THIAMINE

• Molecular FormulaC₁₂H₁₇N₄OS
• Average mass265.354 Da

• 59-43-8    has cl atom
• 70-16-6 [RN]  no cl atom

• Thiazolium, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methyl-, chloride, hydrochloride (1:1:1), Thiamine CL  hcl, 67-03-8, (Component: 70-16-6) 1;1;1,
• C₁₂ H₁₇ N₄ O S . Cl H . Cl

3595616 [Beilstein]

3-[(4-Amino-2-methyl-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methylthiazolium

thiamin hydrochloride
Vitamin B1 hydrochloride
thiamine hydrochloride
aneurin hydrochloride
3-(4-amino-2-methyl-5-pyrimidinyl)methyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride hydrochloride

Some symptoms of ‘dry’ beriberi. There is also a ‘wet’ version of beriberi which mainly affects the heart and circulatory system,
with shortness of breath, swelling of the lower legs, and increased heart rate.

Thiaminpyrophosphate (11) (Figure 1) is an essential cofactor in all forms of life and it plays a key role in carbohydrate and amino acid metabolism by stabilizing acyl carbanion biosynthons. The mechanistic enzymology of thiamin pyrophosphate-dependent enzymes is described in detail in the chapter by Frank Jordan.¹ Here, we will review recent progress on the biosynthesis of thiamin pyrophosphate in bacteria and Saccharomyces cerevisiae with an emphasis on some of the novel organic chemistry that has emerged from these studies. Recent reviews describing the regulation of the pathway,^2,3 the identification of biosynthetic precursors,⁴ and the structural biology of the pathway^5–7 have been published.

Figure 1. Thiamin biosynthesis in Bacillus subtilis as representative of the major bacterial thiamin biosynthetic pathway.

SYN

Vitamin B1 338 Commercial production involves a six-step synthetic procedure (Williams & Cline, 1936). Beginning with 339 ethyl 3-ethoxypropionate as the feedstock for vitamin B1 production, the synthetic reactions include (1) 340 formylation using ethyl formate, (2) reaction with acetamidine hydrochloride leading to aminopyrimidine 341 ring formation, (3) replacement of aminopyrimidine hydroxyl group with a chlorine atom (chlorination) 342 using phosphorus(V) oxychloride, (4) replacement of the labile chlorine atom with an amino group using 343 alcoholic ammonia, (5) ammonium salt formation using hydrobromic acid, (6) introduction of the thiazole 344 ring using 4-methyl 5-hydroxyethyl thiazole.

 

A search of the patent literature revealed two methods for vitamin B1 (thiamine) production by 349 fermentative methods. The first patent describes the development of mutants of the genus Saccharomyces 350 Meyen emend Reess (yeast) for synthesizing vitamin B1 from sugars and inorganic salts (Silhankova, 1980). A 351 more recent invention provides a method for producing thiamine products using a microorganism of the 352 genus Bacillus containing a mutation (i.e., gene deletions or other mutations) that causes it to overproduce 353 and release thiamine products into the medium (Goese, 2012).

PATENT

CN109467553 – PURIFICATION METHOD OF FORMYL PYRIMIDINE AND SYNTHETIC METHOD OF VITAMIN B1

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN240133393&_cid=P20-KSRJ61-23741-1

The invention relates to the field of vitamin B1 synthesis, and particularly relates to a purification method of formyl pyrimidine and a synthetic method of vitamin B1. The purification method of formyl pyrimidine comprises the following steps: washing formyl pyrimidine with alcohol; washing formyl pyrimidine with water; dissolving formyl pyrimidine with alcohol, and decoloring formyl pyrimidine with activated carbon to obtain a formyl pyrimidine solution; and separating out formyl pyrimidine in the formyl pyrimidine solution and separating the formyl pyrimidine from the solution to obtain purified formyl pyrimidine. According to the purification method of formyl pyrimidine, by washing the formyl pyrimidine with alcohol and water, decoloring the formyl pyrimidine with activated carbon in an alcohol solution and separation the purification method of formyl pyrimidine by water, impurities in the formyl pyrimidine are removed, the content of the formyl pyrimidine reaches 99.5% over, and agood basis is provided for further synthesizing vitamin B1.

