View source for Thiamine

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{{Pathnav|Dietary supplement|Vitamin|frame=1}}
{{Short description|Chemical compound}}
{{Infobox drug
| drug_name          =
| INN                =
| type               = <!-- empty -->
| IUPAC_name         = 2-[3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-1,3-thiazol-3-ium-5-yl]ethanol
| image              = Thiamin.svg
| width              =
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| image2             = Thiamine-cation-from-xtal-3D-bs-17.png
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| caption            = Skeletal formula and ball-and-stick model of the thiamine [[Ion#Anions and cations|cation]]
<!-- Clinical data -->| pronounce          = {{IPAc-en|ˈ|θ|aɪ|.|ə|m|ᵻ|n}} {{respell|THY|ə-min}}
| tradename          =
| Drugs.com          = {{Drugs.com|monograph|thiamine-hydrochloride}}
| MedlinePlus        =
| licence_EU         = <!-- EMA requires brand name -->
| licence_US         = Thiamine
| DailyMedID         = Thiamine
| pregnancy_AU       = <!-- A/B1/B2/B3/C/D/X -->
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| routes_of_administration = by mouth, IV, IM
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| legal_US           = OTC
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| legal_UN           = <!-- N I, II, III, IV / P I, II, III, IV-->
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| legal_status       = <!--For countries not listed above-->
<!-- Pharmacokinetic data -->| bioavailability = 3.7% to 5.3% (Thiamine hydrochloride)
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| excretion          = <!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 70-16-6
| index_label = cation
| index2_label = Cl<sup>−</sup> salt
| CAS_number2_Ref = {{cascite|correct|CAS}}
| CAS_number2 = 59-43-8 
| CAS_supplemental =<br>{{CAS|67-03-8}}(Cl<sup>−</sup>.HCl)
| UNII2_Ref = {{fdacite|correct|FDA}}
| UNII2 = X66NSO3N35
| class              = [[vitamin]]
| ATCvet             =
| ATC_prefix         = A11
| ATC_suffix         = DA01
| ATC_supplemental   =
| PubChem            = 1130
| PubChem2   = 6042
| IUPHAR_ligand      =
| DrugBank           = DB00152
| ChemSpiderID       = 1098
| UNII               = 4ABT0J945J
| KEGG               = C00378
| ChEBI              = 18385
| ChEMBL             = 1547
| NIAID_ChemDB       =
| synonyms           = Vitamin B<sub>1</sub>, aneurine, thiamin
<!-- Chemical and physical data -->| chemical_formula   = | C= 12| H= 17| N= 4| O= 1| S= 1
| charge             = +
| SMILES             = Cc2ncc(C[n+]1csc(CCO)c1C)c(N)n2
| Jmol               =
| StdInChI           = 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
| StdInChI_Ref       = {{stdinchicite|correct|chemspider}}
| StdInChIKey        = JZRWCGZRTZMZEH-UHFFFAOYSA-N
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<!--T:2-->
'''Thiamine''', also known as '''thiamin''' and '''vitamin B<sub>1</sub>''', is a [[vitamin]], an [[Nutrient#Micronutrients|essential micronutrient]] for humans and animals. It is found in food and commercially synthesized to be a [[dietary supplement]] or [[medication]]. [[Phosphorylated]] forms of thiamine are required for some [[Metabolism|metabolic reactions]], including the breakdown of [[Carbohydrate metabolism|glucose]] and [[amino acid]]s.

<!--T:3-->
Food sources of thiamine include [[whole grain]]s, [[legumes]], and some meats and fish. [[Refined grain|Grain processing]] removes much of the vitamin content, so in many countries [[cereals]] and [[flour]]s are [[food fortification|enriched]] with thiamine. Supplements and medications are available to treat and prevent [[thiamine deficiency]] and the disorders that result from it such as [[Thiamine deficiency#Dry beriberi|beriberi]] and [[Wernicke encephalopathy]]. They are also used to treat [[maple syrup urine disease]] and [[Leigh syndrome]]. Supplements and medications are typically taken [[Route of administration#Oral|by mouth]], but may also be given by [[intravenous therapy|intravenous]] or [[intramuscular injection]].

