Thiamine
Thiamin.svg
Thiamine cation 3D ball.png
Skeletal formula and ball-and-stick model of the cation in thiamine
Clinical data
Pronunciation/ˈθaɪ.əmɪn/ THY-ə-min
Other namesVitamin B1, aneurine, thiamin
AHFS/Drugs.comMonograph
License data
Routes of
administration		by mouth, IV, IM[1]
Drug classvitamin
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability3.7% to 5.3%[medical citation needed]
Identifiers
  • 2-[3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-1,3-thiazol-3-ium-5-yl]ethanol
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC12H17N4OS+
Molar mass265.36 g·mol−1
3D model (JSmol)
  • cation: Cc2ncc(C[n+]1csc(CCO)c1C)c(N)n2
  • cation: InChI=1S/C12H17N4OS/c1-8-11(3-4-17)18-7-16(8)6-10-5-14-9(2)15-12(10)13/h5,7,17H,3-4,6H2,1-2H3,(H2,13,14,15)/q+1 checkY
  • Key:JZRWCGZRTZMZEH-UHFFFAOYSA-N

Thiamine, also known as thiamin and vitamin B1, is a vitamin, an essential micronutrient, which cannot be made in the body.[2][3] It is found in food and commercially synthesized to be a dietary supplement or medication.[1][4] Food sources of thiamine include whole grains, legumes, and some meats and fish.[1][5] Grain processing removes much of the thiamine content, so in many countries cereals and flours are enriched with thiamine.[1] Supplements and medications are available to treat and prevent thiamine deficiency and disorders that result from it, including beriberi and Wernicke encephalopathy. Other uses include the treatment of maple syrup urine disease and Leigh syndrome. They are typically taken by mouth, but may also be given by intravenous or intramuscular injection.[6]

Thiamine supplements are generally well tolerated. Allergic reactions, including anaphylaxis, may occur when repeated doses are given by injection.[6][7] Thiamine is required for metabolism including that of glucose, amino acids, and lipids.[1] Thiamine is on the World Health Organization's List of Essential Medicines.[8] Thiamine is available as a generic medication, and as an over-the-counter drug.[6]

Definition

Thiamine, also known as vitamin B1, is one of the B vitamins.[2][3] Unlike folate and vitamin B6, which occur in several chemically related forms known as vitamers, thiamine is only one chemical compound. It is an organosulfur compound, usually supplied as thiamine hydrochloride., dry, a white powder, colorless in solution. It is soluble in water, methanol, and glycerol and practically insoluble in less polar organic solvents. It is degraded by exposure to heat.[9][10] Physiologically, the best-characterized form is thiamine pyrophosphate (TPP), also referred to as thiamine diphosphate, functioning as a coenzyme in the catabolism of sugars and amino acids.[2]

Deficiency

Main article: Thiamine deficiency

Non-specific signs of thiamine deficiency include malaise, weight loss, irritability and confusion.[9][11] 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.[12]

In Western countries, chronic alcoholism is a secondary cause. 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.[citation needed]

Chemistry

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 a cation and is usually supplied as its chloride salt. The amino group can form additional salts with further acids. It is stable at acidic pH, but is unstable in alkaline solutions and from exposure to heat.[9][10] Thiamine reacts strongly in Maillard-type reactions.[9]

Functions

Thiamine 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. Five natural thiamine phosphate derivatives are known: thiamine monophosphate (ThMP), thiamine diphosphate (ThDP), also called thiamine pyrophosphate (TPP), thiamine triphosphate (ThTP), 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.[13]

Thiamine diphosphate

No physiological role is known for the monophosphate. The diphosphate ThPP is physiologically relevant. Its synthesis is catalyzed by the enzyme 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:

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.[10]

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.[14] However, it was shown that ThTP exists in bacteria, fungi, plants and animals suggesting a much more general cellular role.[15] In particular in E. coli, it seems to play a role in response to amino acid starvation.[16]

Adenosine thiamine diphosphate

AThDP exists in small amounts in vertebrate liver, but its role remains unknown.[16]

Adenosine thiamine triphosphate

AThTP is present in Escherichia coli, where it accumulates as a result of carbon starvation. 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.[16]


