Thiamin Mononitrate
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Thiamine, also known as thiamin and vitamin B1, is a
vitamin A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an Nutrient#Essential nutrients, essential micronutrient that an organism needs in small quantities for the proper functioning of its ...
, an essential micronutrient, that cannot be made in the body. It is found in food and commercially synthesized to be a
dietary supplement A dietary supplement is a manufactured product intended to supplement one's diet by taking a pill, capsule, tablet, powder, or liquid. A supplement can provide nutrients either extracted from food sources or that are synthetic in order ...
or
medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...
.
Phosphorylated In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...
forms of thiamine are required for some metabolic reactions, including the breakdown of
glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
and
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s. Food sources of thiamine include
whole grain A whole grain is a grain of any cereal and pseudocereal that contains the endosperm, germ, and bran, in contrast to refined grains, which retain only the endosperm. As part of a general healthy diet, consumption of whole grains is associated w ...
s,
legumes A legume () is a plant in the family Fabaceae (or Leguminosae), or the fruit or seed of such a plant. When used as a dry grain, the seed is also called a pulse. Legumes are grown agriculturally, primarily for human consumption, for livestock fo ...
, and some meats and fish. Grain processing removes much of the vitamin content, so in many countries
cereals A cereal is any grass cultivated for the edible components of its grain (botanically, a type of fruit called a caryopsis), composed of the endosperm, germ, and bran. Cereal grain crops are grown in greater quantities and provide more food en ...
and
flour Flour is a powder made by grinding raw grains, roots, beans, nuts, or seeds. Flours are used to make many different foods. Cereal flour, particularly wheat flour, is the main ingredient of bread, which is a staple food for many culture ...
s are enriched with thiamine. Supplements and medications are available to treat and prevent
thiamine deficiency Thiamine deficiency is a medical condition of low levels of thiamine (Vitamin B1). A severe and chronic form is known as beriberi. The two main types in adults are wet beriberi and dry beriberi. Wet beriberi affects the cardiovascular system, r ...
and disorders that result from it include
beriberi Thiamine deficiency is a medical condition of low levels of thiamine (Vitamin B1). A severe and chronic form is known as beriberi. The two main types in adults are wet beriberi and dry beriberi. Wet beriberi affects the cardiovascular system, r ...
and
Wernicke encephalopathy Wernicke encephalopathy (WE), also Wernicke's encephalopathy, or wet brain is the presence of neurological symptoms caused by biochemical lesions of the central nervous system after exhaustion of B-vitamin reserves, in particular thiamine (vita ...
. They are also used to treat
maple syrup urine disease Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder affecting branched-chain amino acids. It is one type of organic acidemia. The condition gets its name from the distinctive sweet odor of affected infants' urine and ear ...
and
Leigh syndrome Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who fir ...
. Supplements and medications are typically taken
by mouth Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...
, but may also be given by
intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
or
intramuscular injection Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have ...
. Thiamine supplements are generally well tolerated.
Allergic reactions Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...
, including
anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follow ...
, may occur when repeated doses are given by injection. Thiamine is on the
World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...
. It is available as a
generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
, and in some countries as a non-prescription dietary supplement.


Definition

Thiamine is one of the
B vitamins B vitamins are a class of water-soluble vitamins that play important roles in cell metabolism and synthesis of red blood cells. Though these vitamins share similar names (B1, B2, B3, etc.), they are chemically distinct compounds that often coexist ...
and is also known as vitamin B1. It is a
cation An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
that is usually supplied as a
chloride The chloride ion is the anion (negatively charged ion) Cl−. It is formed when the element chlorine (a halogen) gains an electron or when a compound such as hydrogen chloride is dissolved in water or other polar solvents. Chloride salts ...
salt Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quantitie ...
. It is
soluble In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solubil ...
in water,
methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is a ...
and
glycerol Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids known ...
, but practically insoluble in less polar
organic solvent A solvent (s) (from the Latin '' solvō'', "loosen, untie, solve") is a substance that dissolves a solute, resulting in a solution. A solvent is usually a liquid but can also be a solid, a gas, or a supercritical fluid. Water is a solvent for p ...
s. In the body, thiamine can form
derivatives The derivative of a function is the rate of change of the function's output relative to its input value. Derivative may also refer to: In mathematics and economics * Brzozowski derivative in the theory of formal languages * Formal derivative, an ...
; the most well-characterized of which is
thiamine pyrophosphate Thiamine pyrophosphate (TPP or ThPP), or thiamine diphosphate (ThDP), or cocarboxylase is a thiamine (vitamin B1) derivative which is produced by the enzyme thiamine diphosphokinase. Thiamine pyrophosphate is a cofactor that is present in all liv ...
(TPP), a
coenzyme A cofactor is a non-protein chemical compound or metallic ion that is required for an enzyme's role as a catalyst (a catalyst is a substance that increases the rate of a chemical reaction). Cofactors can be considered "helper molecules" that ass ...
in the
catabolism Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipids, ...
of sugars and amino acids. The chemical structure consists of an aminopyrimidine and a
thiazolium Thiazole, or 1,3-thiazole, is a heterocyclic compound that contains both sulfur and nitrogen. The term 'thiazole' also refers to a large family of derivatives. Thiazole itself is a pale yellow liquid with a pyridine-like odor and the molecular for ...
ring linked by a
methylene bridge In organic chemistry, a methylene bridge, methylene spacer, or methanediyl group is any part of a molecule with formula ; namely, a carbon atom bound to two hydrogen atoms and connected by single bonds to two other distinct atoms in the rest of ...
. The thiazole is substituted with methyl and hydroxyethyl side chains. Thiamine is stable at acidic pH, but it is unstable in alkaline solutions and from exposure to
heat In thermodynamics, heat is defined as the form of energy crossing the boundary of a thermodynamic system by virtue of a temperature difference across the boundary. A thermodynamic system does not ''contain'' heat. Nevertheless, the term is al ...
. It reacts strongly in Maillard-type reactions.
Oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
yields the fluorescent derivative
thiochrome Thiochrome (TChr)is a tricyclic organic compound that arises from the oxidation of the vitamin thiamine. Being highly fluorescent, it is often the derivative that is quantified in the analysis of thiamine. The oxidation can be effected with ceric ...
, which can be used to determine the amount of the vitamin present in biological samples.