<!--T:4-->
Thiamine supplements are generally well tolerated. [[Allergic reactions]], including [[anaphylaxis]], may occur when repeated doses are given by injection. Thiamine is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]]. It is available as a [[generic medication]], and in some countries as a non-prescription dietary supplement.

==Definition== <!--T:5-->
Thiamine is one of the [[B vitamins]] and is also known as vitamin B<sub>1</sub>. It is a [[cation]] that is usually supplied as a [[chloride]] [[salt (chemistry)|salt]]. It is [[Solubility|soluble]] in water, [[methanol]] and [[glycerol]], but practically insoluble in less polar [[organic solvent]]s. In the body, thiamine can form [[Derivative (chemistry)|derivatives]]; the most well-characterized of which is [[thiamine pyrophosphate]] (TPP), a [[coenzyme]] in the [[catabolism]] of sugars and amino acids.

<!--T:6-->
The chemical structure consists of an [[pyrimidine|aminopyrimidine]] and a [[thiazolium]] ring linked by a [[methylene bridge]]. The thiazole is substituted with methyl and [[Ethanol|hydroxyethyl side chains]]. Thiamine is stable at acidic [[pH]], but it is unstable in [[Alkali|alkaline solutions]] and from exposure to [[heat]]. It reacts strongly in [[Maillard reaction|Maillard-type reactions]]. [[Redox|Oxidation]] yields the fluorescent derivative [[thiochrome]], which can be used to determine the amount of the vitamin present in biological samples.

==Deficiency== <!--T:7-->
{{Main|Thiamine deficiency}}
Well-known disorders caused by thiamine deficiency include [[Thiamine deficiency#Dry beriberi|beriberi]], [[Wernicke–Korsakoff syndrome]], [[Toxic and nutritional optic neuropathy#Nutritional optic neuropathy|optic neuropathy]], [[Leigh syndrome|Leigh's disease]], African seasonal [[ataxia]] (or Nigerian seasonal ataxia), and [[central pontine myelinolysis]]. Symptoms include [[malaise]], weight loss, irritability and confusion.

<!--T:8-->
In Western countries, chronic alcoholism is a risk factor for deficiency. Also at risk are older adults, persons with [[HIV/AIDS]] or [[diabetes]], and those who have had [[bariatric surgery]]. Varying degrees of thiamine insufficiency have been associated with the long-term use of [[diuretic]]s.

== Biological functions == <!--T:9-->
[[Image:Thiamine monophosphate coloured.svg|thumb|Thiamine monophosphate (ThMP)]]
Five natural thiamine phosphate derivatives are known: [[thiamine monophosphate]] (ThMP), thiamine pyrophosphate (TPP), [[thiamine triphosphate]] (ThTP), [[adenosine thiamine diphosphate]] (AThDP) and [[adenosine thiamine triphosphate]] (AThTP). They are involved in many cellular processes. The best-characterized form is TPP, a [[coenzyme]] in the [[catabolism]] of sugars and amino acids. While its role is well-known, the non-coenzyme action of thiamine and derivatives may be realized through binding to proteins which do not use that mechanism. No physiological role is known for the monophosphate except as an intermediate in cellular conversion of thiamine to the di- and triphosphates.