PAPER

HELVETICA CHIMICA ACTA ~ Vol. 73 (1990)

1. 3-Mercapto-4-oxopentyl Acetate (5a). Anh. KSH (7.22 g, 0.1 mol) was suspended in 50 ml of abs. MeOH. The mixture was cooled to 0″ in an ice-bath and 3-chloro-4-oxopentyl acetate (3; 17.9 g, 0.1 mol), previously dissolved in 50 ml of abs. MeOH, was added dropwise in order to maintain the temp. in the mixture between 0 and 5″. After complete addition, stirring was continued at r.t. for 1 h, while a slow stream of N, was passed through the mixture to remove residual H2S. The precipitated KC1 was filtered off and the solvent evaporated under reduced pressure. The residue was taken up in 50 ml of CH,C12 and the insoluble material removed by filtration. Evaporation of the solvent in uamo at 30″ gave 14.9 g of slightly yellow liquid. Bulb-to-bulb distillation of the crude mixture at 120″/0.3 mm yielded 12.95 g (0.07 mol, 73.5%) of 5a as a colourless liquid7). IR (film): 2960w, 2550~. 1740s, 17153, 1370m, 1245s, 1050m. ‘H-NMR (CDCI,): 1.74 (d, J= 12, SH); 1.95-2.25 (m, CH,); 2.05 (s, AcO); 2.35(s,Me);3.42(td,J= 12,5.7,SCH);4.2(t,J=5.7,CH20).EI-MS: 134(2), 116(36),74(21),73(58),43(100). Anal. calc. for C7HI2O,S (176.23): C 47.71, H 6.86, S 18.19; found: C 47.94, H 6.95, S 17.24.

2. 3,4-Dihydro-7-methylpyrimido[4,5-d]pyrimidine (4). From 4-amino-2-methyl-5-(aminomethyl)pyrimidine (Za) and DMF-DMA. In a flask equipped with a Vigreux column and a Liebig condenser, Zag) (69 g, 0.5 mol) was suspended in dimethylformamide dimethyl acetal(59.6 g, 0.5 mol). The stirred suspension was slowly heated to ca. 8&85″, until the temp. at the head of the Vigreux column reached 60°9). The MeOH/Me,NH mixture was then distilled off, until the mixture in the flask became a thick mass. The temp. was increased to 90″ for 30 min, 250 ml of toluene were added, and the obtained suspension was further stirred for 1 h at 90°. It was then allowed to cool to r.t., filtered, and washed twice with 100 ml of hexane. The crude material was dried at SOo under reduced pressure: 69.6 g of a tan solid was obtained, which was then sublimated at 1 SOo (oil-bath temp.) under high vacuum (0.2 mm) togive65.5g(0.44mol,88.5%)of4asawhitesolid. M.p. 173″(dec.).UV:202(4),298(3,7).1R(KBr): 3430m(br.), 2860m, 2840s, 16703, 1620s, 15803, 15303, 1450s. 1210s. ‘H-NMR ((D,)DMSO): 2.4 (s, Me); 4.5 (s, CH,); 7.2 (br. s, vinyl. CH); 8.03 (s, arom. H); 9.9 (br. s, NH). EI-MS: 148 (50, M’), 147 (loo), 106 (12), 53 (17), 42 (20). Anal. calc. for C7H,N, (148.169): C 56.74, H 5.44, N 37.81; found: C 56.79, H 5.44, N 37.75.

From 2a and Triethyl Orthoformate. In a flask equipped with a 20-cm Vigreux column and a Liebig condenser, Zag) (69 g, 0.5 mol), triethyl orthoformate (148.2 g, 1 rnol), and TsOH (2.5 g)”) were introduced. The stirred suspension was slowly heated to ca. 110″ so that the temp. at the head of the Vigreux column reached 80-85″. The EtOH was then distilled off, until the mixture in the flask became a thick mass. The temp. was maintained at 100-1 10″ for 30 min, then 250 ml of toluene were added, and theobtained suspension was further stirred for 1 h at90°. It was cooled to r.t. and placed overnight in the refrigerator. The light-brown precipitate was filtered and washed twice with 50 ml of toluene. The crude material was dried at 50″ under reduced pressure to give 59.3 g of a beige solid which was sublimated at 150″ (oil-bath temp.) under high vacuuni (0.2 mm) to yield 52.5 g (0.35 mol, 71 %) of 4 as a white solid. M.p. 182O (dec.).

