Thiamine
Encyclopedia
Thiamine or thiamin or vitamin B1 (icon ), named as the "thio-vitamine" ("sulfur-containing vitamin") is a water-soluble vitamin
of the B complex
. First named aneurin for the detrimental neurological effects if not present in the diet, it was eventually assigned the generic descriptor name vitamin B1. 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. Thiamine is used in the biosynthesis the neurotransmitter acetylcholine and gamma-aminobutyric acid (GABA). In yeast
, TPP is also required in the first step of alcoholic fermentation.
All living organisms use thiamine in their biochemistry, but it is only synthesized in bacteria
, fungi, and plant
s. Animal
s must obtain it from their diet, and, thus, for them, it is a vitamin. Insufficient intake in birds produces a characteristic polyneuritis, and in mammals results in a disease called beriberi
affecting the peripheral nervous system
(polyneuritis) and/or the cardiovascular system, with fatal outcome if not cured by thiamine administration. In less severe deficiency, nonspecific signs include malaise
, weight loss, irritability and confusion.
There is still much research devoted to elucidating the exact mechanisms by which thiamine deficiency leads to the specific symptoms observed (see below). New thiamine phosphate derivatives have recently been discovered, emphasizing the complexity of thiamine metabolism.
Thiamine derivatives with improved pharmacokinetics have been discovered and are to be considered more effective in alleviating the symptoms of thiamine deficiency and other thiamine-related conditions such as impaired glucose metabolism
in diabetes. These compounds include allithiamine
, prosultiamine
, fursultiamine
, benfotiamine
, and sulbutiamine
, among others.
with a chemical formula
C
12H
17N
4O
S
. Its structure contains a aminopyrimidine ring and a thiazole
ring with methyl and hydroxyethyl side chains linked by a methylene bridge. Thiamine is soluble in water
, methanol
, and glycerol
and practically insoluble in acetone
, ether
, chloroform
, and benzene
. It is stable at acidic pH, but is unstable in alkaline solutions. Thiamine, which is a N-heterocyclic carbene, can be used in place of cyanide
as a catalyst for benzoin condensation
. 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
.
Complex thiamine biosynthetic pathways occur in bacteria, some protozoans, plants and fungi. The thiazole
and pyrimidine
moieties are synthesized separately and then assembled to form ThMP by thiamine-phosphate synthase (EC 2.5.1.3). The exact biosynthetic pathways may differ among organisms. In E. coli and other enterobacteriaceae
ThMP may be phosphorylated to the cofactor
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, that may then be pyrophosphorylated to ThDP by thiamine diphosphokinase (thiamine + ATP → ThDP + AMP, EC 2.7.6.2).
The biosynthetic pathways are regulated by riboswitch
es in all organisms that synthesise thiamine. If there is sufficient thiamine present in the cell then the thiamine binds to the mRNA encoding genes required in the pathway, preventing the translation of the enzymes. 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 riboswitch identified in both eukaryotic and prokaryotic organisms.
diet is therefore recommended for deficiency.
Some other foods rich in thiamine are oatmeal
, flax
, and sunflower seeds, brown rice
, whole grain rye
, asparagus
, kale
, cauliflower
, potatoes, oranges
, liver
(beef, pork, and chicken), and eggs
.
Thiamine hydrochloride
(Betaxin) is a (when by itself) white, crystalline hygroscopic food-additive used to add a brothy/meaty flavor to gravies or soups. It is a natural intermediary resulting from a thiamine-HCl reaction, which precedes hydrolysis and phosphorylation, before it is finally employed (in the form of TPP) in a number of enzymatic amino, fatty acid, and carbohydrate reactions.
in most countries is set at about 1.4 mg. However, tests on female volunteers at daily doses of about 50 mg have claimed an increase in mental acuity. There are no reports available of adverse effects from consumption of excess thiamine by ingestion of food and supplements. Because the data is inadequate for a quantitative risk assessment, no Tolerable Upper Intake Level (UL) can be derived for thiamine.
s, 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 thiaminase
s (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.
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.
(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).
according to the reaction thiamine + ATP → ThDP + AMP (EC 2.7.6.2). ThDP is a coenzyme for several enzymes that catalyze the transfer of two-carbon units and in particular the dehydrogenation
(decarboxylation
and subsequent conjugation with coenzyme A
) of 2-oxoacids (alpha-keto acids). Examples include:
The enzymes transketolase
, pyruvate dehydrogenase
(PDH), and 2-oxoglutarate dehydrogenase
(OGDH) are all important in carbohydrate metabolism
. The cytosolic enzyme transketolase is a key player in the pentose phosphate pathway
, a major route for the biosynthesis of the pentose 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 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-limting 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.
(ThTP) was long considered a specific neuroactive form of thiamine. However, recently it was shown that ThTP exists in bacteria
, fungi, plant
s and animal
s suggesting a much more general cellular role. In particular in E. coli, it seems to play a role in response to amino acid starvation.
(AThTP) or thiaminylated adenosine triphosphate has recently been discovered in Escherichia coli
, where it accumulates as a result of carbon starvation. In E. coli, AThTP may account for up to 20% of total thiamine. It also exists in lesser amounts in yeast
, roots of higher plants and animal tissue.
(AThDP) or thiaminylated adenosine diphosphate exists in small amounts in vertebrate liver, but its role remains unknown.
Thiamine deficiency can lead to severe fatigue of eyes and myriad problems including neurodegeneration
, wasting, and death
. A lack of thiamine can be caused by malnutrition
, a diet high in thiaminase
-rich foods (raw freshwater fish, raw shellfish
, fern
s) and/or foods high in anti-thiamine factors (tea
, coffee
, betel nut
s) and by grossly impaired nutritional status associated with chronic diseases, such as alcoholism, gastrointestinal diseases, HIV-AIDS, and persistent vomiting. It is thought that many people with diabetes have a deficiency of thiamine and that this may be linked to some of the complications that can occur.
Well-known syndromes caused by thiamine deficiency include beriberi
and Wernicke-Korsakoff syndrome
, diseases also common with chronic alcoholism.
Following thiamine treatment, rapid improvement occurs, in general, within 24 hours. Improvements of peripheral neuropathy may require several months of thiamine treatment.
) and Korsakoff’s psychosis (alcohol amnestic disorder) as well as varying degrees of cognitive impairment.
Wernicke’s encephalopathy is the most frequently encountered manifestation of thiamine deficiency in Western society, though it may also occur in patients with impaired nutrition from other causes, such as gastrointestinal disease, those with HIV-AIDS, and with the injudicious administration of parenteral glucose or hyperalimentation without adequate B-vitamin supplementation. This is a striking neuro-psychiatric disorder characterized by paralysis of eye movements, abnormal stance and gait, and markedly deranged mental function.