===Thiamine pyrophosphate=== <!--T:10-->
{{main|thiamine pyrophosphate}}
{{multiple image
 | align = right
 | direction = vertical
 | width = 220
 | header =
 | image1 = Thiamine_diphosphate_coloured.svg
 | caption1 = Thiamine pyrophosphate (TPP)
 | image2 = TPP-ylide.svg
 | caption2 = The ylide form of TPP
}}
Thiamine pyrophosphate (TPP), also called thiamine diphosphate (ThDP), participates as a coenzyme in metabolic reactions, including those in which [[umpolung|polarity inversion]] takes place. Its synthesis is catalyzed by the enzyme [[thiamine diphosphokinase]] according to the reaction thiamine + ATP → TPP + AMP (EC 2.7.6.2). TPP 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). The mechanism of action of TPP as a coenzyme relies on its ability to form an [[ylide]]. Examples include:
* Present in most species
** [[pyruvate dehydrogenase]] and 2-[[oxoglutarate dehydrogenase]] (also called [[alpha-ketoglutarate dehydrogenase|α-ketoglutarate dehydrogenase]])
** [[branched-chain α-keto acid dehydrogenase]]
** [[2-hydroxyphytanoyl-CoA lyase]]
** [[transketolase]]
* Present in some species:
** [[pyruvate decarboxylase]] (in [[yeast]])
** several additional [[bacteria]]l enzymes

<!--T:11-->
The enzymes transketolase, pyruvate dehydrogenase (PDH), and 2-oxoglutarate dehydrogenase (OGDH) are important in [[carbohydrate metabolism]]. PDH links glycolysis to the [[citric acid cycle]]. OGDH catalyzes the overall conversion of [[Alpha-Ketoglutaric acid|2-oxoglutarate]] (alpha-ketoglutarate) to [[succinyl-CoA]] and CO<sub>2</sub> during the [[citric acid cycle]]. The reaction catalyzed by OGDH is a rate-limiting step in the citric acid cycle. The cytosolic enzyme transketolase is central to the [[pentose phosphate pathway]], a major route for the biosynthesis of the pentose [[sugar]]s [[deoxyribose]] and [[ribose]]. The mitochondrial PDH and OGDH are part of biochemical pathways that result in the generation of [[adenosine triphosphate]] (ATP), which is the main energy transfer molecule for the cell. In the nervous system, PDH is also involved in the synthesis of [[myelin]] and the neurotransmitter [[acetylcholine]].

=== Thiamine triphosphate === <!--T:12-->
[[File:Thiamine triphosphate coloured.svg|thumb|right|Thiamine triphosphate (ThTP)]]
ThTP is implicated in [[chloride channel]] activation in the neurons of mammals and other animals, although its role is not well understood. ThTP has been found in bacteria, fungi and plants, suggesting that it has other cellular roles. In ''[[Escherichia coli]]'', it is implicated in the response to amino acid starvation.

===Adenosine derivatives=== <!--T:13-->
{{multiple image
 | align = right
 | direction = vertical
 | width = 220
 | header =
 | image1 = Adenosine_thiamine_diphosphate_coloured.svg
 | caption1 = Adenosine thiamine diphosphate (AThDP)
 | image2 = Adenosine_thiamine_triphosphate_coloured.svg
 | caption2 = Adenosine thiamine triphosphate (AThTP)
}}
AThDP exists in small amounts in vertebrate liver, but its role remains unknown.

<!--T:14-->
AThTP is present in ''E. coli'', where it accumulates as a result of carbon starvation. In this bacterium, AThTP may account for up to {{Percentage|20}} of total thiamine. It also exists in lesser amounts in [[yeast]], roots of higher plants and animal tissue.

==Medical uses== <!--T:15-->
{{See also|Prenatal vitamins}}
During pregnancy, thiamine is sent to the [[fetus]] via the [[placenta]]. Pregnant women have a greater requirement for the vitamin than other adults, especially during the [[Pregnancy#Third trimester|third trimester]]. Pregnant women with [[hyperemesis gravidarum]] are at an increased risk of thiamine deficiency due to losses when vomiting. In [[Lactation|lactating]] women, thiamine is delivered in breast milk even if it results in thiamine deficiency in the mother.