3. 3-1 (4-Amino-2-methylpyrimidin-5-yl)methyl]-5-(2-hydroxyethyl)-4-methylthiazolium Chloride Hydrochloride (Thiamine Hydrochloride, la). Compound 4 (7.4 g, 0.05 mol) was dissolved in 100 ml of HCOOH. To this slightly yellow soh, 5a (9.25 g, 0.052 mol) was immediately added at such a rate so that the temp. did not exceed 3540″. The mixture was further stirred for 30 min at r.t. and then 25 ml of a freshly prepared sat. soh. of HCI in abs. EtOH was added dropwise. The temp. rose to 35-36O, and the mixture was further stirred for 30 min at r.t.”), The crude mixture was then poured into a 500-ml flask and evaporated at 50″ under reduced pressure to give 26.07 g of a green-yellow solid residue, which was taken up in 100 ml of ahs. EtOH. Aq. HCI soh. (25%, 30 ml) was then added and the crude mixture heated on a steam-bath, until a clear soln. was obtained. The soln. was cooled to r.t. and placed overnight in the refrigerator. The resulting white crystals were collected and dried in vucuo to yield 14.56 g (86.3%) of la. M.p. 245-246′ (dec.). The mother-liquor was then evaporated at 50O under reduced pressure and the residue taken up in 50 ml of H,O. The aq. phase was then washed twice with 25 ml of CH2C1, and evaporated under reduced pressure to give 3.29 g of a still slightly greenish residue, which was again taken up in 20 ml of abs. EtOH. Aq. HCI soln. (25%, 5 ml) was added and the mixture heated on a steam-bath, until a clear soln. was obtained. It was then cooled to r.t. and kept overnight in the refrigerator. The white crystals were filtered to give 1.42 g (8.4%) of la. M.p. 244-24So(dec.) (combined yieldI2) of la: 94.7% based on 4).

Recrystallization. The two crops of la were combined and dissolved in 100 ml of warm abs. EtOH. Aq. HCI soh (25 %, 40 ml) was added. The soln. was then allowed to cool slowly to r.t. and kept at Oo overnight. The white crystals were filtered and dried in vucuo at 50″ to give 13.6 g (0.04 mol, 80.6 %) of la.

M.p. 243-244″ (dec.). UV: 234 (4.1), 266 (3.9).

IR (KBr): 3500m, 3430m. 3340m. 3240m. 3065s. 2615m. 1660s, 1607m, 1380m.

‘H-NMR (D,O): 2.54(s,Me);2.62(s,Me);3.19(t,J= 5.8,CH2);3.88(t,J= 5.8,CH20);5.56(s,1H,CH2N);8.02(s,1arom.H); proton of thiazole ring is exchanged with deuterium of D,O.

FAB-MS: 265 (100, M+), 181 (18), 144 (30), 123 (65), 122 (65), 91 (78).

Anal. calc. for C,2H18C1,N40S (337.27): C 42.74, H 5.38, N 16.61, S 9.51, CI 21.02; found: C 42.93, H 5.28, N 16.70, S 9.61, C121.17.

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Thiamine, also known as thiamin or vitamin B₁, is a vitamin found in food and manufactured as a dietary supplement and medication.^[1][4] Food sources of thiamine include whole grains, legumes, and some meats and fish.^[1] Grain processing removes much of the thiamine content, so in many countries cereals and flours are enriched with thiamine.^[1][5] Supplements and medications are available to treat and prevent thiamine deficiency and disorders that result from it, including beriberi and Wernicke encephalopathy.^[3] Other uses include the treatment of maple syrup urine disease and Leigh syndrome.^[3] They are typically taken by mouth, but may also be given by intravenous or intramuscular injection.^[3][6]

Thiamine supplements are generally well tolerated.^[3][7] Allergic reactions, including anaphylaxis, may occur when repeated doses are given by injection.^[3][7] Thiamine is in the B complex family.^[3] It is an essential micronutrient, which cannot be made in the body.^[8] Thiamine is required for metabolism including that of glucose, amino acids, and lipids.^[1]

Thiamine was discovered in 1897, was the first B vitamin to be isolated in 1926, and was first made in 1936.^[9] It is on the World Health Organization’s List of Essential Medicines.^[10] Thiamine is available as a generic medication, and as an over-the-counter drug.^[3]

Medical uses

Thiamine deficiency

Thiamine is used to treat thiamine deficiency which when severe can prove fatal.^[11] In less severe cases, non-specific signs include malaise, weight loss, irritability and confusion.^[12] Well-known disorders caused by thiamine deficiency include beriberi, Wernicke–Korsakoff syndrome, optic neuropathy, Leigh’s disease, African seasonal ataxia (or Nigerian seasonal ataxia), and central pontine myelinolysis.^[13]

