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Skeletal formula and ball-and-stick model of the cation in thiamine
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| Pronunciation | /ˈθaɪ.əmɪn/ THY-ə-min |
| Synonyms | Vitamin B1, aneurine, thiamin |
| AHFS/Drugs.com | Monograph |
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| Routes of administration | by mouth, IV, IM |
| Drug class | vitamin |
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| Pharmacokinetic data | |
| Bioavailability | 3.7% to 5.3% |
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| Chemical and physical data | |
| Formula | C12H17N4OS+ |
| Molar mass | 265.35 g mol−1 g·mol−1 |
| 3D model (JSmol) | |
Thiamine, also known as thiamin or vitamin B1, is a vitamin found in food, and manufactured as a dietary supplement and medication. Food sources of thiamine include whole grains, legumes, and some meats and fish. Grain processing removes much of the thiamine content, so in many countries cereals and flours are enriched with thiamine. Supplements and medications are available to treat and prevent thiamine deficiency and disorders that result from it, including beriberi and Wernicke encephalopathy. Other uses include the treatment of maple syrup urine disease and Leigh syndrome. They are typically taken by mouth, but may also be given by intravenous or intramuscular injection.
Thiamine supplements are generally well tolerated. Allergic reactions, including anaphylaxis, may occur when repeated doses are given by injection. Thiamine is in the B complex family. It is an essential micronutrient, which cannot be made in the body. Thiamine is required for metabolism including that of glucose, amino acids, and lipids.
Thiamine was discovered in 1897, was the first vitamin to be isolated in 1926, and was first made in 1936. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. Thiamine is available as a generic medication, and as an over-the-counter drug. The wholesale cost in the developing world (as of 2016) is about US$2.17 per one gm vial. In the United States a month's supply of a multivitamin containing thiamine is less than US$25.
Medical uses
Thiamine deficiency
Thiamine is used to treat thiamine deficiency which when severe can prove fatal. In less severe cases, non-specific signs include malaise, weight loss, irritability and confusion. Well-known disorders caused by thiamine deficiency include beriberi, Wernicke-Korsakoff syndrome, optic neuropathy, Leigh's disease, African Seasonal Ataxia, and central pontine myelinolysis. It has also been suggested that thiamine deficiency plays a role in the poor development of the infant brain that can lead to sudden infant death syndrome (SIDS). In Western countries, thiamine deficiency is seen mainly in chronic alcoholism. Also at risk are older adults, persons with HIV/AIDS or diabetes, and persons who have had bariatric surgery. Varying degrees of thiamine deficiency have been associated with the long-term use of high doses of diuretics, particularly furosemide in the treatment of heart failure.[17] Thiamine deficiency is often present in alcohol misuse disorder.
Other uses
Thiamine is a treatment for some types of maple syrup urine disease and Leigh disease.
Adverse effects
Adverse effects are generally few. Allergic reactions including anaphylaxis may occur.
Chemistry
Thiamine is a colorless organosulfur compound with a chemical formula C12H17N4OS. Its structure consists of an aminopyrimidine and a thiazolium ring linked by a methylene bridge. The thiazole is substituted with methyl and hydroxyethyl side chains. Thiamine is soluble in water, methanol, and glycerol and practically insoluble in less polar organic solvents. It is stable at acidic pH, but is unstable in alkaline solutions. Thiamine, which is a persistent carbene, is used by enzymes to catalyze benzoin condensations in vivo. Thiamine is unstable to heat, but stable during frozen storage. It is unstable when exposed to ultraviolet light and gamma irradiation. Thiamine reacts strongly in Maillard-type reactions.
Biosynthesis
A 3D representation of the TPP riboswitch with thiamine bound
Complex thiamine biosynthesis occurs in bacteria, some protozoans, plants, and fungi. The thiazole and pyrimidine moieties are biosynthesized separately and then combined to form thiamine monophosphate (ThMP) by the action of thiamine-phosphate synthase (EC2.5.1.3). The biosynthetic pathways may differ among organisms. In E. coli and other enterobacteriaceae, ThMP may be phosphorylated to the cofactor thiamine diphospate (ThDP) by a thiamine-phosphate kinase (ThMP + ATP → ThDP + ADP, EC 2.7.4.16). In most bacteria and in eukaryotes, ThMP is hydrolyzed to thiamine, which may then be pyrophosphorylated to ThDP by thiamine diphosphokinase (thiamine + ATP → ThDP + AMP, EC 2.7.6.2).