<!--T:16-->
Thiamine is important not only for [[Mitochondrion|mitochondrial membrane]] development, but also for [[Synaptosome|synaptic membrane]] function. It has also been suggested that a deficiency hinders brain development in infants and may be a cause of [[sudden infant death syndrome]].

==Dietary recommendations== <!--T:17-->
{| class="wikitable floatright" style="font-size: 90%; text-align: center;"
|-
| colspan="2" style="background: blue; color: white; font-size: 110%; text-align: center;" | '''US National Academy of Medicine'''
|-
! width="8" scope="col" | Age group
! width="6" scope="col" | RDA (mg/day)
|-
| Infants 0–6 months || 0.2*
|-
| 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
|-
| colspan="2" style="text-align: center;" | * Adequate intake for infants, as an RDA has yet to be established
|-
| colspan="2" style="background: blue; color: white; font-size: 110%; text-align: center;" | '''European Food Safety Authority'''
|-
! scope="col" | Age group
! scope="col" | Adequate intake<br>(mg/MJ)
|-
| All persons 7 months+ || 0.1
|-
! width="14" colspan="2" scope="col" | Neither the US National Academy of Medicine nor the European Food Safety Authority have determined the tolerable upper intake level for thiamine
|}

<!--T:18-->
The [[National Academy of Medicine|US National Academy of Medicine]] updated the Estimated Average Requirements (EARs) and [[Reference Daily Intake|Recommended Dietary Allowances]] (RDAs) for thiamine in 1998. The EARs for thiamine for women and men aged 14 and over are 0.9&nbsp;mg/day and 1.1&nbsp;mg/day, respectively; the RDAs are 1.1 and 1.2&nbsp;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&nbsp;mg/day. For infants up to the age of 12 months, the Adequate Intake (AI) is 0.2–0.3&nbsp;mg/day and for children aged 1–13 years the RDA increases with age from 0.5 to 0.9&nbsp;mg/day.

<!--T:19-->
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. For women (including those pregnant or lactating), men and children the PRI is 0.1&nbsp;mg thiamine per megajoule (MJ) of energy in their diet. As the conversion is 1 MJ = 239 kcal, an adult consuming 2390 kilocalories ought to be consuming 1.0&nbsp;mg thiamine. This is slightly lower than the US RDA.

<!--T:20-->
Neither the National Academy of Medicine nor EFSA have set an upper intake level for thiamine, as there is no human data for adverse effects from high doses.

===Safety=== <!--T:21-->
Thiamine is generally well tolerated and non-toxic when [[oral administration|administered orally]]. There are rare reports of adverse side effects when thiamine is given [[Route of administration#Parenteral|intravenously]], including allergic reactions, [[nausea]], [[lethargy]], and [[Ataxia|impaired coordination]].

===Labeling=== <!--T:22-->
For US food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value. Since May 27, 2016, the Daily Value has been 1.2&nbsp;mg, in line with the RDA.

==Sources== <!--T:23-->
Thiamine is found in a wide variety of processed and whole foods, including [[lentil]]s, [[pea]]s, [[whole grains]], [[pork]], and [[nut (fruit)|nuts]]. A typical daily prenatal vitamin product contains around 1.5&nbsp;mg of thiamine.

===Food fortification=== <!--T:24-->
{{main|Food fortification}}
Some countries require or recommend fortification of grain foods such as [[wheat]], [[rice]] or [[maize]] (corn) because processing lowers vitamin content. 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&nbsp;mg/kg. An additional 18 countries have a voluntary fortification program. For example, the [[Government of India|Indian government]] recommends 3.5&nbsp;mg/kg for [[Maida (flour)|"maida" (white)]] and [[Atta flour|"atta" (whole wheat)]] flour.

==Synthesis== <!--T:25-->
===Biosynthesis===
Thiamine biosynthesis occurs in bacteria, some protozoans, plants, and fungi. The [[thiazole]] and [[pyrimidine]] moieties are biosynthesized separately and are then combined to form ThMP by the action of [[Thiamine-phosphate diphosphorylase|thiamine-phosphate synthase]].