Deficiency

Well-known disorders caused by thiamine deficiency include
beriberi Thiamine deficiency is a medical condition of low levels of thiamine (Vitamin B1). A severe and chronic form is known as beriberi. The two main types in adults are wet beriberi and dry beriberi. Wet beriberi affects the cardiovascular system, r ...
,
Wernicke–Korsakoff syndrome Wernicke–Korsakoff syndrome (WKS) is the combined presence of Wernicke encephalopathy (WE) and Korsakoff syndrome. Due to the close relationship between these two disorders, people with either are usually diagnosed with WKS as a single syndrome ...
,
optic neuropathy Optic neuropathy is damage to the optic nerve from any cause. The optic nerve is a bundle of millions of fibers in the retina that sends visual signals to the brain. Damage and death of these nerve cells, or neurons, leads to characteristic featu ...
,
Leigh's disease Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who fir ...
,
African seasonal ataxia ''Anaphe venata'' is a moth of the family Notodontidae. It was described by Arthur Gardiner Butler in 1878. It lives in Angola, Cameroon, the Central African Republic, the Republic of the Congo, the Democratic Republic of the Congo, Equatorial G ...
(or Nigerian seasonal ataxia), and
central pontine myelinolysis Central pontine myelinolysis is a neurological condition involving severe damage to the myelin sheath of nerve cells in the ''pons'' (an area of the brainstem). It is predominately iatrogenic (treatment-induced), and is characterized by acute par ...
. Symptoms include
malaise As a medical term, malaise is a feeling of general discomfort, uneasiness or lack of wellbeing and often the first sign of an infection or other disease. The word has existed in French since at least the 12th century. The term is often used ...
, weight loss, irritability and confusion. In Western countries, chronic alcoholism is a risk factor for deficiency. Also at risk are older adults, persons with
HIV/AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...
or
diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
, and those who have had
bariatric surgery Bariatric surgery (or weight loss surgery) includes a variety of procedures performed on people who are obese. Long term weight loss through the standard of care procedures ( Roux en-Y bypass, sleeve gastrectomy, and biliopancreatic diversion ...
. Varying degrees of thiamine insufficiency have been associated with the long-term use of
diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics in ...
s.


Biological functions

Five natural thiamine phosphate derivatives are known:
thiamine monophosphate Thiamine monophosphate is a thiamine Thiamine, also known as thiamin and vitamin B1, is a vitamin, an essential micronutrient, that cannot be made in the body. It is found in food and commercially synthesized to be a dietary supplement or ...
(ThMP), thiamine pyrophosphate (TPP),
thiamine triphosphate Thiamine triphosphate (ThTP) is a biomolecule found in most organisms including bacteria, fungi, plants and animals. Chemically, it is the triphosphate derivative of the vitamin thiamine. Function It has been proposed that ThTP has a specific ro ...
(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 A cofactor is a non-protein chemical compound or metallic ion that is required for an enzyme's role as a catalyst (a catalyst is a substance that increases the rate of a chemical reaction). Cofactors can be considered "helper molecules" that ass ...
in the
catabolism Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipids, ...
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.