The biosynthetic pathways are regulated by riboswitches. If there is sufficient thiamine present in the cell then the thiamine binds to the mRNAs for the enzymes that are required in the pathway and prevents their translation.
If there is no thiamine present then there is no inhibition, and the
enzymes required for the biosynthesis are produced. The specific
riboswitch, the TPP riboswitch (or ThDP), is the only riboswitch identified in both eukaryotic and prokaryotic organisms.
Nutrition
Occurrence in foods
Thiamine is found in a wide variety of processed and whole foods, with edible seeds, legumes, rice, pork, and processed foods, such as breakfast cereals, having among the highest contents.
The salt thiamine mononitrate, rather than thiamine
hydrochloride, is used for food fortification, as the mononitrate is
more stable, and does not absorb water from natural humidity (is
non-hygroscopic), whereas thiamine hydrochloride is hygroscopic. When thiamine mononitrate dissolves in water, it releases nitrate
(about 19% of its weight) and is thereafter absorbed as the thiamine
cation.
Dietary recommendations
In
the U.S. the Estimated Average Requirements (EARs) and Recommended
Dietary Allowances (RDAs) for thiamine were updated in 1998, by the
Institute of Medicine now known as the National Academy of Medicine (NAM).
The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values,
with Population Reference Intake (PRI) instead of RDA, and Average
Requirement instead of EAR. AI and UL defined the same as in United
States. For women (including those pregnant or lactating), men and
children the PRI is 0.1 mg thiamine per megajoule (MJ) of energy
consumed. As the conversion is 1 MJ = 238.8 kcal, an adult consuming
2388 calories should be consuming 1.0 mg thiamine. This is slightly
lower than the U.S. RDA.
The EFSA reviewed the same safety question and also reached the
conclusion that there was not sufficient evidence to set a UL for
thiamine.
For U.S. food and dietary supplement labeling purposes the amount
in a serving is expressed as a percentage of Daily Value (%DV). For
thiamine labeling purposes 100% of the Daily Value was 1.5 mg, but as of
May 27, 2016 it was revised to 1.2 mg to bring it into agreement with
the RDA. A table of the old and new adult Daily Values is provided at Reference Daily Intake.
The original deadline to be in compliance was July 28, 2018, but on
September 29, 2017 the FDA released a proposed rule that extended the
deadline to January 1, 2020 for large companies and January 1, 2021 for
small companies.
Antagonists
Thiamine in foods can be degraded in a variety of ways. Sulfites, which are added to foods usually as a preservative, will attack thiamine at the methylene bridge in the structure, cleaving the pyrimidine ring from the thiazole ring. The rate of this reaction is increased under acidic conditions. Thiamine is degraded by thermolabile thiaminases (present in raw fish and shellfish).
Some thiaminases are produced by bacteria. Bacterial thiaminases are
cell surface enzymes that must dissociate from the membrane before being
activated; the dissociation can occur in ruminants under acidotic
conditions. Rumen bacteria also reduce sulfate to sulfite, therefore
high dietary intakes of sulfate can have thiamine-antagonistic
activities.
Plant thiamine antagonists are heat-stable and occur as both the
ortho- and para-hydroxyphenols. Some examples of these antagonists are caffeic acid, chlorogenic acid, and tannic acid.
These compounds interact with the thiamine to oxidize the thiazole
ring, thus rendering it unable to be absorbed. Two flavonoids, quercetin and rutin, have also been implicated as thiamine antagonists.
Food fortification
Refining
grain removes its bran and germ, and thus subtracts its naturally
occurring vitamins and minerals. In the United States, B-vitamin
deficiencies became common in the first half of the 20th century due to
white flour consumption. The American Medical Association successfully
lobbied for restoring these vitamins by enrichment of grain, which began
in the US in 1939. The UK followed in 1940 and Denmark in 1953. As of
2016, about 85 countries had passed legislation mandating fortification
of wheat flour with at least some nutrients, and 28% of industrially
milled flour was fortified, often with thiamine and other B vitamins.
Absorption and transport
Absorption
Thiamine is released by the action of phosphatase and pyrophosphatase
in the upper small intestine. At low concentrations, the process is
carrier-mediated. At higher concentrations, absorption also occurs via passive diffusion. Active transport is greatest in the jejunum and ileum, but it can be inhibited by alcohol consumption or by folate deficiency. Decline in thiamine absorption occurs at intakes above 5 mg/day. On the serosal side of the intestine, discharge of the vitamin by those cells is dependent on Na+-dependent ATPase.