<!--T:26-->
The pyrimidine ring system is formed in a reaction catalysed by [[phosphomethylpyrimidine synthase]] (ThiC), an enzyme in the [[radical SAM]] superfamily of [[iron–sulfur protein]]s, which use [[S-adenosyl methionine]] as a [[Cofactor (biochemistry)|cofactor]].
:[[File:Pyrimidine biosynthesis.svg|650px]]

<!--T:27-->
The starting material is [[5-aminoimidazole ribotide]], which undergoes a [[rearrangement reaction]] via [[Radical (chemistry)|radical]] intermediates which incorporate the blue, green and red fragments shown into the product.

<!--T:28-->
The thiazole ring is formed in a reaction catalysed by [[thiazole synthase]] (EC 2.8.1.10). The ultimate precursors are 1-deoxy-D-xylulose 5-phosphate, 2-iminoacetate and a [[Sulfur carrier protein ThiS adenylyltransferase|sulfur carrier protein]] called ThiS. An additional protein, ThiG, is also required to bring together all the components of the ring at the enzyme active site.
:[[File:Thiamine biosynthesis.svg|780px| ]]

<!--T:29-->
[[Image:TPP riboswitch pdb-2hoj.png|thumb|upright|A 3D representation of the [[TPP riboswitch]] with thiamine bound]]
The final step to form ThMP involves [[decarboxylation]] of the thiazole intermediate, which reacts with the [[pyrophosphate]] derivative of phosphomethylpyrimidine, itself a product of a [[kinase]], [[phosphomethylpyrimidine kinase]].

<!--T:30-->
The biosynthetic pathways differ among organisms. In ''E. coli'' and other [[enterobacteriaceae]], ThMP is phosphorylated to the cofactor TPP by a [[thiamine-phosphate kinase]] (ThMP + ATP → TPP + ADP). In most bacteria and in [[eukaryote]]s, ThMP is hydrolyzed to thiamine and then pyrophosphorylated to TPP by [[thiamine diphosphokinase]] (thiamine + ATP → TPP + AMP).

<!--T:31-->
The biosynthetic pathways are regulated by [[riboswitch]]es. If there is sufficient thiamine present in the cell then the thiamine binds to the [[mRNA]]s for the enzymes that are required in the pathway and prevents their [[translation (biology)|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]], is the only known riboswitch found in both eukaryotic and [[Prokaryote|prokaryotic]] organisms.

===Laboratory synthesis=== <!--T:32-->
:[[File:Thiamine synthesis.svg|800px]]
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 [[Amidine|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]]. In the final stage, thiamine (as its dibromide salt) was formed in an [[alkylation]] reaction using 4-methyl-5-(2-hydroxyethyl)thiazole.

===Industrial synthesis=== <!--T:33-->
[[File:Grewe diamine.svg|thumb|Diamine used in the manufacture of thiamine]]
[[Merck & Co.]] adapted the 1936 laboratory-scale synthesis, allowing them to manufacture thiamine in [[Rahway]] in 1937. However, an alternative route using the intermediate Grewe [[diamine]] (5-(aminomethyl)-2-methyl-4-pyrimidinamine), first published in 1937, was investigated by [[Hoffman La Roche]] and competitive manufacturing processes followed. Efficient routes to the diamine have continued to be of interest. In the [[European Economic Area]], thiamine is registered under [[Registration, Evaluation, Authorisation and Restriction of Chemicals|REACH regulation]] and between 100 and 1,000 tonnes per annum are manufactured or imported there.

===Synthetic analogues=== <!--T:34-->
Many [[Vitamin B1 analogues|vitamin B<sub>1</sub> analogues]], such as [[Benfotiamine]], [[fursultiamine]], and [[sulbutiamine]], are synthetic derivatives of thiamine. Most were developed in Japan in the 1950s and 1960s as forms that were intended to improve absorption compared to thiamine. Some are approved for use in some countries as a drug or non-prescription dietary supplement for treatment of [[diabetic neuropathy]] or other health conditions.