Alcoholics may have thiamine deficiency because of the following:
Korsakoff Psychosis is, in general, considered to occur with deterioration of brain function in patients initially diagnosed with WE. This is an amnestic-confabulatory syndrome characterized by retrograde and anterograde amnesia, impairment of conceptual functions, and decreased spontaneity and initiative.<
Following improved nutrition and the removal of alcohol consumption, some impairments linked with thiamine deficiency are reversed, in particular poor brain functionality, although in more severe cases, Wernicke-Korsakoff syndrome leaves permanent damage. (See delirium tremens
.)
Mature chickens show signs 3 weeks after being fed a deficient diet. In young chicks, it can appear before 2 weeks of age.
Onset is sudden in young chicks. There is anorexia and an unsteady gait. Later on, there are locomotor signs, beginning with an apparent paralysis of the flexor of the toes. The characteristic position is called "stargazing", meaning a chick "sitting on its hocks and the head in opisthotonos".
Response to administration of the vitamin is rather quick, occurring a few hours later.
Differential diagnosis include riboflavin deficiency and avian encephalomyelitis. In riboflavin deficiency, the "curled toes" is a characteristic symptom. Muscle tremor is typical of avian encephalomyelitis. A therapeutic diagnosis
can be tried by supplementing thiamine only in the affected bird. If the animals do not respond in a few hours, thiamine deficiency can be excluded.
(PEM) is the most common thiamine deficiency disorder in young ruminant and nonruminant animals. Symptoms of PEM include a profuse, but transient, diarrhea, listlessness, circling movements, star gazing or opisthotonus (head drawn back over neck), and muscle tremors. The most common cause is high-carbohydrate feeds, leading to the overgrowth of thiaminase-producing bacteria, but dietary ingestion of thiaminase (e.g., in bracken
fern), or inhibition of thiamine absorption by high sulfur intake are also possible. Another cause of PEM is Clostridium sporogenes or Bacillus aneurinolyticus infection. These bacteria produce thiaminase
s that will cause an acute thiamine deficiency in the affected animal.
(Somateria mollissima). Researches noted, "Because the investigated species occupy a wide range of ecological niches and positions in the food web, we are open to the possibility that other animal classes may suffer from thiamine deficiency as well."p. 12006
A positive diagnosis test for thiamine deficiency can be ascertained by measuring the activity of the enzyme transketolase
in erythrocytes (Erythrocyte Transketolase Activation Assay). Thiamine, as well as its phosphate derivatives, can also be detected directly in whole blood, tissues, foods, animal feed, and pharmaceutical preparations following the conversion of thiamine to fluorescent thiochrome derivatives (Thiochrome Assay) and separation by high-performance liquid chromatography
(HPLC). In recent reports, a number of Capillary Electrophoresis (CE) techniques and in-capillary enzyme reaction methods have emerged as potential alternative techniques for the determination and monitoring of thiamine in samples.
and sensorineural deafness is an autosomal recessive disorder caused by mutations in the gene SLC19A2
, a high affinity thiamine transporter. TRMA patients do not show signs of systemic thiamine deficiency, suggesting redundancy in the thiamine transport system. This has led to the discovery of a second high-affinity thiamine transporter, SLC19A3
. Leigh disease (subacute necrotising encephalomyelopathy) is an inherited disorder that affects mostly infants in the first years of life and is invariably fatal. Pathological similarities between Leigh disease and WE led to the hypothesis that the cause was a defect in thiamine metabolism. One of the most consistent findings has been an abnormality of the activation of the pyruvate dehydrogenase
complex.
Other disorders in which a putative role for thiamine has been implicated include subacute necrotising encephalomyelopathy, opsoclonic cerebellopathy (a paraneoplastic syndrome), and Nigerian seasonal ataxia. In addition, several inherited disorders of ThDP-dependent enzymes have been reported, which may respond to thiamine treatment.
.
In 1884, Kanehiro Takaki
(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 diet on a navy ship, he discovered that substituting a diet of white rice only, with one also containing meat, milk, bread, and vegetables nearly eliminated beriberi on a 9-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. Nor was the Navy convinced for 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 brown barley rice, 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, 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 a nerve poison in the endosperm of rice, from which the outer layers of the grain gave protection to the body. 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. These compounds were named by Casimir Funk. In 1911, Casimir Funk isolated the antineuritic substance from rice bran that he called a "vitamine" (on account of its containing an amino group). 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 (“sulfur-containing vitamin”) was synthesized in 1936 by the same 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 animal will die after a few days. Administration of thiamine at the stage of opithotonos will lead to a complete cure of the animal within 30 min.
As no morphological modifications were observed in the brain of the pigeons before and after treatment with thiamine, Peeters introduced the concept of 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.
Finally, the mechanism by which the thiamine moiety of ThDP exerts its coenzyme function by proton substitution on position 2 of the thiazoliumring was elucidated by Ronald Breslow
in 1958.
(ThTP) and adenosine thiamine triphosphate
(AThTP) are thought to have non-cofactor roles, though at present it is not known to what extent they participate in the symptoms
from furfural
is catalyzed by thiamine through a relatively stable carbene
(an organic molecule containing unbonded valence electrons pairs at a carbon center). This reaction, studied in 1957 by R. Breslow
, was the first evidence for the existence of persistent carbene
s.
Vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...
of the B complex
B vitamins
B vitamins are a group of water-soluble vitamins that play important roles in cell metabolism. The B vitamins were once thought to be a single vitamin, referred to as vitamin B . Later research showed that they are chemically distinct vitamins that often coexist in the same foods...
. First named aneurin for the detrimental neurological effects if not present in the diet, it was eventually assigned the generic descriptor name vitamin B1. Its phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
derivatives are involved in many cellular processes. The best-characterized form is thiamine pyrophosphate
Thiamine pyrophosphate
Thiamine pyrophosphate , or thiamine diphosphate , is a thiamine derivative which is produced by the enzyme thiamine pyrophosphatase. Thiamine pyrophosphate is a coenzyme that is present in all living systems, in which it catalyzes several biochemical reactions...
(TPP), a coenzyme in the catabolism
Catabolism
Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, lipids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides, and amino...
of sugars and amino acids. Thiamine is used in the biosynthesis the neurotransmitter acetylcholine and gamma-aminobutyric acid (GABA). In yeast
Yeast
Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...
, TPP is also required in the first step of alcoholic fermentation.
All living organisms use thiamine in their biochemistry, but it is only synthesized in bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
, fungi, and plant
Plant
Plants are living organisms belonging to the kingdom Plantae. Precise definitions of the kingdom vary, but as the term is used here, plants include familiar organisms such as trees, flowers, herbs, bushes, grasses, vines, ferns, mosses, and green algae. The group is also called green plants or...
s. Animal
Animal
Animals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...
s must obtain it from their diet, and, thus, for them, it is a vitamin. Insufficient intake in birds produces a characteristic polyneuritis, and in mammals results in a disease called beriberi
Beriberi
Beriberi is a nervous system ailment caused by a thiamine deficiency in the diet. Thiamine is involved in the breakdown of energy molecules such as glucose and is also found on the membranes of neurons...
affecting the peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
(polyneuritis) and/or the cardiovascular system, with fatal outcome if not cured by thiamine administration. In less severe deficiency, nonspecific signs include malaise
Malaise
Malaise is a feeling of general discomfort or uneasiness, of being "out of sorts", often the first indication of an infection or other disease. Malaise is often defined in medicinal research as a "general feeling of being unwell"...