Thiamine pyrophosphate

Thiamine pyrophosphate (TPP), also called thiamine diphosphate (ThDP), participates as a coenzyme in metabolic reactions, including those in which polarity inversion takes place. Its synthesis is catalyzed by the enzyme
thiamine diphosphokinase In enzymology, a thiamine diphosphokinase () is an enzyme that catalysis, catalyzes the chemical reaction :ATP + thiamine \rightleftharpoons AMP + thiamine diphosphate Thus, the two substrate (biochemistry), substrates of this enzyme are adenosi ...
according to the reaction thiamine + ATP → TPP + AMP (EC 2.7.6.2). TPP is a
coenzyme A cofactor is a non-protein chemical compound or metallic ion that is required for an enzyme's role as a catalyst (a catalyst is a substance that increases the rate of a chemical reaction). Cofactors can be considered "helper molecules" that ass ...
for several enzymes that catalyze the transfer of two-carbon units and in particular the
dehydrogenation In chemistry, dehydrogenation is a chemical reaction that involves the removal of hydrogen, usually from an organic molecule. It is the reverse of hydrogenation. Dehydrogenation is important, both as a useful reaction and a serious problem. At ...
(
decarboxylation Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is t ...
and subsequent conjugation with
coenzyme A Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...
) of 2-oxoacids (alpha-keto acids). The mechanism of action of TPP as a coenzyme relies on its ability to form an
ylide An ylide or ylid () is a neutral dipolar molecule containing a formally negatively charged atom (usually a carbanion) directly attached to a heteroatom with a formal positive charge (usually nitrogen, phosphorus or sulfur), and in which both atoms h ...
. Examples include: * Present in most species **
pyruvate dehydrogenase Pyruvate dehydrogenase is an enzyme that catalyzes the reaction of pyruvate and a lipoamide to give the acetylated dihydrolipoamide and carbon dioxide. The conversion requires the coenzyme thiamine pyrophosphate. Pyruvate dehydrogenase is us ...
and 2-
oxoglutarate dehydrogenase The oxoglutarate dehydrogenase complex (OGDC) or α-ketoglutarate dehydrogenase complex is an enzyme complex, most commonly known for its role in the citric acid cycle. Units Much like pyruvate dehydrogenase complex (PDC), this enzyme forms a co ...
(also called α-ketoglutarate dehydrogenase) **
branched-chain α-keto acid dehydrogenase The branched-chain α-ketoacid dehydrogenase complex (BCKDC or BCKDH complex) is a multi-subunit complex of enzymes that is found on the mitochondrial inner membrane. This enzyme complex catalyzes the oxidative decarboxylation of branched, short-ch ...
** 2-hydroxyphytanoyl-CoA lyase **
transketolase Transketolase (abbreviated as TK) is an enzyme that is encoded by the TKT gene. It participates in both the pentose phosphate pathway in all organisms and the Calvin cycle of photosynthesis. Transketolase catalyzes two important reactions, which ...
* Present in some species: **
pyruvate decarboxylase Pyruvate decarboxylase is an enzyme () that catalyses the decarboxylation of pyruvic acid to acetaldehyde. It is also called 2-oxo-acid carboxylase, alpha-ketoacid carboxylase, and pyruvic decarboxylase. In anaerobic conditions, this enzyme is ...
(in
yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constitut ...
) ** several additional
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
l enzymes The enzymes transketolase, pyruvate dehydrogenase (PDH), and 2-oxoglutarate dehydrogenase (OGDH) are important in
carbohydrate metabolism Carbohydrate metabolism is the whole of the biochemistry, biochemical processes responsible for the metabolic anabolism, formation, catabolism, breakdown, and interconversion of carbohydrates in life, living organisms. Carbohydrates are central t ...
. The cytosolic enzyme transketolase is central to the
pentose phosphate pathway The pentose phosphate pathway (also called the phosphogluconate pathway and the hexose monophosphate shunt and the HMP Shunt) is a metabolic pathway parallel to glycolysis. It generates NADPH and pentoses (5-carbon sugars) as well as ribose 5-pho ...
, a major route for the biosynthesis of the pentose
sugar Sugar is the generic name for sweet-tasting, soluble carbohydrates, many of which are used in food. Simple sugars, also called monosaccharides, include glucose, fructose, and galactose. Compound sugars, also called disaccharides or double ...
s
deoxyribose Deoxyribose, or more precisely 2-deoxyribose, is a monosaccharide with idealized formula H−(C=O)−(CH2)−(CHOH)3−H. Its name indicates that it is a deoxy sugar, meaning that it is derived from the sugar ribose by loss of a hydroxy group. D ...
and
ribose Ribose is a simple sugar and carbohydrate with molecular formula C5H10O5 and the linear-form composition H−(C=O)−(CHOH)4−H. The naturally-occurring form, , is a component of the ribonucleotides from which RNA is built, and so this compo ...
. The mitochondrial PDH and OGDH are part of biochemical pathways that result in the generation of
adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms of ...
(ATP), which is the main energy transfer molecule for the cell. PDH links glycolysis to the
citric acid cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins ...
, 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 synthesis of
myelin Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...
and the neurotransmitter
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
.


Thiamine triphosphate

ThTP was long considered a neurone-specific form of thiamine. It is implicated in
chloride channel Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration ''in vivo'' is much higher than other anions. Severa ...
activation in mammals and other animals, although its precise role is not completely understood. Recently, ThTP has been found in bacteria, fungi and plants, suggesting that it also has a much more general cellular role. In ''
Escherichia coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
'', it is implicated in the response to amino acid starvation.