==Absorption, metabolism and excretion== <!--T:35-->
In the upper small intestine, thiamine phosphate esters present in food are hydrolyzed by alkaline [[phosphatase]] enzymes. At low concentrations, the absorption process is carrier-mediated. At higher concentrations, absorption also occurs via [[passive diffusion]]. Active transport can be inhibited by alcohol consumption or by [[folate deficiency]].

<!--T:36-->
The majority of thiamine in [[serum (blood)|serum]] is bound to proteins, mainly [[albumin]]. Approximately {{Percentage|90}} of total thiamine in blood is in [[erythrocyte]]s. A specific binding protein called thiamine-binding protein has been identified in rat serum and is believed to be a hormone-regulated carrier protein important for tissue distribution of thiamine. Uptake of thiamine by cells of the blood and other tissues occurs via active transport and passive diffusion. Two members of the family of transporter proteins encoded by the genes [[Thiamine transporter 1|SLC19A2]] and [[Thiamine transporter 2|SLC19A3]] are capable of thiamine transport. In some tissues, thiamine uptake and secretion appear to be mediated by a Na<sup>+</sup>-dependent transporter and a transcellular proton gradient.

<!--T:37-->
Human storage of thiamine is about 25 to 30&nbsp;mg, with the greatest concentrations in skeletal muscle, heart, brain, liver, and kidneys. ThMP and free (unphosphorylated) thiamine are 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. Thiamine contents in human tissues are less than those of other species.

<!--T:38-->
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.

===Interference=== <!--T:39-->
The [[bioavailability]] of thiamine in foods can be interfered with in a variety of ways. [[Sulfite]]s, added to foods as a preservative, will attack thiamine at the methylene bridge, cleaving the pyrimidine ring from the thiazole ring. The rate of this reaction is increased under acidic conditions. Thiamine is degraded by thermolabile [[thiaminase]]s present in some species of fish, shellfish and other foods. The pupae of an African silk worm, ''[[Anaphe venata]]'', is a traditional food in Nigeria. Consumption leads to thiamine deficiency. Older literature reported that in Thailand, consumption of fermented, uncooked fish caused thiamine deficiency, but either abstaining from eating the fish or heating it first reversed the deficiency. In ruminants, intestinal bacteria synthesize thiamine and thiaminases. The bacterial thiaminases are cell surface enzymes that must dissociate from the cell membrane before being activated; the dissociation can occur in ruminants under [[acidosis|acidotic conditions]]. In [[dairy cattle|dairy cows]], over-feeding with grain causes subacute ruminal acidosis and increased ruminal bacteria thiaminase release, resulting in thiamine deficiency.

<!--T:40-->
From reports on two small studies conducted in Thailand, chewing slices of [[areca nut]] wrapped in [[betel]] leaves and chewing tea leaves reduced food thiamine bioavailability by a mechanism that may involve [[tannins]].

<!--T:41-->
Bariatric surgery for weight loss is known to interfere with vitamin absorption. A meta-analysis reported that {{Percentage|27}} of people who underwent bariatric surgeries experience vitamin B<sub>1</sub> deficiency.

==History== <!--T:42-->
{{See|Vitamin#History}}
Thiamine was the first of the water-soluble vitamins to be isolated. The earliest observations in humans and in chickens had shown that diets of primarily polished white rice caused beriberi, but did not attribute it to the absence of a previously unknown essential nutrient.