, weight loss, irritability and confusion.
There is still much research devoted to elucidating the exact mechanisms by which thiamine deficiency leads to the specific symptoms observed (see below). New thiamine phosphate derivatives have recently been discovered, emphasizing the complexity of thiamine metabolism.
Thiamine derivatives with improved pharmacokinetics have been discovered and are to be considered more effective in alleviating the symptoms of thiamine deficiency and other thiamine-related conditions such as impaired glucose metabolism
Carbohydrate metabolism
Carbohydrate metabolism denotes the various biochemical processes responsible for the formation, breakdown and interconversion of carbohydrates in living organisms....
in diabetes. These compounds include allithiamine
Allithiamine
Allithiamine , or thiamine allyl disulfide , is a lipid-soluble form of vitamin B1 which occurs naturally in garlic. It is more bioavailable than the water-soluble form of vitamin B1, thiamine, and is the preferred form to be taken in case of a vitamin deficiency....
, prosultiamine
Prosultiamine
Prosultiamine , also known as thiamine propyl disulfide , is a disulfide thiamine derivative developed in Japan in the 1950s as a treatment for vitamin B1 deficiency...
, fursultiamine
Fursultiamine
Fursultiamine , also known as thiamine tetrahydrofurfuryl disulfide , is a disulfide derivative of thiamine, or an allithiamine...
, benfotiamine
Benfotiamine
Benfotiamine is a synthetic S-acyl derivative of thiamine . After absorption, benfotiamine can be dephosphorylated by cells bearing an ecto-alkaline phosphatase to the lipid-soluble S-benzoylthiamine...
, and sulbutiamine
Sulbutiamine
Sulbutiamine is a synthetic derivative of thiamine . As a dimer of two modified thiamine molecules, it is a lipophilic compound that crosses the blood-brain barrier more readily than thiamine and increases the levels of thiamine and thiamine phosphate esters in the brain...
, among others.
Chemical properties
Thiamine is a colorless compoundChemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...
with a chemical formula
Chemical formula
A chemical formula or molecular formula is a way of expressing information about the atoms that constitute a particular chemical compound....
C
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...
12H
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
17N
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
4O
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
S
Sulfur
Sulfur or sulphur is the chemical element with atomic number 16. In the periodic table it is represented by the symbol S. It is an abundant, multivalent non-metal. Under normal conditions, sulfur atoms form cyclic octatomic molecules with chemical formula S8. Elemental sulfur is a bright yellow...
. Its structure contains a aminopyrimidine ring and a thiazole
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 formula C3H3NS...
ring with methyl and hydroxyethyl side chains linked by a methylene bridge. Thiamine is soluble in water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
, methanol
Methanol
Methanol, also known as methyl alcohol, wood alcohol, wood naphtha or wood spirits, is a chemical with the formula CH3OH . It is the simplest alcohol, and is a light, volatile, colorless, flammable liquid with a distinctive odor very similar to, but slightly sweeter than, ethanol...
, and glycerol
Glycerol
Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
and practically insoluble in acetone
Acetone
Acetone is the organic compound with the formula 2CO, a colorless, mobile, flammable liquid, the simplest example of the ketones.Acetone is miscible with water and serves as an important solvent in its own right, typically as the solvent of choice for cleaning purposes in the laboratory...
, ether
Ether
Ethers are a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...
, chloroform
Chloroform
Chloroform is an organic compound with formula CHCl3. It is one of the four chloromethanes. The colorless, sweet-smelling, dense liquid is a trihalomethane, and is considered somewhat hazardous...
, and benzene
Benzene
Benzene is an organic chemical compound. It is composed of 6 carbon atoms in a ring, with 1 hydrogen atom attached to each carbon atom, with the molecular formula C6H6....
. It is stable at acidic pH, but is unstable in alkaline solutions. Thiamine, which is a N-heterocyclic carbene, can be used in place of cyanide
Cyanide
A cyanide is a chemical compound that contains the cyano group, -C≡N, which consists of a carbon atom triple-bonded to a nitrogen atom. Cyanides most commonly refer to salts of the anion CN−. Most cyanides are highly toxic....
as a catalyst for benzoin condensation
Benzoin condensation
The benzoin condensation is a reaction between two aromatic aldehydes, particularly benzaldehyde. The reaction is catalyzed by a nucleophile such as the cyanide anion or an N-heterocyclic carbene. The reaction product is an aromatic acyloin with benzoin as the parent compound...
. 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
Maillard reaction
The Maillard reaction is a form of nonenzymatic browning similar to caramelization. It results from a chemical reaction between an amino acid and a reducing sugar, usually requiring heat....
.
Biosynthesis
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 formula C3H3NS...
and pyrimidine
Pyrimidine
Pyrimidine is a heterocyclic aromatic organic compound similar to benzene and pyridine, containing two nitrogen atoms at positions 1 and 3 of the six-member ring...
moieties are synthesized separately and then assembled to form ThMP by thiamine-phosphate synthase (EC 2.5.1.3). The exact biosynthetic pathways may differ among organisms. In E. coli and other enterobacteriaceae
Enterobacteriaceae
The Enterobacteriaceae is a large family of bacteria that includes many of the more familiar pathogens, such as Salmonella, Escherichia coli, Yersinia pestis, Klebsiella and Shigella. This family is the only representative in the order Enterobacteriales of the class Gammaproteobacteria in the...
ThMP may be phosphorylated to the cofactor
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
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, that may then be pyrophosphorylated to ThDP by thiamine diphosphokinase (thiamine + ATP → ThDP + AMP, EC 2.7.6.2).
The biosynthetic pathways are regulated by riboswitch
Riboswitch
In molecular biology, a riboswitch is a part of an mRNA molecule that can directly bind a small target molecule, and whose binding of the target affects the gene's activity. Thus, an mRNA that contains a riboswitch is directly involved in regulating its own activity, in response to the...
es in all organisms that synthesise thiamine. If there is sufficient thiamine present in the cell then the thiamine binds to the mRNA encoding genes required in the pathway, preventing the translation of the enzymes. 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 riboswitch identified in both eukaryotic and prokaryotic organisms.