In Western countries, thiamine deficiency is seen mainly in chronic alcoholism.^[14] Thiamine deficiency is often present in alcohol misuse disorder. Also at risk are older adults, persons with HIV/AIDS or diabetes, and persons who have had bariatric surgery.^[1] Varying degrees of thiamine deficiency have been associated with the long-term use of high doses of diuretics, particularly furosemide in the treatment of heart failure.^[15]

Prenatal supplementation

Women who are pregnant or lactating require more thiamine. For pregnant and lactating women, the consequences of thiamine deficiency are the same as those of the general population but the risk is greater due to their temporarily increased need for this nutrient. In pregnancy, this is likely due to thiamine being preferentially sent to the fetus and placenta, especially during the third trimester. For lactating women, thiamine is delivered in breast milk even if it results in thiamine deficiency in the mother.^[16] Pregnant women with hyperemesis gravidarum are also at an increased risk for thiamine deficiency due to losses when vomiting.^[17]

Thiamine is important for not only mitochondrial membrane development, but also synaptosomal membrane function.^[18] It has also been suggested that thiamine deficiency plays a role in the poor development of the infant brain that can lead to sudden infant death syndrome (SIDS).^[19]

Other uses

Thiamine is a treatment for some types of maple syrup urine disease and Leigh disease.^[3]

Adverse effects

Thiamine is generally well tolerated and non-toxic when administered orally.^[3] Rarely, adverse side effects have been reported when thiamine is given intravenously including allergic reactions, nausea, lethargy, and impaired coordination.^[20][21]

Chemistry

Thiamine is a colorless organosulfur compound with an unpleasant sulfur odor and the chemical formula C₁₂H₁₇N₄O S. Its structure consists of an aminopyrimidine and a thiazolium ring linked by a methylene bridge. The thiazole is substituted with methyl and hydroxyethyl side chains. Thiamine is soluble in water, methanol, and glycerol and practically insoluble in less polar organic solvents. As a base it can form salts with acids, such as hydrochloride. It is stable at acidic pH, but is unstable in alkaline solutions.^[11][22] Thiamine, which is a persistent carbene, is used by enzymes to catalyze benzoin condensations in vivo.^[23] Thiamine is unstable to heat, but stable during frozen storage.^[24] It is unstable when exposed to ultraviolet light^[22] and gamma irradiation.^[25][26] Thiamine reacts strongly in Maillard-type reactions.^[11]

Biosynthesis

Complex thiamine biosynthesis occurs in bacteria, some protozoans, plants, and fungi.^[27][28] The thiazole and pyrimidine moieties are biosynthesized separately and then combined to form thiamine monophosphate (ThMP) by the action of thiamine-phosphate synthase (EC 2.5.1.3). The biosynthetic pathways may differ among organisms. In E. coli and other enterobacteriaceae, ThMP may be phosphorylated to the cofactor thiamine diphospate (ThDP) by a thiamine-phosphate kinase (ThMP + ATP → ThDP + ADP, EC 2.7.4.16). In most bacteria and in eukaryotes, ThMP is hydrolyzed to thiamine, which may then be pyrophosphorylated to ThDP by thiamine diphosphokinase (thiamine + ATP → ThDP + AMP, EC 2.7.6.2).

The biosynthetic pathways are regulated by riboswitches.^[21] If there is sufficient thiamine present in the cell then the thiamine binds to the mRNAs for the enzymes that are required in the pathway and prevents their translation. If there is no thiamine present then there is no inhibition, and the enzymes required for the biosynthesis are produced. The specific riboswitch, the TPP riboswitch (or ThDP), is the only riboswitch identified in both eukaryotic and prokaryotic organisms.^[29]

Nutrition

Occurrence in foods

Thiamine is found in a wide variety of processed and whole foods. Whole grains, legumes, pork, fruits, and yeast are rich sources.^[30][31]

The salt thiamine mononitrate, rather than thiamine hydrochloride, is used for food fortification, as the mononitrate is more stable, and does not absorb water from natural humidity (is non-hygroscopic), whereas thiamine hydrochloride is hygroscopic.^{[citation needed]} When thiamine mononitrate dissolves in water, it releases nitrate (about 19% of its weight) and is thereafter absorbed as the thiamine cation.