<!--T:43-->
In 1884, [[Takaki Kanehiro]], a surgeon general in the [[Imperial Japanese Navy]], rejected the previous [[Germ theory of disease|germ theory]] for beriberi and suggested instead that the disease was due to insufficiencies in the diet. 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 at the time. The Navy was not convinced of the need for such an expensive 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 [[Bran#Rice bran|rice bran]] (removed by [[rice polisher|polishing into white rice]]) and in barley bran, was Takaki's experiment rewarded. He was made a baron in the Japanese peerage system, after which he was affectionately called "Barley Baron".

<!--T:44-->
The specific connection to grain was made in 1897 by [[Christiaan Eijkman]], a military doctor in the [[Dutch East Indies]], who discovered that fowl fed on a diet of cooked, polished rice developed paralysis that could be reversed by discontinuing rice polishing. 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. 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. Eijkman was eventually awarded the [[Nobel Prize in Physiology and Medicine]] in 1929, because his observations led to the discovery of vitamins.

<!--T:45-->
In 1910, a Japanese agricultural chemist of [[University of Tokyo|Tokyo Imperial University]], [[Umetaro Suzuki]], isolated a water-soluble thiamine compound from rice bran, which he named ''aberic acid''. (He later renamed it ''Orizanin''.) He described the compound as not only an anti-beriberi factor, but also as being essential to human nutrition; however, this finding failed to gain publicity outside of Japan, because a claim that the compound was a new finding was omitted in translation of his publication from Japanese to German. In 1911 a Polish biochemist [[Casimir Funk]] isolated the [[Wikt:antineuritic|antineuritic]] substance from rice bran (the modern thiamine) that he called a "vitamine" (on account of its containing an amino group). 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, whose structure was determined by [[Robert Runnels Williams]], in 1934. Thiamine was named by the Williams team as a [[portmanteau]] of "thio" (meaning sulfur-containing) and "vitamin". The term "vitamin" coming indirectly, by way of Funk, from the amine group of thiamine itself (although by this time, vitamins were known to not always be amines, for example, [[vitamin C]]). Thiamine was also synthesized by the Williams group in 1936.

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Sir [[Rudolph Peters]], in [[Oxford University|Oxford]], used pigeons to understand how thiamine deficiency results in the pathological-physiological symptoms of beriberi. Pigeons fed exclusively on polished rice developed [[opisthotonos]], a condition characterized by head retraction. If not treated, the animals died after a few days. Administration of thiamine after opisthotonos was observed led to a complete cure within 30 minutes. As no morphological modifications were seen in the brain of the pigeons before and after treatment with thiamine, Peters introduced the concept of a biochemical-induced injury. In 1937, Lohmann and Schuster showed that the diphosphorylated thiamine derivative, TPP, was a cofactor required for the oxidative decarboxylation of pyruvate.

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<gallery caption="Some contributors to the discovery of thiamine" mode="nolines">
File:Takaki Kanehiro.jpg|[[Takaki Kanehiro]]
File:Eijkman.jpg|[[Christiaan Eijkman]]
File:Portrait_of_Gerrit_Grijns_Wellcome_M0010254.jpg|[[Gerrit Grijns]]
File:Umetarosuzuki-pre1943.jpg|[[Umetaro Suzuki]]
File:Casimir_Funk_01.jpg|[[Casimir Funk]]
File:Rudolph Albert Peters.jpg|[[Rudolph Peters]]
</gallery>

== External links == <!--T:48-->
* {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/thiamine | publisher = US National Library of Medicine| work = Drug Information Portal| title = Thiamine }}

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{{Vitamins}}
{{Portal bar|Medicine}}

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{{二次利用|date=11 January 2024}}

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[[Category:Thiamine| ]]
[[Category:Aminopyrimidines]]
[[Category:B vitamins]]
[[Category:Coenzymes]]
[[Category:Poultry diseases]]
[[Category:Primary alcohols]]
[[Category:Thiazoles]]
[[Category:World Health Organization essential medicines]]
[[Category:Wikipedia medicine articles ready to translate]]
[[Category:Quaternary ammonium compounds]]
[[Category:Cations]]
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