Bound to serum proteins
The majority of thiamine in serum is bound to proteins, mainly albumin. Approximately 90% of total thiamine in blood is in erythrocytes.
A specific binding protein called thiamine-binding protein (TBP) has
been identified in rat serum and is believed to be a hormone-regulated
carrier protein important for tissue distribution of thiamine.
Cellular uptake
Uptake of thiamine by cells of the blood and other tissues occurs via active transport and passive diffusion.
About 80% of intracellular thiamine is phosphorylated and most is bound
to proteins. Two members of the SLC gene family of transporter
proteins, SLC19A2 and SLC19A3, are capable of the thiamine transport. In some tissues, thiamine uptake and secretion appears to be mediated by a soluble thiamine transporter that is dependent on Na+ and a transcellular proton gradient.
Tissue distribution
Human
storage of thiamine is about 25 to 30 mg, with the greatest
concentrations in skeletal muscle, heart, brain, liver, and kidneys. ThMP and free (unphosphorylated) thiamine is present in plasma, milk, cerebrospinal fluid, and, it is presumed, all extracellular fluid.
Unlike the highly phosphorylated forms of thiamine, ThMP and free
thiamine are capable of crossing cell membranes. Calcium and Magnesium
have been shown to affect the distribution of thiamine in the body and
Magnesium deficiency has been shown to aggravate thiamine deficiency. Thiamine contents in human tissues are less than those of other species.
Excretion
Thiamine
and its acid metabolites (2-methyl-4-amino-5-pyrimidine carboxylic
acid, 4-methyl-thiazole-5-acetic acid, and thiamine acetic acid) are
excreted principally in the urine.
Function
Its phosphate derivatives are involved in many cellular processes. The best-characterized form is thiamine pyrophosphate (TPP), a coenzyme in the catabolism of sugars and amino acids. In yeast, TPP is also required in the first step of alcoholic fermentation.
All organisms use thiamine, but it is made only in bacteria, fungi, and
plants. Animals must obtain it from their diet, and thus, for humans,
it is an essential nutrient. Insufficient intake in birds produces a characteristic polyneuritis.
Thiamine is usually considered as the transport form of the
vitamin. There are five known natural thiamine phosphate derivatives: thiamine monophosphate (ThMP), thiamine diphosphate (ThDP), also sometimes called thiamine pyrophosphate (TPP), thiamine triphosphate (ThTP), and the recently discovered adenosine thiamine triphosphate (AThTP), and adenosine thiamine diphosphate
(AThDP). While the coenzyme role of thiamine diphosphate is well-known
and extensively characterized, the non-coenzyme action of thiamine and
derivatives may be realized through binding to a number of recently
identified proteins which do not use the catalytic action of thiamine
diphosphate
Thiamine diphosphate
No
physiological role is known for thiamine monophosphate (ThMP); however,
the diphosphate is physiologically relevant. The synthesis of thiamine diphosphate (ThDP), also known as thiamine pyrophosphate (TPP) or cocarboxylase, is catalyzed by an enzyme called thiamine diphosphokinase according to the reaction thiamine + ATP → ThDP + AMP (EC 2.7.6.2). ThDP is a coenzyme for several enzymes that catalyze the transfer of two-carbon units and in particular the dehydrogenation (decarboxylation and subsequent conjugation with coenzyme A) of 2-oxoacids (alpha-keto acids). Examples include:
- Present in most species
- Present in some species:
- pyruvate decarboxylase (in yeast)
- several additional bacterial enzymes
The enzymes transketolase, pyruvate dehydrogenase (PDH), and 2-oxoglutarate dehydrogenase (OGDH) are all important in carbohydrate metabolism. The cytosolic enzyme transketolase is a key player in the pentose phosphate pathway, a major route for the biosynthesis of the pentose sugars deoxyribose and ribose. The mitochondrial PDH and OGDH are part of biochemical pathways that result in the generation of adenosine triphosphate
(ATP), which is a major form of energy for the cell. PDH links
glycolysis to the citric acid cycle, while the reaction catalyzed by
OGDH is a rate-limiting step in the citric acid cycle. In the nervous system, PDH is also involved in the production of acetylcholine, a neurotransmitter, and for myelin synthesis.
Thiamine triphosphate
Thiamine triphosphate
(ThTP) was long considered a specific neuroactive form of thiamine,
playing a role in chloride channels in the neurons of mammals and other
animals, although this is not completely understood. However, recently it was shown that ThTP exists in bacteria, fungi, plants and animals suggesting a much more general cellular role. In particular in E. coli, it seems to play a role in response to amino acid starvation.