Occurrence in foods
Thiamine is found in a wide variety of foods at low concentrations. Yeast, yeast extract (e.g., Marmite), and pork are the most highly concentrated sources of thiamine. In general, cereal grains are the most important dietary sources of thiamine, by virtue of their ubiquity. Of these, whole grains contain more thiamine than refined grains, as thiamine is found mostly in the outer layers of the grain and in the germ (which are removed during the refining process). For example, 100 g of whole-wheat flour contains 0.55 mg of thiamine, while 100 g of white flour contains only 0.06 mg of thiamine. In the US, processed flour must be enriched with thiamine mononitrate (along with niacin, ferrous iron, riboflavin, and folic acid) to replace that lost in processing. In Australia, thiamine, folic acid, and iodised salt are added for the same reason. A whole foodsWhole foods
Whole foods are foods that are unprocessed and unrefined, or processed and refined as little as possible, before being consumed. Whole foods typically do not contain added ingredients, such as salt, carbohydrates, or fat. Examples of whole foods include unpolished grains, beans, fruits, vegetables...
diet is therefore recommended for deficiency.
Some other foods rich in thiamine are oatmeal
Oatmeal
Oatmeal is ground oat groats , or a porridge made from oats . Oatmeal can also be ground oat, steel-cut oats, crushed oats, or rolled oats....
, flax
Flax
Flax is a member of the genus Linum in the family Linaceae. It is native to the region extending from the eastern Mediterranean to India and was probably first domesticated in the Fertile Crescent...
, and sunflower seeds, brown rice
Brown rice
Brown rice is unmilled or partly milled rice, a kind of whole, natural grain. It has a mild nutty flavor, is chewier and more nutritious than white rice, but goes rancid more quickly because the germ—which is removed to make white rice—contains fats that can spoil...
, whole grain rye
Rye
Rye is a grass grown extensively as a grain and as a forage crop. It is a member of the wheat tribe and is closely related to barley and wheat. Rye grain is used for flour, rye bread, rye beer, some whiskeys, some vodkas, and animal fodder...
, asparagus
Asparagus
Asparagus officinalis is a spring vegetable, a flowering perennialplant species in the genus Asparagus. It was once classified in the lily family, like its Allium cousins, onions and garlic, but the Liliaceae have been split and the onion-like plants are now in the family Amaryllidaceae and...
, kale
Kale
Kale is very high in beta carotene, vitamin K, vitamin C, lutein, zeaxanthin, and reasonably rich in calcium. Kale, as with broccoli and other brassicas, contains sulforaphane , a chemical with potent anti-cancer properties. Boiling decreases the level of sulforaphane; however, steaming,...
, cauliflower
Cauliflower
Cauliflower is one of several vegetables in the species Brassica oleracea, in the family Brassicaceae. It is an annual plant that reproduces by seed...
, potatoes, oranges
Orange (fruit)
An orange—specifically, the sweet orange—is the citrus Citrus × sinensis and its fruit. It is the most commonly grown tree fruit in the world....
, liver
Liver (food)
The liver of mammals, fowl, and fish are commonly eaten as food by humans. Domestic pig, ox, lamb, calf, chicken, and goose livers are widely available from butchers and supermarkets....
(beef, pork, and chicken), and eggs
Egg (food)
Eggs are laid by females of many different species, including birds, reptiles, amphibians, and fish, and have probably been eaten by mankind for millennia. Bird and reptile eggs consist of a protective eggshell, albumen , and vitellus , contained within various thin membranes...
.
Thiamine hydrochloride
Hydrochloride
In chemistry, hydrochlorides are salts resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base . This is also known as muriate, derived from hydrochloric acid's other name: muriatic acid....
(Betaxin) is a (when by itself) white, crystalline hygroscopic food-additive used to add a brothy/meaty flavor to gravies or soups. It is a natural intermediary resulting from a thiamine-HCl reaction, which precedes hydrolysis and phosphorylation, before it is finally employed (in the form of TPP) in a number of enzymatic amino, fatty acid, and carbohydrate reactions.
Reference Daily Intake and high doses
The RDAReference Daily Intake
The Reference Daily Intake or Recommended Daily Intake is the daily intake level of a nutrient that is considered to be sufficient to meet the requirements of 97–98% of healthy individuals in every demographic in the United States .The RDI is used to determine the Daily Value of foods,...
in most countries is set at about 1.4 mg. However, tests on female volunteers at daily doses of about 50 mg have claimed an increase in mental acuity. There are no reports available of adverse effects from consumption of excess thiamine by ingestion of food and supplements. Because the data is inadequate for a quantitative risk assessment, no Tolerable Upper Intake Level (UL) can be derived for thiamine.
Antagonists
Thiamine in foods can be degraded in a variety of ways. SulfiteSulfite
Sulfites are compounds that contain the sulfite ion SO. The sulfite ion is the conjugate base of bisulfite. Although the acid itself is elusive, its salts are widely used.-Structure:...
s, 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 thiaminase
Thiaminase
Thiaminase is an enzyme that metabolizes or breaks down thiamine into two molecular parts.The old name was "Aneurinase".There are two types: -Sources:Source include:* Bracken , Nardoo and other plants.* Some fish including carp and goldfish....
s (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
Caffeic acid
Caffeic acid is a hydroxycinnamic acid, a naturally occurring organic compound. This yellow solid consists of both phenolic and acrylic functional groups...
, chlorogenic acid
Chlorogenic acid
Chlorogenic acid is a hydroxycinnamic acid, a member of a family of naturally occurring organic compounds. These are esters of polyphenolic caffeic acid and cyclitol -quinic acid. It is an important biosynthetic intermediate. It also is one of the phenols found in coffee, bamboo Phyllostachys...
, and tannic acid
Tannic acid
Tannic acid is a specific commercial form of tannin, a type of polyphenol. Its weak acidity is due to the numerous phenol groups in the structure...
. These compounds interact with the thiamine to oxidize the thiazole ring, thus rendering it unable to be absorbed. Two flavonoids, quercetin
Quercetin
Quercetin , a flavonol, is a plant-derived flavonoid found in fruits, vegetables, leaves and grains. It also may be used as an ingredient in supplements, beverages or foods.-Occurrence:...
and rutin
Rutin
Rutin, also called rutoside, quercetin-3-O-rutinoside and sophorin, is a citrus flavonoid glycoside found in buckwheat, the leaves and petioles of Rheum species, and asparagus...
, have also been implicated as thiamine antagonists.