Adenosine derivatives

AThDP exists in small amounts in vertebrate liver, but its role remains unknown. AThTP is present in ''E. coli'', where it accumulates as a result of carbon starvation. In this bacterium, AThTP may account for up to 20% of total thiamine. It also exists in lesser amounts in
yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constitut ...
, roots of higher plants and animal tissue.


Medical uses

During pregnancy, thiamine is sent to the
fetus A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal deve ...
via the
placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mater ...
. Pregnant women have a greater requirement for the vitamin than other adults, especially during the
third trimester Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but can ...
. Pregnant women with
hyperemesis gravidarum Hyperemesis gravidarum (HG) is a pregnancy complication that is characterized by severe nausea, vomiting, weight loss, and possibly dehydration. Feeling faint may also occur. It is considered more severe than morning sickness. Symptoms often get ...
are at an increased risk of thiamine deficiency due to losses when vomiting. In lactating women, thiamine is delivered in breast milk even if it results in thiamine deficiency in the mother. Thiamine is important not only for
mitochondrial membrane A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used t ...
development, but also for 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 Sudden infant death syndrome (SIDS) is the sudden unexplained death of a child of less than one year of age. Diagnosis requires that the death remain unexplained even after a thorough autopsy and detailed death scene investigation. SIDS usuall ...
.


Dietary recommendations

The US National Academy of Medicine updated the Estimated Average Requirements (EARs) and
Recommended Dietary Allowances The Reference Daily Intake (RDI) used in nutrition labeling on food and dietary supplement products in the U.S. and Canada is the daily intake level of a nutrient that is considered to be sufficient to meet the requirements of 97–98% of healthy ...
(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. The
European Food Safety Authority The European Food Safety Authority (EFSA) is the agency of the European Union (EU) that provides independent scientific advice and communicates on existing and emerging risks associated with the food chain. EFSA was established in February 2002, ...
(EFSA) refers to the collective set of information as
Dietary Reference Values Dietary Reference Values (DRV) is the name of the nutritional requirements systems used by the United Kingdom Department of Health and the European Union's European Food Safety Authority. In 1991, the United Kingdom Department of Health publis ...
, 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 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 mg thiamine. This is slightly lower than the US RDA. 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

Thiamine is generally well tolerated and non-toxic when administered orally. There are rare reports of adverse side effects when thiamine is given
intravenously Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
, including allergic reactions,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
,
lethargy Lethargy is a state of tiredness, sleepiness, weariness, fatigue, sluggishness or lack of energy. It can be accompanied by depression, decreased motivation, or apathy. Lethargy can be a normal response to inadequate sleep, overexertion, overwo ...
, and impaired coordination.


Labeling

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 mg, in line with the RDA.


Sources

Thiamine is found in a wide variety of processed and whole foods, including
lentil The lentil (''Lens culinaris'' or ''Lens esculenta'') is an edible legume. It is an annual plant known for its lens-shaped seeds. It is about tall, and the seeds grow in pods, usually with two seeds in each. As a food crop, the largest pro ...
s,
pea The pea is most commonly the small spherical seed or the seed-pod of the flowering plant species ''Pisum sativum''. Each pod contains several peas, which can be green or yellow. Botanically, pea pods are fruit, since they contain seeds and d ...
s,
whole grains A whole grain is a grain of any cereal and pseudocereal that contains the endosperm, germ, and bran, in contrast to refined grains, which retain only the endosperm. As part of a general healthy diet, consumption of whole grains is associated wi ...
,
pork Pork is the culinary name for the meat of the domestic pig (''Sus domesticus''). It is the most commonly consumed meat worldwide, with evidence of pig husbandry dating back to 5000 BCE. Pork is eaten both freshly cooked and preserved; ...
, and nuts. A typical daily prenatal vitamin product contains around 1.5 mg of thiamine.


Food fortification

Some countries require or recommend fortification of grain foods such as
wheat Wheat is a grass widely cultivated for its seed, a cereal grain that is a worldwide staple food. The many species of wheat together make up the genus ''Triticum'' ; the most widely grown is common wheat (''T. aestivum''). The archaeologi ...
,
rice Rice is the seed of the grass species ''Oryza sativa'' (Asian rice) or less commonly ''Oryza glaberrima ''Oryza glaberrima'', commonly known as African rice, is one of the two domesticated rice species. It was first domesticated and grown i ...
or
maize Maize ( ; ''Zea mays'' subsp. ''mays'', from es, maíz after tnq, mahiz), also known as corn (North American and Australian English), is a cereal grain first domesticated by indigenous peoples in southern Mexico about 10,000 years ago. Th ...
(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 mg/kg. An additional 18 countries have a voluntary fortification program. For example, the
Indian government The Government of India (ISO 15919, ISO: ; often abbreviated as GoI), known as the Union Government or Central Government but often simply as the Centre, is the Government, national government of the Republic of India, a federal democracy lo ...
recommends 3.5 mg/kg for "maida" (white) and "atta" (whole wheat) flour.