Dietary recommendations

In the U.S. the Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for thiamine were updated in 1998, by the Institute of Medicine now known as the National Academy of Medicine (NAM).^[32]

The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL defined the same as in United States. For women (including those pregnant or lactating), men and children the PRI is 0.1 mg thiamine per megajoule (MJ) of energy consumed. As the conversion is 1 MJ = 239 kcal, an adult consuming 2390 kilocalories should be consuming 1.0 mg thiamine. This is slightly lower than the U.S. RDA.^[33] The EFSA reviewed the same safety question and also reached the conclusion that there was not sufficient evidence to set a UL for thiamine.^[20]

To aid with adequate micronutrient intake, pregnant women are often advised to take a daily prenatal multivitamin. While micronutrient compositions vary among different vitamins, a typical prenatal vitamin contains around 1.5 mg of thiamine.^[34]

For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percentage of Daily Value (%DV). For thiamine labeling purposes 100% of the Daily Value was 1.5 mg, but as of 27 May 2016 it was revised to 1.2 mg to bring it into agreement with the RDA.^[35][36] Compliance with the updated labeling regulations was required by 1 January 2020 for manufacturers with US$10 million or more in annual food sales, and by 1 January 2021 for manufacturers with lower volume food sales.^[37][38] A table of the old and new adult daily values is provided at Reference Daily Intake.

Antagonists

Thiamine in foods can be degraded in a variety of ways. Sulfites, which are added to foods usually as a preservative,^[39] will attack thiamine at the methylene bridge in the structure, cleaving the pyrimidine ring from the thiazole ring.^[12] The rate of this reaction is increased under acidic conditions. Thiamine is degraded by thermolabile thiaminases (present in raw fish and shellfish).^[11] Some thiaminases are produced by bacteria. Bacterial thiaminases are cell surface enzymes that must dissociate from the membrane before being activated; the dissociation can occur in ruminants under acidotic conditions. Rumen bacteria also reduce sulfate to sulfite, therefore high dietary intakes of sulfate can have thiamine-antagonistic activities.

Plant thiamine antagonists are heat-stable and occur as both the ortho- and para-hydroxyphenols. Some examples of these antagonists are caffeic acid, chlorogenic acid, and tannic acid. These compounds interact with the thiamine to oxidize the thiazole ring, thus rendering it unable to be absorbed. Two flavonoids, quercetin and rutin, have also been implicated as thiamine antagonists.^[12]

Food fortification

Refining grain removes its bran and germ, and thus subtracts its naturally occurring vitamins and minerals. In the United States, B-vitamin deficiencies became common in the first half of the 20th century due to white flour consumption. The American Medical Association successfully lobbied for restoring these vitamins by enrichment of grain, which began in the US in 1939. The UK followed in 1940 and Denmark in 1953. As of 2016, about 85 countries had passed legislation mandating fortification of wheat flour with at least some nutrients, and 28% of industrially milled flour was fortified, often with thiamine and other B vitamins.^[40]

Absorption and transport

Absorption

Thiamine is released by the action of phosphatase and pyrophosphatase in the upper small intestine. At low concentrations, the process is carrier-mediated. At higher concentrations, absorption also occurs via passive diffusion. Active transport is greatest in the jejunum and ileum, but it can be inhibited by alcohol consumption or by folate deficiency.^[11] Decline in thiamine absorption occurs at intakes above 5 mg/day.^[41] On the serosal side of the intestine, discharge of the vitamin by those cells is dependent on Na⁺-dependent ATPase.^[12]

Bound to serum proteins

The majority of thiamine in serum is bound to proteins, mainly albumin. Approximately 90% of total thiamine in blood is in erythrocytes. A specific binding protein called thiamine-binding protein (TBP) has been identified in rat serum and is believed to be a hormone-regulated carrier protein important for tissue distribution of thiamine.^[12]

Cellular uptake

Uptake of thiamine by cells of the blood and other tissues occurs via active transport and passive diffusion.^[11] About 80% of intracellular thiamine is phosphorylated and most is bound to proteins. Two members of the SLC gene family of transporter proteins, SLC19A2 and SLC19A3, are capable of the thiamine transport.^[19] In some tissues, thiamine uptake and secretion appears to be mediated by a soluble thiamine transporter that is dependent on Na⁺ and a transcellular proton gradient.^[12]