Adenosine thiamine triphosphate
Adenosine thiamine triphosphate (AThTP) or thiaminylated adenosine triphosphate has recently been discovered in Escherichia coli, where it accumulates as a result of carbon starvation.[42] In E. coli, AThTP may account for up to 20% of total thiamine. It also exists in lesser amounts in yeast, roots of higher plants and animal tissue.
Adenosine thiamine diphosphate
Adenosine thiamine diphosphate (AThDP) or thiaminylated adenosine diphosphate exists in small amounts in vertebrate liver, but its role remains unknown.
History
Some contributors to the discovery of thiamine
Thiamine was the first of the water-soluble vitamins to be described, leading to the discovery of more essential nutrients and to the notion of vitamin.
In 1884, Takaki Kanehiro (1849–1920), a surgeon general in the Japanese navy, rejected the previous germ theory for beriberi and hypothesized that the disease was due to insufficiencies in the diet instead.
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 nitrogen intake, as
vitamins were unknown substances at the time. The Navy was not convinced
of the need for so expensive a program of dietary improvement, and many
men continued to die of beriberi, even during the Russo-Japanese war of 1904–5. Not until 1905, after the anti-beriberi factor had been discovered in rice bran (removed by polishing into white rice)
and in barley bran, was Takaki's experiment rewarded by making him a
baron in the Japanese peerage system, after which he was affectionately
called "Barley Baron".
The specific connection to grain was made in 1897 by Christiaan Eijkman
(1858–1930), a military doctor in the Dutch Indies, who discovered that
fowl fed on a diet of cooked, polished rice developed paralysis, which
could be reversed by discontinuing rice polishing.
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
(1865–1944), correctly interpreted the connection between excessive
consumption of polished rice and beriberi in 1901: He concluded that
rice contains an essential nutrient in the outer layers of the grain
that is removed by polishing. Eijkman was eventually awarded the Nobel Prize in Physiology and Medicine in 1929, because his observations led to the discovery of vitamins.
In 1910 a Japanese scientist Umetaro Suzuki first isolated the compound which he described as aberic acid. In translation from the Japanese paper in which it was claimed to be a new finding this claim was omitted. In 1911 a Polish biochemist Casimir Funk isolated the antineuritic
substance from rice bran (the modern thiamine) that he called a
"vitamine" (on account of its containing an amino group. However, Funk
did not completely characterize its chemical structure. Dutch chemists, Barend Coenraad Petrus Jansen (1884–1962) and his closest collaborator Willem Frederik Donath (1889–1957), went on to isolate and crystallize the active agent in 1926, whose structure was determined by Robert Runnels Williams
(1886–1965), a US chemist, in 1934. Thiamine was named by the Williams
team as "thio" or “sulfur-containing vitamin”, with the term "vitamin"
coming indirectly, by way of Funk, from the amine group of thiamine
itself (by this time in 1936, vitamins were known to not always be
amines, for example, vitamin C). Thiamine was synthesized in 1936 by the
Williams group.
Thiamine was first named "aneurin" (for anti-neuritic vitamin). Sir Rudolph Peters,
in Oxford, introduced thiamine-deprived pigeons as a model for
understanding how thiamine deficiency can lead to the
pathological-physiological symptoms of beriberi. Indeed, feeding the
pigeons upon polished rice leads to an easily recognizable behavior of
head retraction, a condition called opisthotonos.
If not treated, the animals died after a few days. Administration of
thiamine at the stage of opisthotonos led to a complete cure within 30
minutes. As no morphological modifications were observed in the brain of
the pigeons before and after treatment with thiamine, Peters introduced
the concept of a biochemical lesion.
When Lohman and Schuster (1937) showed that the diphosphorylated
thiamine derivative (thiamine diphosphate, ThDP) was a cofactor required
for the oxydative decarboxylation of pyruvate, a reaction now known to be catalyzed by pyruvate dehydrogenase,
the mechanism of action of thiamine in the cellular metabolism seemed
to be elucidated. At present, this view seems to be oversimplified:
pyruvate dehydrogenase is only one of several enzymes requiring thiamine
diphosphate as a cofactor; moreover, other thiamine phosphate
derivatives have been discovered since then, and they may also
contribute to the symptoms observed during thiamine deficiency. Lastly,
the mechanism by which the thiamine moiety of ThDP exerts its coenzyme
function by proton substitution on position 2 of the thiazole ring was elucidated by Ronald Breslow in 1958.