Synthesis


Biosynthesis

Thiamine biosynthesis occurs in bacteria, some protozoans, plants, and fungi. The
thiazole Thiazole, or 1,3-thiazole, is a heterocyclic compound that contains both sulfur and nitrogen. The term 'thiazole' also refers to a large family of derivatives. Thiazole itself is a pale yellow liquid with a pyridine-like odor and the molecular for ...
and
pyrimidine Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The other ...
moieties are biosynthesized separately and are then combined to form ThMP by the action of thiamine-phosphate synthase. The pyrimidine ring system is formed in a reaction catalysed by
phosphomethylpyrimidine synthase Phosphomethylpyrimidine synthase (, ''thiC (gene)'') is an enzyme with List of enzymes, systematic name ''5-amino-1-(5-phospho-D-ribosyl)imidazole formate-lyase (decarboxylating, 4-amino-2-methyl-5-phosphomethylpyrimidine-forming)''. This enzyme ca ...
(ThiC), an enzyme in the
radical SAM Radical SAM is a designation for a superfamily of enzymes that use a +_cluster.html" ;"title="Fe-4Ssup>+ cluster">Fe-4Ssup>+ cluster to reductively cleave ''S''-adenosyl-L-methionine (SAM) to generate a radical, usually a 5′-deoxyadenosyl radi ...
superfamily of
iron–sulfur protein Iron–sulfur proteins (or iron–sulphur proteins in British spelling) are proteins characterized by the presence of iron–sulfur clusters containing sulfide-linked di-, tri-, and tetrairon centers in variable oxidation states. Iron–sulfur clu ...
s, which use
S-adenosyl methionine ''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throug ...
as a cofactor. : The starting material is
5-aminoimidazole ribotide 5′-Phosphoribosyl-5-aminoimidazole (or aminoimidazole ribotide, AIR) is a biochemical intermediate in the formation of purine nucleotides via inosine-5-monophosphate, and hence is a building block for DNA and RNA. The vitamins thiamine and coba ...
, which undergoes a
rearrangement reaction In organic chemistry, a rearrangement reaction is a broad class of organic reactions where the carbon skeleton of a molecule is rearranged to give a structural isomer of the original molecule. Often a substituent moves from one atom to another ...
via
radical Radical may refer to: Politics and ideology Politics *Radical politics, the political intent of fundamental societal change *Radicalism (historical), the Radical Movement that began in late 18th century Britain and spread to continental Europe and ...
intermediates which incorporate the blue, green and red fragments shown into the product. The thiazole ring is formed in a reaction catalysed by
thiazole synthase Thiazole synthase (, ''thiG (gene)'') is an enzyme with systematic name ''1-deoxy-D-xylulose 5-phosphate:thiol sulfurtransferase''. This enzyme catalyses the following chemical reaction A chemical reaction is a process that leads to the IUPAC ...
(EC 2.8.1.10). The ultimate precursors are 1-deoxy-D-xylulose 5-phosphate, 2-iminoacetate and a 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. : The final step to form ThMP involves
decarboxylation Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is t ...
of the thiazole intermediate, which reacts with the
pyrophosphate In chemistry, pyrophosphates are phosphorus oxyanions that contain two phosphorus atoms in a P–O–P linkage. A number of pyrophosphate salts exist, such as disodium pyrophosphate (Na2H2P2O7) and tetrasodium pyrophosphate (Na4P2O7), among other ...
derivative of phosphomethylpyrimidine, itself a product of a
kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
, phosphomethylpyrimidine kinase. The biosynthetic pathways differ among organisms. In ''E. coli'' and other
enterobacteriaceae Enterobacteriaceae is a large family (biology), family of Gram-negative bacteria. It was first proposed by Rahn in 1936, and now includes over 30 genera and more than 100 species. Its classification above the level of family is still a subject ...
, ThMP is phosphorylated to the cofactor TPP by a thiamine-phosphate kinase (ThMP + ATP → TPP + ADP). In most bacteria and in
eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
s, ThMP is hydrolyzed to thiamine and then pyrophosphorylated to TPP by
thiamine diphosphokinase In enzymology, a thiamine diphosphokinase () is an enzyme that catalysis, catalyzes the chemical reaction :ATP + thiamine \rightleftharpoons AMP + thiamine diphosphate Thus, the two substrate (biochemistry), substrates of this enzyme are adenosi ...
(thiamine + ATP → TPP + AMP). The biosynthetic pathways are regulated by
riboswitch In molecular biology, a riboswitch is a regulatory segment of a messenger RNA molecule that binds a small molecule, resulting in a change in production of the proteins encoded by the mRNA. Thus, an mRNA that contains a riboswitch is directly invo ...
es. If there is sufficient thiamine present in the cell then the thiamine binds to the
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
s for the enzymes that are required in the pathway and prevents their
translation Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...
. 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 The TPP riboswitch, also known as the THI element and Thi-box riboswitch, is a highly conserved RNA secondary structure. It serves as a riboswitch that binds thiamine pyrophosphate (TPP) directly and modulates gene expression through a variety ...
, is the only known riboswitch found in both eukaryotic and
prokaryotic A prokaryote () is a Unicellular organism, single-celled organism that lacks a cell nucleus, nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek language, Greek wikt:πρό#Ancient Greek, πρό (, 'before') a ...
organisms.