Tissue distribution

Human storage of thiamine is about 25 to 30 mg, with the greatest concentrations in skeletal muscle, heart, brain, liver, and kidneys. ThMP and free (unphosphorylated) thiamine is present in plasma, milk, cerebrospinal fluid, and, it is presumed, all extracellular fluid. Unlike the highly phosphorylated forms of thiamine, ThMP and free thiamine are capable of crossing cell membranes. Calcium and magnesium have been shown to affect the distribution of thiamine in the body and magnesium deficiency has been shown to aggravate thiamine deficiency.^[19] Thiamine contents in human tissues are less than those of other species.^[12][42]

Excretion

Thiamine and its acid metabolites (2-methyl-4-amino-5-pyrimidine carboxylic acid, 4-methyl-thiazole-5-acetic acid, and thiamine acetic acid) are excreted principally in the urine.^[22]

Function

Its phosphate derivatives are involved in many cellular processes. The best-characterized form is thiamine pyrophosphate (TPP), a coenzyme in the catabolism of sugars and amino acids. In yeast, TPP is also required in the first step of alcoholic fermentation. All organisms use thiamine, but it is made only in bacteria, fungi, and plants. Animals must obtain it from their diet, and thus, for humans, it is an essential nutrient. Insufficient intake in birds produces a characteristic polyneuritis.

Thiamine is usually considered as the transport form of the vitamin. Five natural thiamine phosphate derivatives are known: thiamine monophosphate (ThMP), thiamine diphosphate (ThDP), also sometimes called thiamine pyrophosphate (TPP), thiamine triphosphate (ThTP), the most recently discovered adenosine thiamine triphosphate (AThTP), and adenosine thiamine diphosphate (AThDP). While the coenzyme role of thiamine diphosphate is well-known and extensively characterized, the non-coenzyme action of thiamine and derivatives may be realized through binding to a number of recently identified proteins which do not use the catalytic action of thiamine diphosphate.^[43]

Thiamine diphosphate

No physiological role is known for thiamine monophosphate (ThMP); however, the diphosphate is physiologically relevant. The synthesis of thiamine diphosphate (ThDP), also known as thiamine pyrophosphate (TPP) or cocarboxylase, is catalyzed by an enzyme called thiamine diphosphokinase according to the reaction thiamine + ATP → ThDP + AMP (EC 2.7.6.2). ThDP is a coenzyme for several enzymes that catalyze the transfer of two-carbon units and in particular the dehydrogenation (decarboxylation and subsequent conjugation with coenzyme A) of 2-oxoacids (alpha-keto acids). Examples include:

• Present in most species
  • pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase (also called α-ketoglutarate dehydrogenase)
  • branched-chain α-keto acid dehydrogenase
  • 2-hydroxyphytanoyl-CoA lyase
  • transketolase
• Present in some species:
  • pyruvate decarboxylase (in yeast)
  • several additional bacterial enzymes

The enzymes transketolase, pyruvate dehydrogenase (PDH), and 2-oxoglutarate dehydrogenase (OGDH) are all important in carbohydrate metabolism. The cytosolic enzyme transketolase is a key player in the pentose phosphate pathway, a major route for the biosynthesis of the pentose sugars deoxyribose and ribose. The mitochondrial PDH and OGDH are part of biochemical pathways that result in the generation of adenosine triphosphate (ATP), which is a major form of energy for the cell. PDH links glycolysis to the citric acid cycle, while the reaction catalyzed by OGDH is a rate-limiting step in the citric acid cycle. In the nervous system, PDH is also involved in the production of acetylcholine, a neurotransmitter, and for myelin synthesis.^[44]

Thiamine triphosphate

Thiamine triphosphate (ThTP) was long considered a specific neuroactive form of thiamine, playing a role in chloride channels in the neurons of mammals and other animals, although this is not completely understood.^[19] However, recently it was shown that ThTP exists in bacteria, fungi, plants and animals suggesting a much more general cellular role.^[45] In particular in E. coli, it seems to play a role in response to amino acid starvation.^[46]

Adenosine thiamine triphosphate

Adenosine thiamine triphosphate (AThTP) or thiaminylated adenosine triphosphate has recently been discovered in Escherichia coli, where it accumulates as a result of carbon starvation.^[47] In E. coli, AThTP may account for up to 20% of total thiamine. It also exists in lesser amounts in yeast, roots of higher plants and animal tissue.^[48]

Adenosine thiamine diphosphate

Adenosine thiamine diphosphate (AThDP) or thiaminylated adenosine diphosphate exists in small amounts in vertebrate liver, but its role remains unknown.^[48]

History

Thiamine was the first of the water-soluble vitamins to be described,^[11] leading to the discovery of more essential nutrients and to the notion of vitamin.