Absorption
Thiamine is released by the action of phosphatase and pyrophosphatase in the upper small intestine. At low concentrations, the process is carrier-mediated, and, at higher concentrations, absorption occurs via passive diffusion. Active transport is greatest in the jejunum and ileum (it is inhibited by alcohol consumption and by folic deficiency). Decline in thiamine absorption occurs at intakes above 5 mg. The cells of the intestinal mucosa have thiamine pyrophosphokinase activity, but it is unclear as to whether the enzyme is linked to active absorption. The majority of thiamine present in the intestine is in the pyrophosphorylated form ThDP, but when thiamine arrives on the serosal side of the intestine it is often in the free form. The uptake of thiamine by the mucosal cell is likely coupled in some way to its phosphorylation/dephosphorylation. On the serosal side of the intestine, evidence has shown that discharge of the vitamin by those cells is dependent on Na+-dependent ATPase.Bound to serum proteins
The majority of thiamine in serumBlood serum
In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...
is bound to proteins, mainly albumin
Albumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
. 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. The brain requires a much greater amount of thiamine than in other cells of the body. Much of ingested thiamine never reaches the brain because of passive diffusion and the blood brain barrier. About 80% of intracellular thiamine is phosphorylated and most is bound to proteins. 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 fluids. Unlike the highly phosphorylated forms of thiamine, ThMP and free thiamine are capable of crossing cell membranes. 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.Thiamine phosphate derivatives and function
Thiamine is mainly the transport form of the vitamin, while the active forms are phosphorylated thiamine derivatives. There are five known natural thiamine phosphate derivatives: thiamine monophosphateThiamine monophosphate
Thiamine monophosphate is a thiamine derivative....
(ThMP), thiamine diphosphate (ThDP), also sometimes called thiamine pyrophosphate
Thiamine pyrophosphate
Thiamine pyrophosphate , or thiamine diphosphate , is a thiamine derivative which is produced by the enzyme thiamine pyrophosphatase. Thiamine pyrophosphate is a coenzyme that is present in all living systems, in which it catalyzes several biochemical reactions...
(TPP), thiamine triphosphate
Thiamine triphosphate
Thiamine triphosphate is found in most organisms, bacteria, fungi, plants and animals.-Function:It has been proposed that ThTP has a specific role in nerve excitability but this has never been confirmed and recent results suggest that ThTP probably plays a role in cell energy metabolism...
(ThTP), and the recently discovered adenosine thiamine triphosphate
Adenosine thiamine triphosphate
Adenosine thiamine triphosphate , or thiaminylated adenosine triphosphate, is a natural thiamine adenine nucleotide. It was discovered in Escherichia coli where it may account for up to 15 - 20 % of total thiamine under carbon starvation...
(AThTP), and adenosine thiamine diphosphate
Adenosine thiamine diphosphate
Adenosine thiamine diphosphate , or thiaminylated adenosine diphosphate is a natural thiamine adenine nucleotide. It was chemically synthesized and exists in small amounts in vertebrate liver. Its biological significance remains unknown....
(AThDP).
Thiamine diphosphate
The synthesis of thiamine diphosphate (ThDP), also known as thiamine pyrophosphate (TPP) or cocarboxylase, is catalyzed by an enzyme called thiamine diphosphokinaseThiamine diphosphokinase
In enzymology, a thiamine diphosphokinase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are ATP and thiamine, whereas its two products are AMP and thiamine diphosphate....
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
Dehydrogenation
Dehydrogenation is a chemical reaction that involves the elimination of hydrogen . It is the reverse process of hydrogenation. Dehydrogenation reactions may be either large scale industrial processes or smaller scale laboratory procedures....
(decarboxylation
Decarboxylation
Decarboxylation is a chemical reaction that releases carbon dioxide . Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is the first chemical step in photosynthesis, is called carbonation, the addition of CO2 to...
and subsequent conjugation with coenzyme A
Coenzyme A
Coenzyme A 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 sequenced genomes encode enzymes that use coenzyme A as a substrate, and around 4% of cellular enzymes use it as a substrate...
) of 2-oxoacids (alpha-keto acids). Examples include:
- Present in most species
- pyruvate dehydrogenasePyruvate dehydrogenasePyruvate dehydrogenase complex is a complex of three enzymes that transform pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, and this complex links the glycolysis metabolic pathway to the...
and 2-oxoglutarate dehydrogenaseOxoglutarate dehydrogenaseThe oxoglutarate dehydrogenase complex or α-ketoglutarate dehydrogenase complex is an enzyme complex, most commonly known for its role in the citric acid cycle.-Units:...
(also called α-ketoglutarate dehydrogenase) - branched-chain α-keto acid dehydrogenase
- 2-hydroxyphytanoyl-CoA lyase2-hydroxyphytanoyl-CoA lyase2-Hydroxyphytanoyl-CoA lyase is a peroxisomal enzyme involved in the catabolism of phytanoic acid by α-oxidation. It requires thiamine diphosphate as cofactor.It is classified under EC number 4.1.400px...
- transketolaseTransketolaseTransketolase, an enzyme of both the pentose phosphate pathway in animals and the Calvin cycle of photosynthesis, catalyzes two important reactions, which operate in opposite directions in these two pathways...
- pyruvate dehydrogenase
- Present in some species:
- pyruvate decarboxylasePyruvate decarboxylaseNot to be confused with pyruvate dehydrogenase, the enzyme which catalyses the link reaction.Pyruvate decarboxylase is a homotetrameric enzyme that catalyses the decarboxylation of pyruvic acid to acetaldehyde and carbon dioxide in the cytoplasm. It is also called 2-oxo-acid carboxylase,...
(in yeastYeastYeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...
) - several additional bacteriaBacteriaBacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
l enzymes
- pyruvate decarboxylase
The enzymes transketolase
Transketolase
Transketolase, an enzyme of both the pentose phosphate pathway in animals and the Calvin cycle of photosynthesis, catalyzes two important reactions, which operate in opposite directions in these two pathways...
, pyruvate dehydrogenase
Pyruvate dehydrogenase
Pyruvate dehydrogenase complex is a complex of three enzymes that transform pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, and this complex links the glycolysis metabolic pathway to the...
(PDH), and 2-oxoglutarate dehydrogenase
Oxoglutarate dehydrogenase
The oxoglutarate dehydrogenase complex or α-ketoglutarate dehydrogenase complex is an enzyme complex, most commonly known for its role in the citric acid cycle.-Units:...
(OGDH) are all important in carbohydrate metabolism
Carbohydrate metabolism
Carbohydrate metabolism denotes the various biochemical processes responsible for the formation, breakdown and interconversion of carbohydrates in living organisms....
. The cytosolic enzyme transketolase is a key player in the pentose phosphate pathway
Pentose phosphate pathway
The pentose phosphate pathway is a process that generates NADPH and pentoses . There are two distinct phases in the pathway. The first is the oxidative phase, in which NADPH is generated, and the second is the non-oxidative synthesis of 5-carbon sugars...
, a major route for the biosynthesis of the pentose sugar
Sugar
Sugar is a class of edible crystalline carbohydrates, mainly sucrose, lactose, and fructose, characterized by a sweet flavor.Sucrose in its refined form primarily comes from sugar cane and sugar beet...
s deoxyribose
Deoxyribose
Deoxyribose, more, precisely 2-deoxyribose, is a monosaccharide with idealized formula H---3-H. Its name indicates that it is a deoxy sugar, meaning that it is derived from the sugar ribose by loss of an oxygen atom...
and ribose
Ribose
Ribose is an organic compound with the formula C5H10O5; specifically, a monosaccharide with linear form H––4–H, which has all the hydroxyl groups on the same side in the Fischer projection....