Laboratory synthesis

: In the first
total synthesis Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes ...
in 1936, ethyl 3-ethoxypropanoate was treated with
ethyl formate Ethyl formate is an ester formed when ethanol (an alcohol) reacts with formic acid (a carboxylic acid). Ethyl formate has the characteristic smell of rum and is also partially responsible for the flavor of raspberries. It occurs naturally in th ...
to give an intermediate dicarbonyl compound which when reacted with acetamidine formed a substituted
pyrimidine Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The other ...
. Conversion of its hydroxyl group to an amino group was carried out by
nucleophilic aromatic substitution A nucleophilic aromatic substitution is a substitution reaction in organic chemistry in which the nucleophile displaces a good leaving group, such as a halide, on an aromatic ring. Aromatic rings are usually nucleophilic, but some aromatic compou ...
, first to the chloride derivative using
phosphorus oxychloride Phosphoryl chloride (commonly called phosphorus oxychloride) is a colourless liquid with the formula . It hydrolyses in moist air releasing phosphoric acid and fumes of hydrogen chloride. It is manufactured industrially on a large scale from phosp ...
, followed by treatment with
ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous was ...
. The ethoxy group was then converted to a bromo derivative using
hydrobromic acid Hydrobromic acid is a strong acid formed by dissolving the diatomic molecule hydrogen bromide (HBr) in water. "Constant boiling" hydrobromic acid is an aqueous solution that distills at and contains 47.6% HBr by mass, which is 8.77 mol/L. H ...
. In the final stage, thiamine (as its dibromide salt) was formed in an
alkylation Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting ...
reaction using 4-methyl-5-(2-hydroxyethyl)thiazole.


Industrial synthesis

Merck & Co. adapted the 1936 laboratory-scale synthesis, allowing them to manufacture thiamine in
Rahway Rahway () is a city in southern Union County, in the U.S. state of New Jersey. A bedroom community of New York City, it is centrally located in the Rahway Valley region, in the New York metropolitan area. The city is southwest of Manhattan ...
in 1937. However, an alternative route using the intermediate Grewe
diamine A diamine is an amine with exactly two amino groups. Diamines are used as monomers to prepare polyamides, polyimides, and polyureas. The term ''diamine'' refers mostly to primary diamines, as those are the most reactive. In terms of quantities p ...
(5-(aminomethyl)-2-methyl-4-pyrimidinamine), first published in 1937, was investigated by
Hoffman La Roche F. Hoffmann-La Roche AG, commonly known as Roche, is a Swiss multinational corporation, multinational healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has ...
and competitive manufacturing processes followed. Efficient routes to the diamine have continued to be of interest. In the
European Economic Area The European Economic Area (EEA) was established via the ''Agreement on the European Economic Area'', an international agreement which enables the extension of the European Union's single market to member states of the European Free Trade Ass ...
, thiamine is registered under
REACH regulation Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) is a European Union regulation dating from 18 December 2006. REACH addresses the production and use of chemical substances, and their potential impacts on both human he ...
and between 100 and 1,000 tonnes per annum are manufactured or imported there.


Synthetic analogues

Many vitamin B1 analogues, such as
Benfotiamine Benfotiamine (rINN, or ''S''-benzoylthiamine ''O''-monophosphate) is a synthetic, fat-soluble, ''S''-acyl derivative of thiamine (vitamin B1) that is approved in some countries as a medication or dietary supplement to treat diabetic sensorimoto ...
,
fursultiamine Fursultiamine ( INN; chemical name thiamine tetrahydrofurfuryl disulfide or TTFD; brand names Adventan, Alinamin-F, Benlipoid, Bevitol Lipophil, Judolor, Lipothiamine) is a medication and vitamin used to treat thiamine deficiency. Chemically, it ...
, 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 Diabetic neuropathy is various types of nerve damage associated with diabetes mellitus. Symptoms depend on the site of nerve damage and can include motor changes such as weakness; sensory symptoms such as numbness, tingling, or pain; or autonomic c ...
or other health conditions.