Medical uses

Prenatal supplementation

See also: Prenatal vitamins

Women who are pregnant or lactating require more thiamine 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.[3][17] Pregnant women with hyperemesis gravidarum are also at an increased risk for thiamine deficiency due to losses when vomiting.[18]

Thiamine is important for not only mitochondrial membrane development, but also synaptosomal membrane function.[19] 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).[14]

Dietary recommendations

The US National Academy of Medicine updated the Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for thiamine in 1998. The EARs for thiamine for women and men aged 14 and over are 0.9 mg/day and 1.1 mg/day, respectively; the RDAs are 1.1 and 1.2 mg/day, respectively. RDAs are higher than EARs to provide adequate intake levels for individuals with higher than average requirements. The RDA during pregnancy and for lactating females is 1.4 mg/day. For infants up to the age of 12 months, the Adequate Intake (AI) is 0.2–0.3 mg/day and for children aged 1–13 years the RDA increases with age from 0.5 to 0.9 mg/day. As for safety, the IOM sets tolerable upper intake levels (ULs) for vitamins and minerals when evidence is sufficient. In the case of riboflavin there is no UL, as there is no human data for adverse effects from high doses. Collectively the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes (DRIs).[3]

The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intakes (PRIs) instead of RDAs, and Average Requirements instead of EARs. 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.[20] The EFSA reviewed the same safety question and also reached the conclusion that there was not sufficient evidence to set a UL for thiamine.[21]

United States
Age group RDA (mg/day) Tolerable upper intake level[3]
Infants 0–6 months 0.2* ND
Infants 6–12 months 0.3*
1–3 years 0.5
4–8 years 0.6
9–13 years 0.9
Females 14–18 years 1.0
Males 14+ years 1.2
Females 19+ years 1.1
Pregnant/lactating females 14–50 1.4
* Adequate intake for infants, as an RDA has yet to be established[3]
European Food Safety Authority
Age group Adequate Intake (mg/MJ)[21] Tolerable upper limit[21]
All persons 7 months+ 0.1 ND

Safety

Thiamine is generally well tolerated and non-toxic when administered orally.[6] Rarely, adverse side effects have been reported when thiamine is given intravenously including allergic reactions, nausea, lethargy, and impaired coordination.[21][2]

Labeling

For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For thiamine labeling purposes 100% of the Daily Value was 1.5 mg, but as of May 27, 2016, it was revised to 1.2 mg to bring it into agreement with the RDA.[22][23] A table of the old and new adult daily values is provided at Reference Daily Intake.

Sources

Thiamine is found in a wide variety of processed and whole foods. Lentils, peas, whole grains, pork, and nuts are rich sources.[5][24]

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.[25]

Antagonists

Thiamine in foods can be degraded in a variety of ways. Sulfites, which are added to foods usually as a preservative,[26] will attack thiamine at the methylene bridge in the structure, cleaving the pyrimidine ring from the thiazole ring.[11] The rate of this reaction is increased under acidic conditions. Thiamine is degraded by thermolabile thiaminases (present in raw fish and shellfish).[9] 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.[11]

Food fortification

Main article: Food fortification

Some countries require or recommend fortification of grain foods such as wheat, rice or maize (corn) because processing lowers vitamin content.[27] As of February 2022, 59 countries, mostly in North and Sub-Saharan Africa, require food fortification of wheat, rice or maize with thiamine or thiamine mononitrate. The amounts stipulated range from 2.0 to 10.0 mg/kg.[28] An additional 18 countries have a voluntary fortification program. For example, the Indian government recommends 3.5 mg/kg for "maida" (white) and "atta" (whole wheat) flour.[29]

Synthesis

Biosynthesis

Thiamine biosynthesis occurs in bacteria, some protozoans, plants, and fungi.[30][31] The thiazole and pyrimidine moieties are biosynthesized separately and then combined to form thiamine monophosphate (ThMP) by the action of thiamine-phosphate synthase.