In 1884, Takaki Kanehiro (1849–1920), a surgeon general in the Japanese navy, rejected the previous germ theory for beriberi and hypothesized that the disease was due to insufficiencies in the diet instead.^[49] Switching diets on a navy ship, he discovered that replacing a diet of white rice only with one also containing barley, meat, milk, bread, and vegetables, nearly eliminated beriberi on a nine-month sea voyage. However, Takaki had added many foods to the successful diet and he incorrectly attributed the benefit to increased protein intake, as vitamins were unknown substances at the time. The Navy was not convinced of the need for so expensive a program of dietary improvement, and many men continued to die of beriberi, even during the Russo-Japanese war of 1904–5. Not until 1905, after the anti-beriberi factor had been discovered in rice bran (removed by polishing into white rice) and in barley bran, was Takaki’s experiment rewarded by making him a baron in the Japanese peerage system, after which he was affectionately called “Barley Baron”.

The specific connection to grain was made in 1897 by Christiaan Eijkman (1858–1930), a military doctor in the Dutch Indies, who discovered that fowl fed on a diet of cooked, polished rice developed paralysis, which could be reversed by discontinuing rice polishing.^[50] He attributed beriberi to the high levels of starch in rice being toxic. He believed that the toxicity was countered in a compound present in the rice polishings.^[51] An associate, Gerrit Grijns (1865–1944), correctly interpreted the connection between excessive consumption of polished rice and beriberi in 1901: He concluded that rice contains an essential nutrient in the outer layers of the grain that is removed by polishing.^[52] Eijkman was eventually awarded the Nobel Prize in Physiology and Medicine in 1929, because his observations led to the discovery of vitamins.

In 1910, a Japanese agricultural chemist of Tokyo Imperial University, Umetaro Suzuki (1874-1943), first isolated a water-soluble thiamine compound from rice bran and named it as aberic acid (He renamed it as Orizanin later). He described the compound is not only anti beri-beri factor but also essential nutrition to human in the paper, however, this finding failed to gain publicity outside of Japan, because a claim that the compound is a new finding was omitted in translation from Japanese to German.^[53] In 1911 a Polish biochemist Casimir Funk isolated the antineuritic substance from rice bran (the modern thiamine) that he called a “vitamine” (on account of its containing an amino group).^[54][55] However, Funk did not completely characterize its chemical structure. Dutch chemists, Barend Coenraad Petrus Jansen (1884–1962) and his closest collaborator Willem Frederik Donath (1889–1957), went on to isolate and crystallize the active agent in 1926,^[56] whose structure was determined by Robert Runnels Williams (1886–1965), a US chemist, in 1934. Thiamine was named by the Williams team as “thio” or “sulfur-containing vitamin”, with the term “vitamin” coming indirectly, by way of Funk, from the amine group of thiamine itself (by this time in 1936, vitamins were known to not always be amines, for example, vitamin C). Thiamine was synthesized in 1936 by the Williams group.^[57]

Thiamine was first named “aneurin” (for anti-neuritic vitamin).^[58] Sir Rudolph Peters, in Oxford, introduced thiamine-deprived pigeons as a model for understanding how thiamine deficiency can lead to the pathological-physiological symptoms of beriberi. Indeed, feeding the pigeons upon polished rice leads to an easily recognizable behavior of head retraction, a condition called opisthotonos. If not treated, the animals died after a few days. Administration of thiamine at the stage of opisthotonos led to a complete cure within 30 minutes. As no morphological modifications were observed in the brain of the pigeons before and after treatment with thiamine, Peters introduced the concept of a biochemical lesion.^[59]

When Lohman and Schuster (1937) showed that the diphosphorylated thiamine derivative (thiamine diphosphate, ThDP) was a cofactor required for the oxydative decarboxylation of pyruvate,^[60] a reaction now known to be catalyzed by pyruvate dehydrogenase, the mechanism of action of thiamine in the cellular metabolism seemed to be elucidated. At present, this view seems to be oversimplified: pyruvate dehydrogenase is only one of several enzymes requiring thiamine diphosphate as a cofactor; moreover, other thiamine phosphate derivatives have been discovered since then, and they may also contribute to the symptoms observed during thiamine deficiency. Lastly, the mechanism by which the thiamine moiety of ThDP exerts its coenzyme function by proton substitution on position 2 of the thiazole ring was elucidated by Ronald Breslow in 1958.^[61]