Absorption, metabolism and excretion

In the upper small intestine, thiamine phosphate esters present in food are hydrolyzed by alkaline
phosphatase In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid Ester, monoester into a phosphate ion and an Alcohol (chemistry), alcohol. Because a phosphatase enzyme catalysis, catalyzes the hydrolysis of its Substrate ...
enzymes. At low concentrations, the absorption process is carrier-mediated. At higher concentrations, absorption also occurs via
passive diffusion Passive transport is a type of membrane transport that does not require energy to move substances across cell membranes. Instead of using cellular energy, like active transport, passive transport relies on the second law of thermodynamics to d ...
. Active transport can be inhibited by alcohol consumption or by
folate deficiency Folate deficiency, also known as vitamin B9 deficiency, is a low level of folate and derivatives in the body. Signs of folate deficiency are often subtle. A low number of red blood cells (anemia) is a late finding in folate deficiency and folate ...
. The majority of thiamine in serum is bound to proteins, mainly
albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...
. Approximately 90% of total thiamine in blood is in
erythrocyte Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
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 SLC19A2 and
SLC19A3 Thiamine transporter 2 (ThTr-2), also known as solute carrier family 19 member 3, is a protein that in humans is encoded by the ''SLC19A3'' gene. SLC19A3 is a thiamine transporter. Function ThTr-2 is a ubiquitously expressed transmembrane thiam ...
are capable of thiamine transport. In some tissues, thiamine uptake and secretion appear to be mediated by a Na+-dependent transporter and a transcellular proton gradient. 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 are present in plasma, milk,
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...
, and, it is presumed, all
extracellular fluid In cell biology, extracellular fluid (ECF) denotes all body fluid outside the cells of any multicellular organism. Total body water in healthy adults is about 60% (range 45 to 75%) of total body weight; women and the obese typically have a lower ...
. 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 Magnesium deficiency is an electrolyte disturbance in which there is a low level of magnesium in the body. It can result in multiple symptoms. Symptoms include tremor, poor coordination, muscle spasms, loss of appetite, personality changes, and ...
has been shown to aggravate thiamine deficiency. Thiamine contents in human tissues are less than those of other species. 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

The bioavailability of thiamine in foods can be interfered with in a variety of ways.
Sulfite Sulfites or sulphites are compounds that contain the sulfite ion (or the sulfate(IV) ion, from its correct systematic name), . The sulfite ion is the conjugate base of bisulfite. Although its acid ( sulfurous acid) is elusive, its salts are wide ...
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 Thiaminase is an enzyme that metabolizes or breaks down thiamine into two molecular parts. It is an antinutrient when consumed. The old name was "aneurinase". There are two types: * Thiamine pyridinylase, Thiaminase I (, ) * Aminopyrimidine am ...
s present in some species of fish, shellfish and other foods. The pupae of an African silk worm, ''
Anaphe venata ''Anaphe venata'' is a moth of the family Notodontidae. It was described by Arthur Gardiner Butler in 1878. It lives in Angola, Cameroon, the Central African Republic, the Republic of the Congo, the Democratic Republic of the Congo, Equatorial G ...
'', 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 acidotic conditions. In
dairy cows Dairy cattle (also called dairy cows) are cattle bred for the ability to produce large quantities of milk, from which dairy products are made. Dairy cattle generally are of the species ''Bos taurus''. Historically, little distinction was mad ...
, over-feeding with grain causes subacute ruminal acidosis and increased ruminal bacteria thiaminase release, resulting in thiamine deficiency. From reports on two small studies conducted in Thailand, chewing slices of
areca nut ''Areca'' is a genus of 51 species of palms in the family Arecaceae, found in humid tropical forests from the islands of the Philippines, Malaysia and India, across Southeast Asia to Melanesia. The generic name ''Areca'' is derived from a name u ...
wrapped in
betel The betel (''Piper betle'') is a vine of the family Piperaceae, which includes pepper and kava. The betel plant is native to Southeast Asia. It is an evergreen, dioecious perennial, with glossy heart-shaped leaves and white catkins. Betel plan ...
leaves and chewing tea leaves reduced food thiamine bioavailability by a mechanism that may involve
tannins Tannins (or tannoids) are a class of astringent, polyphenolic biomolecules that bind to and precipitate proteins and various other organic compounds including amino acids and alkaloids. The term ''tannin'' (from Anglo-Norman ''tanner'', f ...
. Bariatric surgery for weight loss is known to interfere with vitamin absorption. A meta-analysis reported that 27% of people who underwent bariatric surgeries experience vitamin B1 deficiency.