. The mitochondrial PDH and OGDH are part of biochemical pathways that result in the generation of adenosine triphosphate
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
(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-limting step in the citric acid cycle
Citric acid cycle
The citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...
. In the nervous system, PDH is also involved in the production of acetylcholine, a neurotransmitter, and for myelin synthesis.
Thiamine triphosphate
Thiamine triphosphateThiamine triphosphate
Thiamine triphosphate is found in most organisms, bacteria, fungi, plants and animals.-Function:It has been proposed that ThTP has a specific role in nerve excitability but this has never been confirmed and recent results suggest that ThTP probably plays a role in cell energy metabolism...
(ThTP) was long considered a specific neuroactive form of thiamine. However, recently it was shown that ThTP exists in bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
, fungi, plant
Plant
Plants are living organisms belonging to the kingdom Plantae. Precise definitions of the kingdom vary, but as the term is used here, plants include familiar organisms such as trees, flowers, herbs, bushes, grasses, vines, ferns, mosses, and green algae. The group is also called green plants or...
s and animal
Animal
Animals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...
s 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 triphosphateAdenosine thiamine triphosphate
Adenosine thiamine triphosphate , or thiaminylated adenosine triphosphate, is a natural thiamine adenine nucleotide. It was discovered in Escherichia coli where it may account for up to 15 - 20 % of total thiamine under carbon starvation...
(AThTP) or thiaminylated adenosine triphosphate has recently been discovered in Escherichia coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
, where it accumulates as a result of carbon starvation. In E. coli, AThTP may account for up to 20% of total thiamine. It also exists in lesser amounts in yeast
Yeast
Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...
, roots of higher plants and animal tissue.
Adenosine thiamine diphosphate
Adenosine thiamine diphosphateAdenosine thiamine diphosphate
Adenosine thiamine diphosphate , or thiaminylated adenosine diphosphate is a natural thiamine adenine nucleotide. It was chemically synthesized and exists in small amounts in vertebrate liver. Its biological significance remains unknown....
(AThDP) or thiaminylated adenosine diphosphate exists in small amounts in vertebrate liver, but its role remains unknown.
Deficiency
Thiamine derivatives and thiamine-dependent enzymes are present in all cells of the body, thus a thiamine deficiency would seem to adversely affect all of the organ systems. However, the nervous system and the heart are particularly sensitive to thiamine deficiency, because of their high oxidative metabolism.Thiamine deficiency can lead to severe fatigue of eyes and myriad problems including neurodegeneration
Neurodegeneration
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...
, wasting, and death
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
. A lack of thiamine can be caused by malnutrition
Malnutrition
Malnutrition is the condition that results from taking an unbalanced diet in which certain nutrients are lacking, in excess , or in the wrong proportions....
, a diet high in thiaminase
Thiaminase
Thiaminase is an enzyme that metabolizes or breaks down thiamine into two molecular parts.The old name was "Aneurinase".There are two types: -Sources:Source include:* Bracken , Nardoo and other plants.* Some fish including carp and goldfish....
-rich foods (raw freshwater fish, raw shellfish
Shellfish
Shellfish is a culinary and fisheries term for exoskeleton-bearing aquatic invertebrates used as food, including various species of molluscs, crustaceans, and echinoderms. Although most kinds of shellfish are harvested from saltwater environments, some kinds are found only in freshwater...
, fern
Fern
A fern is any one of a group of about 12,000 species of plants belonging to the botanical group known as Pteridophyta. Unlike mosses, they have xylem and phloem . They have stems, leaves, and roots like other vascular plants...
s) and/or foods high in anti-thiamine factors (tea
Tea
Tea is an aromatic beverage prepared by adding cured leaves of the Camellia sinensis plant to hot water. The term also refers to the plant itself. After water, tea is the most widely consumed beverage in the world...
, coffee
Coffee
Coffee is a brewed beverage with a dark,init brooo acidic flavor prepared from the roasted seeds of the coffee plant, colloquially called coffee beans. The beans are found in coffee cherries, which grow on trees cultivated in over 70 countries, primarily in equatorial Latin America, Southeast Asia,...
, betel nut
Betel nut
The Areca nut is the seed of the Areca palm , which grows in much of the tropical Pacific, Asia, and parts of east Africa. It is commonly referred to as "betel nut" as it is often chewed wrapped in betel leaves.-Description:...
s) and by grossly impaired nutritional status associated with chronic diseases, such as alcoholism, gastrointestinal diseases, HIV-AIDS, and persistent vomiting. It is thought that many people with diabetes have a deficiency of thiamine and that this may be linked to some of the complications that can occur.
Well-known syndromes caused by thiamine deficiency include beriberi
Beriberi
Beriberi is a nervous system ailment caused by a thiamine deficiency in the diet. Thiamine is involved in the breakdown of energy molecules such as glucose and is also found on the membranes of neurons...
and Wernicke-Korsakoff syndrome
Wernicke-Korsakoff syndrome
Wernicke–Korsakoff syndrome is a manifestation of thiamine deficiency, or beriberi. This is usually secondary to alcohol abuse...
, diseases also common with chronic alcoholism.
Beriberi
Beriberi is a neurological and cardiovascular disease. The three major forms of the disorder are dry beriberi, wet beriberi, and infantile beriberi.- Dry beriberi is characterized principally by peripheral neuropathy consisting of symmetric impairment of sensory, motor, and reflex functions affecting distal more than proximal limb segments and causing calf muscle tenderness.
- Wet beriberi is associated with mental confusion, muscular atrophy, edemaEdemaEdema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
, tachycardiaTachycardiaTachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, cardiomegalyCardiomegalyCardiomegaly is a medical condition wherein the heart is enlarged. It is generally categorized in the following manner:* Cardiomegaly due to dilation* Cardiomegaly due to ventricular hypertrophy** Left ventricular hypertrophy...
, and congestive heart failure in addition to peripheral neuropathy. - Infantile beriberi occurs in infants breast-fed by thiamin-deficient mothers (who may show no sign of thiamine deficiency). Infants may manifest cardiac, aphonic, or pseudomeningitic forms of the disorder. Infants with cardiac beriberi frequently exhibit a loud piercing cry, vomiting, and tachycardia. Convulsions are not uncommon, and death may ensue if thiamine is not administered promptly.
Following thiamine treatment, rapid improvement occurs, in general, within 24 hours. Improvements of peripheral neuropathy may require several months of thiamine treatment.
Alcoholic brain disease
Nerve cells and other supporting cells (such as glial cells) of the nervous system require thiamine. Examples of neurologic disorders that are linked to alcohol abuse include Wernicke’s encephalopathy (WE, Wernicke-Korsakoff syndromeWernicke-Korsakoff syndrome
Wernicke–Korsakoff syndrome is a manifestation of thiamine deficiency, or beriberi. This is usually secondary to alcohol abuse...
) and Korsakoff’s psychosis (alcohol amnestic disorder) as well as varying degrees of cognitive impairment.