The pyrimidine ring system is formed in a reaction catalysed by phosphomethylpyrimidine synthase (ThiC), an enzyme in the radical SAM superfamily of iron–sulfur proteins, which use S-adenosyl methionine as a cofactor.[32][33]

Pyrimidine biosynthesis.svg

The starting material is 5-aminoimidazole ribotide, which undergoes a rearrangement reaction via radical intermediates which incorporate the blue, green and red fragments shown into the product.[34][35]

The thiazole ring is formed in a reaction catalysed by thiazole synthase.[32] The ultimate precursors are 1-deoxy-D-xylulose 5-phosphate, 2-iminoacetate and a sulfur carrier protein called ThiS. These are assembled by the action of an additional protein component, ThiG.[36]

Thiamine biosynthesis.svg

The final step to form ThMP involves decarboxylation of the thiazole intermediate, which reacts with the pyrophosphate derivative of the phosphomethylpyrimidine, itself a product of a kinase, phosphomethylpyrimidine kinase.[32]

A 3D representation of the TPP riboswitch with thiamine bound
A 3D representation of the TPP riboswitch with thiamine bound

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). 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).

The biosynthetic pathways are regulated by riboswitches.[2] 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.[37]

Laboratory synthesis

Thiamine synthesis.svg

In the first total synthesis in 1936, ethyl 3-ethoxypropanoate was treated with ethyl formate to give an intermediate dicarbonyl compound which when reacted with acetamidine formed a substituted pyrimidine. Conversion of its hydroxyl group to an amino group was carried out by nucleophilic aromatic substitution, first to the chloride derivative using phosphorus oxychloride, followed by treatment with ammonia. The ethoxy group was then converted to a bromo derivative using hydrobromic acid, ready for the final stage in which thiamine (as its dibromide salt) was formed in an alkylation reaction using 4-methyl-5-(2-hydroxyethyl)thiazole.[38]: 7 [39]

Industrial synthesis

Diamine used in the manufacture of thiamine
Diamine used in the manufacture of thiamine

The 1936 laboratory-scale synthesis was developed by Merck & Co., allowing them to manufacture thiamine in Rahway in 1937.[39] However, an alternative route using the intermediate Grewe diamine (5-(aminomethyl)-2-methyl-4-pyrimidinamine), first published in 1937,[40] was investigated by Hoffman La Roche and competitive manufacturing processes followed. Efficient routes to the diamine have continued to be of interest.[39][41] In the European Economic Area, thiamine is registered under REACH regulation and between 100 and 1,000 tonnes per annum are manufactured or imported there.[42]

Absorption, metabolism and excretion

Thiamine phosphate esters in food are hydrolyzed to thiamine by intestinal alkaline phosphatase in the upper small intestine. At low concentrations, the absorption process is carrier-mediated. At higher concentrations, absorption also occurs via passive diffusion.[2] Active transport can be inhibited by alcohol consumption or by folate deficiency.[9]

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.[11] Uptake of thiamine by cells of the blood and other tissues occurs via active transport and passive diffusion.[9] About 80% of intracellular thiamine is phosphorylated and most is bound to proteins. Two members of the SLC gene family of transporter proteins coded by the genes SLC19A2 and SLC19A3 are capable of the thiamine transport.[14] 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.[11]

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.[14] Thiamine contents in human tissues are less than those of other species.[11][43]

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

History

Further information: Vitamin § History

Thiamine was the first of the water-soluble vitamins to be isolated, in 1910.[44] Prior to that, observations in humans and in chickens had shown that diets of primarily polished white rice caused a disease "beriberi", but did not attribute it to the absence of a previously unknown essential nutrient.[45][46]

In 1884, Takaki Kanehiro, 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.[45] 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".[45]

The specific connection to grain was made in 1897 by Christiaan Eijkman, 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.[46] 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.[47] An associate, Gerrit Grijns, 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.[48] 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, 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.[44] 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).[49][50] However, Funk did not completely characterize its chemical structure. Dutch chemists, Barend Coenraad Petrus Jansen and his closest collaborator Willem Frederik Donath, went on to isolate and crystallize the active agent in 1926,[51] whose structure was determined by Robert Runnels Williams, 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.[52]

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.[53] In 1937, when Lohman and Schuster showed that the diphosphorylated thiamine derivative (thiamine diphosphate, ThDP) was a cofactor required for the oxydative decarboxylation of pyruvate, the mechanism of action of thiamine in the cellular metabolism seemed to be elucidated.[54]

See also

References

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