyase (NCU11365) and reconstituted its activity in vitro, which makes the future ergothioneine production through metabolic engineering feasible. (Chemical Equation Presented).

Cysteine as a sustainable sulfur reagent for the protecting-group-free synthesis of sulfur-containing amino acids: Biomimetic synthesis of l-ergothioneine in water

Biomass-derived cysteine was used as a sustainable sulfur source for the synthesis of rare sulfur-containing amino acids, such as l-ergothioneine (4), which might be a new vitamin, and various l- or d-2-thiohistidine compounds. Key in this simple, one-pot two-step procedure in water is a bromine-induced regioselective introduction of cysteine followed by a novel thermal cleavage reaction in the presence of thiols, a safer alternative to hazardous red phosphorus. Besides avoiding hazardous sulfur reagents, the new protecting-group-free approach reduces drastically the total number of steps, compared to described procedures. The main drawback, i.e. handling of liquid bromine as an activating and oxidizing reagent in water, was addressed by evaluating four alternative methods using in situ generation of bromine or HOBr, and first encouraging results are described.

THE METHOD OF SYNTHESIZING ERGOTHIONEINE AND ANALOGS

The present disclosure relates to a method for synthesizing ergothioneine or one of the derivatives thereof of following formula (I): or a physiologically acceptable salt, a tautomer, a stereoisomer or a mixture of stereoisomers in all proportions thereof, from a compound of betaine type of following formula (II): or a physiologically acceptable salt, a tautomer, a stereoisomer or a mixture of stereoisomers in all proportions thereof, by cleavage reaction in the presence of a thiol, at a temperature above or equal to 60° C. The present disclosure also relates to compounds of formula (II) and the method of synthesis thereof.

PROCESS FOR THE SYNTHESIS OF L-(+)-ERGOTHIONEINE

This invention relates to a novel process for the preparation of optically pure L-(+)-ergothioneine. The process for the chemical synthesis of L-ergothioneine comprises steps which consist of reacting L-histidine alkyl ester with an acid halide, chloroformate or pyrocarbonate in the presence of a base, hydrolysis of the alkyl-(S,Z)-2,4,5-triamidopent-4-enoate to obtain a (S)-alkyl 2,5-diamido-4-oxopentanoate, acid catalyzed hydrolysis of the (S)-alkyl 2,5-diamido-4-oxopentanoate followed by reaction with a metal thiocyanate to obtain the thiohistidine, protection of the sulfur of thiohistidine as the tert-butyl thioether, dialkylation of the primary amine to obtain a tertiary amine, quaternization of the tertiary amine, and removal of the protecting group to obtain the desired (S)-3-(2-mercapto-1H-imidazol-5-yl)-2-(trialkylammonio)propanoate (I). This process affords a better yield and is capable of practical application at large scale.

Synthesis of L-(+)-ergothioneine

The first synthesis of L-(+)-ergothioneine (1), a rare natural amino acid, is described. The key step is the direct transformation of the imidazole derivative 11 into imidazole-2-thione 12. This reaction consists of the cleavage and the re-formation of imidazole ring (ANRORC) with phenyl chlorothionoformate via a Bamberger-type intermediate. The conditions used are mild enough to preserve the asymmetric center at the 1a-carbon. The release of enantiomerically pure L-ergothioneine (1) from the ammonium derivative 15 was performed under acidic conditions to avoid the very easy racemization of the betaine function. An efficient and high-yield sypthesis of 2-mercapto-L-histidine (2) which uses the new imidazole-2-thione formation reaction is also described.