Wernicke’s encephalopathy is the most frequently encountered manifestation of thiamine deficiency in Western society, though it may also occur in patients with impaired nutrition from other causes, such as gastrointestinal disease, those with HIV-AIDS, and with the injudicious administration of parenteral glucose or hyperalimentation without adequate B-vitamin supplementation. This is a striking neuro-psychiatric disorder characterized by paralysis of eye movements, abnormal stance and gait, and markedly deranged mental function.
Alcoholics may have thiamine deficiency because of the following:
- Inadequate nutritional intake: Alcoholics tend to intake less than the recommended amount of thiamine.
- Decreased uptake of thiamine from the GI tract: Active transport of thiamine into enterocytes is disturbed during acute alcohol exposure.
- Liver thiamine stores are reduced due to hepatic steatosis or fibrosis.
- Impaired thiamine utilization: Magnesium, which is required for the binding of thiamine to thiamine-using enzymes within the cell, is also deficient due to chronic alcohol consumption. The inefficient utilization of any thiamine that does reach the cells will further exacerbate the thiamine deficiency.
- Ethanol per se inhibits thiamine transport in the gastrointestinal system and blocks phosphorylation of thiamine to its cofactor form (ThDP).
Korsakoff Psychosis is, in general, considered to occur with deterioration of brain function in patients initially diagnosed with WE. This is an amnestic-confabulatory syndrome characterized by retrograde and anterograde amnesia, impairment of conceptual functions, and decreased spontaneity and initiative.<
Following improved nutrition and the removal of alcohol consumption, some impairments linked with thiamine deficiency are reversed, in particular poor brain functionality, although in more severe cases, Wernicke-Korsakoff syndrome leaves permanent damage. (See delirium tremens
Delirium tremens
Delirium tremens is an acute episode of delirium that is usually caused by withdrawal from alcohol, first described in 1813...
.)
Thiamine deficiency in poultry
As most feedstuffs used in poultry diets contain enough quantities of vitamins to meet the requirements in this species, deficiencies in this vitamin do not occur with commercial diets. This was, at least, the opinion in the 1960s.Mature chickens show signs 3 weeks after being fed a deficient diet. In young chicks, it can appear before 2 weeks of age.
Onset is sudden in young chicks. There is anorexia and an unsteady gait. Later on, there are locomotor signs, beginning with an apparent paralysis of the flexor of the toes. The characteristic position is called "stargazing", meaning a chick "sitting on its hocks and the head in opisthotonos".
Response to administration of the vitamin is rather quick, occurring a few hours later.
Differential diagnosis include riboflavin deficiency and avian encephalomyelitis. In riboflavin deficiency, the "curled toes" is a characteristic symptom. Muscle tremor is typical of avian encephalomyelitis. A therapeutic diagnosis
Medical diagnosis
Medical diagnosis refers both to the process of attempting to determine or identify a possible disease or disorder , and to the opinion reached by this process...
can be tried by supplementing thiamine only in the affected bird. If the animals do not respond in a few hours, thiamine deficiency can be excluded.
Thiamine deficiency in ruminants
PolioencephalomalaciaPolioencephalomalacia
Polioencephalomalacia literally means softening of the cerebrocortical grey matter distributed in a laminar pattern. It is also called laminar cortical necrosis or cortical necrosis. PEM is a sporadic disease of unknown cause occurring in cattle, sheep and goats. PEM is most commonly seen in...
(PEM) is the most common thiamine deficiency disorder in young ruminant and nonruminant animals. Symptoms of PEM include a profuse, but transient, diarrhea, listlessness, circling movements, star gazing or opisthotonus (head drawn back over neck), and muscle tremors. The most common cause is high-carbohydrate feeds, leading to the overgrowth of thiaminase-producing bacteria, but dietary ingestion of thiaminase (e.g., in bracken
Bracken
Bracken are several species of large, coarse ferns of the genus Pteridium. Ferns are vascular plants that have alternating generations, large plants that produce spores and small plants that produce sex cells . Brackens are in the family Dennstaedtiaceae, which are noted for their large, highly...
fern), or inhibition of thiamine absorption by high sulfur intake are also possible. Another cause of PEM is Clostridium sporogenes or Bacillus aneurinolyticus infection. These bacteria produce thiaminase
Thiaminase
Thiaminase is an enzyme that metabolizes or breaks down thiamine into two molecular parts.The old name was "Aneurinase".There are two types: -Sources:Source include:* Bracken , Nardoo and other plants.* Some fish including carp and goldfish....
s that will cause an acute thiamine deficiency in the affected animal.
Idiopathic paralytic disease in wild birds
Recently, thiamine deficiency has been identified as the cause of a paralytic disease affecting wild birds in the Baltic Sea area dating back to 1982. In this condition, there is difficulty in keeping the wings folded along the side of the body when resting, loss of the ability to fly and voice, with eventual paralysis of the wings and legs and death. It affects primarily 0.5–1 kg sized birds such as the herring gull (Larus argentatus), Common Starling (Sturnus vulgaris) and Common EiderCommon Eider
The Common Eider, Somateria mollissima, is a large sea-duck that is distributed over the northern coasts of Europe, North America and eastern Siberia. It breeds in Arctic and some northern temperate regions, but winters somewhat farther south in temperate zones, when it can form large flocks on...
(Somateria mollissima). Researches noted, "Because the investigated species occupy a wide range of ecological niches and positions in the food web, we are open to the possibility that other animal classes may suffer from thiamine deficiency as well."p. 12006
Analysis and diagnostic testing
Transketolase
Transketolase, an enzyme of both the pentose phosphate pathway in animals and the Calvin cycle of photosynthesis, catalyzes two important reactions, which operate in opposite directions in these two pathways...
in erythrocytes (Erythrocyte Transketolase Activation Assay). Thiamine, as well as its phosphate derivatives, can also be detected directly in whole blood, tissues, foods, animal feed, and pharmaceutical preparations following the conversion of thiamine to fluorescent thiochrome derivatives (Thiochrome Assay) and separation by high-performance liquid chromatography
High-performance liquid chromatography
High-performance liquid chromatography , HPLC, is a chromatographic technique that can separate a mixture of compounds and is used in biochemistry and analytical chemistry to identify, quantify and purify the individual components of the mixture.HPLC typically utilizes different types of stationary...
(HPLC). In recent reports, a number of Capillary Electrophoresis (CE) techniques and in-capillary enzyme reaction methods have emerged as potential alternative techniques for the determination and monitoring of thiamine in samples.
Genetic diseases
Genetic diseases of thiamine transport are rare but serious. Thiamine responsive megaloblastic anemia (TRMA) with diabetes mellitusDiabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
and sensorineural deafness is an autosomal recessive disorder caused by mutations in the gene SLC19A2
SLC19A2
Thiamine transporter 1, also known as thiamine carrier 1 or solute carrier family 19 member 2 is a protein that in humans is encoded by the SLC19A2 gene...