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. In 1884,
Takaki Kanehiro Baron was a Japanese naval physician. Early life Born in Hyūga Province (present-day Miyazaki Prefecture) as the son of a '' samurai'' retainer to the Satsuma domain, Takaki studied Chinese medicine as a youth and served as a medic in the ...
, a surgeon general in the
Imperial Japanese Navy The Imperial Japanese Navy (IJN; Kyūjitai: Shinjitai: ' 'Navy of the Greater Japanese Empire', or ''Nippon Kaigun'', 'Japanese Navy') was the navy of the Empire of Japan from 1868 to 1945, when it was dissolved following Japan's surrender ...
, rejected the previous
germ theory The germ theory of disease is the currently accepted scientific theory for many diseases. It states that microorganisms known as pathogens or "germs" can lead to disease. These small organisms, too small to be seen without magnification, invade ...
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 The Russo-Japanese War ( ja, 日露戦争, Nichiro sensō, Japanese-Russian War; russian: Ру́сско-япóнская войнá, Rússko-yapónskaya voyná) was fought between the Empire of Japan and the Russian Empire during 1904 and 1 ...
of 1904–5. Not until 1905, after the anti-beriberi factor had been discovered in
rice bran Bran, also known as miller's bran, is the hard outer layers of cereal grain. It consists of the combined aleurone and pericarp. Corn (maize) bran also includes the pedicel (tip cap). Along with germ, it is an integral part of whole grains, ...
(removed by 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". The specific connection to grain was made in 1897 by
Christiaan Eijkman Christiaan Eijkman ( , , ; 11 August 1858 – 5 November 1930) was a Dutch physician and professor of physiology whose demonstration that beriberi is caused by poor diet led to the discovery of antineuritic vitamins (thiamine). Together with S ...
, a military doctor in the
Dutch East Indies The Dutch East Indies, also known as the Netherlands East Indies ( nl, Nederlands(ch)-Indië; ), was a Dutch colony consisting of what is now Indonesia. It was formed from the nationalised trading posts of the Dutch East India Company, which ...
, 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 Starch or amylum is a polymeric carbohydrate consisting of numerous glucose units joined by glycosidic bonds. This polysaccharide is produced by most green plants for energy storage. Worldwide, it is the most common carbohydrate in human diets ...
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 The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, according ...
in 1929, because his observations led to the discovery of vitamins. In 1910, a Japanese agricultural chemist of
Tokyo Imperial University , abbreviated as or UTokyo, is a public research university located in Bunkyō, Tokyo, Japan. Established in 1877, the university was the first Imperial University and is currently a Top Type university of the Top Global University Project by ...
,
Umetaro Suzuki was a Japanese scientist, born in what is now part of Makinohara, Shizuoka, Japan. He was a member of the Imperial Academy, and a recipient of the Grand Cordon of the Order of the Sacred Treasure and the Order of Culture. His research was among t ...
, 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 Kazimierz Funk (; February 23, 1884 – November 19, 1967), commonly anglicized as Casimir Funk, was a Polish-American biochemist generally credited with being among the first to formulate (in 1912) the concept of vitamins, which he called "vita ...
isolated the 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 A portmanteau word, or portmanteau (, ) is a blend of wordsvitamin C Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) an ...
). Thiamine was also synthesized by the Williams group in 1936. Sir
Rudolph Peters Sir Rudolph Albert Peters MC MID FRS H FRSE FRCP LLD (13 April 1889 – 29 January 1982) was a British biochemist. He led the research team at Oxford who developed British Anti-Lewisite (BAL), an antidote for the chemical warfare agent lewisite ...
, in
Oxford Oxford () is a city in England. It is the county town and only city of Oxfordshire. In 2020, its population was estimated at 151,584. It is north-west of London, south-east of Birmingham and north-east of Bristol. The city is home to the ...
, used pigeons to understand how thiamine deficiency results in the pathological-physiological symptoms of beriberi. Pigeons fed exclusively on polished rice developed
opisthotonos Opisthotonus or opisthotonos (from grc, ὄπισθεν, translit=opisthen, lit=behind and grc, τόνος, translit=tonos, lit=tension, label=none) is a state of severe hyperextension and spasticity in which an individual's head, neck and spinal ...
, 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. File:Takaki Kanehiro.jpg,
Takaki Kanehiro Baron was a Japanese naval physician. Early life Born in Hyūga Province (present-day Miyazaki Prefecture) as the son of a '' samurai'' retainer to the Satsuma domain, Takaki studied Chinese medicine as a youth and served as a medic in the ...
File:Eijkman.jpg,
Christiaan Eijkman Christiaan Eijkman ( , , ; 11 August 1858 – 5 November 1930) was a Dutch physician and professor of physiology whose demonstration that beriberi is caused by poor diet led to the discovery of antineuritic vitamins (thiamine). Together with S ...
File:Portrait_of_Gerrit_Grijns_Wellcome_M0010254.jpg, Gerrit Grijns File:Umetarosuzuki-pre1943.jpg,
Umetaro Suzuki was a Japanese scientist, born in what is now part of Makinohara, Shizuoka, Japan. He was a member of the Imperial Academy, and a recipient of the Grand Cordon of the Order of the Sacred Treasure and the Order of Culture. His research was among t ...
File:Casimir_Funk_01.jpg,
Casimir Funk Kazimierz Funk (; February 23, 1884 – November 19, 1967), commonly anglicized as Casimir Funk, was a Polish-American biochemist generally credited with being among the first to formulate (in 1912) the concept of vitamins, which he called "vita ...
File:Rudolph Albert Peters.jpg,
Rudolph Peters Sir Rudolph Albert Peters MC MID FRS H FRSE FRCP LLD (13 April 1889 – 29 January 1982) was a British biochemist. He led the research team at Oxford who developed British Anti-Lewisite (BAL), an antidote for the chemical warfare agent lewisite ...


References


External links

* {{Authority control Aminopyrimidines B vitamins Coenzymes Poultry diseases Primary alcohols Thiazoles World Health Organization essential medicines Wikipedia medicine articles ready to translate Quaternary ammonium compounds Cations