• Some contributors to the discovery of thiamine
• 

  Takaki Kanehiro

• 

  Christiaan Eijkman

• 

  Gerrit Grijns

• 

  Umetaro Suzuki

• 

  Casimir Funk

• 

  Rudolph Peters

• 

  Ronald Breslow

See also

• Vitamin B₁ analogue

References

External links

• “Thiamine”. Drug Information Portal. U.S. National Library of Medicine.

Thiamin

Skeletal formula and ball-and-stick model of the cation in thiamine
Clinical data
Pronunciation	/ˈθaɪ.əmɪn/ THY-ə-min
Other names	Vitamin B1, aneurine, thiamin
AHFS/Drugs.com	Monograph
License data	US DailyMed: Thiamine US FDA: Thiamine
Routes of administration	by mouth, IV, IM[1]
Drug class	vitamin
ATC code	A11DA01 (WHO)
Legal status
Legal status	US: OTC
Pharmacokinetic data
Bioavailability	3.7% to 5.3%[medical citation needed]
Elimination half-life	1.8d[2][better source needed]
Identifiers
show IUPAC name
CAS Number	59-43-8  59-43-8  HCl: 67-03-8
PubChem CID	1130
DrugBank	DB00152
ChemSpider	1098
UNII	X66NSO3N35 HCl: M572600E5P
KEGG	C00378
ChEBI	CHEBI:18385
ChEMBL	ChEMBL1547
CompTox Dashboard (EPA)	DTXSID50220251
Chemical and physical data
Formula	C12H17N4OS+
Molar mass	265.35 g·mol−1
3D model (JSmol)	Interactive image
show SMILES
show InChI

Bibliography

• Wikipedia: Beriberi; Christiaan Eijkman; Adolphe_Vorderman; Casimir_Funk; Rice Polishing; White rice; Thiamine; Thiamine_pyrophosphate; Citric Acid Cycle
• A. Bay, “Beriberi in Modern Japan: The Making of a National Disease”, University of Rochester Press (2012).
• K.J. Carpenter. Beriberi, White Rice and Vitamin B. University of California Press, 2000
• http://www.healthline.com/health/beriberi
• M.C. Latham, . “Chapter 16. Beriberi and thiamine deficiency” in Human nutrition in the developing world, 29 [Rome, Food and Agriculture Organization of the United Nations, 1997].
• D.-T. Nguyen-Khoa, Beriberi (Thiamine Deficiency) Treatment & Management
• M. Golden, Mike . “Diagnosing Beriberi in Emergency Situations”. Field Exchange 1 (1997) 18.
• Y. Itokawa, . “Kanehiro Takaki (1849–1920): A Biographical Sketch”. J. Nutrit. 106 (1976) 581–8.
• R. Breslow. “On the mechanism of thiamine action. IV.1 Evidence from studies on model systems”. J. Am. Chem. Soc. 80 (1958) 3719–3726.
• R.R. Williams, J.K. Cline,. “Synthesis of vitamin B₁“. J. Am. Chem. Soc. 58 (1936) 1504–1505.
• T.P. Begley, A.Chatterjee, J.W. Hanes, A. Hazra, S.E. Ealick,. “Cofactor biosynthesis—still yielding fascinating new biological chemistry”. Curr. Opin. in Chem. Biol. 12 (2008) 118–125.
• L. Bettendorff, F. Mastrogiacomo, S.J. Kish, T. Grisar, “Thiamine, thiamine phosphates and their metabolizing enzymes in human brain”. J. Neurochem. 66 (1996) 250–258.
• B.C.P. Jansen, W.F. Donath, “On the isolation of antiberiberi vitamin”. Proc. Kon. Ned. Akad. Wet. 29 (1926) 1390–1400.
• C. Nordqvist, “What is Thiamin, or Vitamin B₁?“, Medical News Today, (2016)
• Thiamin, NIH Fact Sheet for Health Professionals.
• Thiamine, Oregon State University

//////////THIAMINE, aneurin hydrochloride, vitamin b1

Cc2ncc(C[n+]1csc(CCO)c1C)c(N)n2