, a high affinity thiamine transporter. TRMA patients do not show signs of systemic thiamine deficiency, suggesting redundancy in the thiamine transport system. This has led to the discovery of a second high-affinity thiamine transporter, SLC19A3
SLC19A3
Thiamine transporter 2 , also known as solute carrier family 19 member 3, is a protein that in humans is encoded by the SLC19A3 gene...
. Leigh disease (subacute necrotising encephalomyelopathy) is an inherited disorder that affects mostly infants in the first years of life and is invariably fatal. Pathological similarities between Leigh disease and WE led to the hypothesis that the cause was a defect in thiamine metabolism. One of the most consistent findings has been an abnormality of the activation of the pyruvate dehydrogenase
Pyruvate dehydrogenase
Pyruvate dehydrogenase complex is a complex of three enzymes that transform pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, and this complex links the glycolysis metabolic pathway to the...
complex.
Other disorders in which a putative role for thiamine has been implicated include subacute necrotising encephalomyelopathy, opsoclonic cerebellopathy (a paraneoplastic syndrome), and Nigerian seasonal ataxia. In addition, several inherited disorders of ThDP-dependent enzymes have been reported, which may respond to thiamine treatment.
History
Thiamine was the first of the water-soluble vitamins to be described, leading to the discovery of more such trace compounds essential for survival and to the notion of vitaminVitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...
.
In 1884, Kanehiro Takaki
Kanehiro Takaki
Baron was a Japanese naval physician.-Early life:Born in Hyūga Province 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 Boshin War. He later studied western medical science under British doctor William Willis...
(1849–1920), a surgeon general in the Japanese navy
Imperial Japanese Navy
The Imperial Japanese Navy was the navy of the Empire of Japan from 1869 until 1947, when it was dissolved following Japan's constitutional renunciation of the use of force as a means of settling international disputes...
, rejected the previous germ theory for beriberi and hypothesized that the disease was due to insufficiencies in the diet instead. Switching diet on a navy ship, he discovered that substituting a diet of white rice only, with one also containing meat, milk, bread, and vegetables nearly eliminated beriberi on a 9-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. Nor was the Navy convinced for the need for so expensive a program of dietary improvement, and many men continued to die of beriberi, even during the Russo-Japanese war
Russo-Japanese War
The Russo-Japanese War was "the first great war of the 20th century." It grew out of rival imperial ambitions of the Russian Empire and Japanese Empire over Manchuria and Korea...
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 brown barley rice, 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
Christiaan Eijkman
Christiaan Eijkman was a Dutch physician and professor of physiology whose demonstration that beriberi is caused by poor diet led to the discovery of vitamins...
(1858–1930), a military doctor in the Dutch Indies, 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 a nerve poison in the endosperm of rice, from which the outer layers of the grain gave protection to the body. 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. These compounds were named by Casimir Funk. In 1911, Casimir Funk isolated the antineuritic substance from rice bran that he called a "vitamine" (on account of its containing an amino group). Dutch chemists, Barend Coenraad Petrus Jansen
Barend Coenraad Petrus Jansen
B. C. P. Jansen was a Dutch chemist and biochemist. In the Dutch Indies, with his colleague W. F. Donath, he isolated in crystalline form an anti-beriberi factor from rice polishings and christinaed it thiamine . It was the first vitamine to be obtained in pure form.-References:*Rudolph A...
(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 (“sulfur-containing vitamin”) was synthesized in 1936 by the same group.
Thiamine was first named "aneurin" (for anti-neuritic vitamin). Sir Rudolph Peters
Rudolph Peters
Sir Rudolph Albert Peters was a British biochemist. He was elected a Fellow of the Royal Society in 1935. His effort investigating the mechanism of arsenic war gases was deemed crucial in maintaining battlefield effectiveness facing the threat of lewisite attacks...
, 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 animal will die after a few days. Administration of thiamine at the stage of opithotonos will lead to a complete cure of the animal within 30 min.
As no morphological modifications were observed in the brain of the pigeons before and after treatment with thiamine, Peeters introduced the concept of 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
Pyruvate dehydrogenase
Pyruvate dehydrogenase complex is a complex of three enzymes that transform pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, and this complex links the glycolysis metabolic pathway to the...
), 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.
Finally, the mechanism by which the thiamine moiety of ThDP exerts its coenzyme function by proton substitution on position 2 of the thiazoliumring was elucidated by Ronald Breslow
Ronald Breslow
Ronald C. D. Breslow is an American chemist from Rahway, New Jersey. He is currently University Professor at Columbia University, where he is based in the Department of Chemistry and affiliated with the Departments of Biological Sciences and Pharmacology; he has also been on the faculty of its...
in 1958.
Research
Research in the field mainly concerns the mechanisms by which thiamine deficiency leads to neuronal death in relation to Wernicke Korsakoff Psychosis. Another important field concerns the understanding of the molecular mechanisms involved in ThDP catalysis. More recently, research has been devoted to the understanding of the possible non-cofactor roles of other derivatives such as ThTP and AThTP.Understanding the mechanism by which thiamine deficiency leads to selective neuronal death
Experimentally induced beriberi polyneuropathy in chickens may be a good model for studying these forms of neuropathy in view of diagnosis and treatment. From studies using rat models, a link between thiamine deficiency and colon carcinogenesis was suggested. Rat model is used also in research of Wernicke's encephalopathy. Thiamine deprived mice are a classic model of systemic oxidative stress, used in research of Alzheimer’s disease.Catalytic mechanisms in thiamine diphosphate-dependent enzymes
A lot of work is devoted to the understanding of the interplay between ThDP and ThDP-dependent enzymes in catalysis.Non-cofactor roles of thiamine derivatives
Thiamine compounds other than ThDP exist in most cells from many organisms, including bacteria, fungi, plants and animals. Among those compounds are thiamine triphosphateThiamine triphosphate
Thiamine triphosphate is found in most organisms, bacteria, fungi, plants and animals.-Function:It has been proposed that ThTP has a specific role in nerve excitability but this has never been confirmed and recent results suggest that ThTP probably plays a role in cell energy metabolism...
(ThTP) and adenosine thiamine triphosphate
Adenosine thiamine triphosphate
Adenosine thiamine triphosphate , or thiaminylated adenosine triphosphate, is a natural thiamine adenine nucleotide. It was discovered in Escherichia coli where it may account for up to 15 - 20 % of total thiamine under carbon starvation...
(AThTP) are thought to have non-cofactor roles, though at present it is not known to what extent they participate in the symptoms
Persistent carbenes
The production of furoinFuroin
Furoin or 1,2-di-2-hydroxyethanone is an organic compound with formula C10H8O4. It can be produced from furfural by the catalytic action of cyanide ions.-Reactions:...
from furfural
Furfural
Furfural is an organic compound derived from a variety of agricultural byproducts, including corncobs, oat, wheat bran, and sawdust. The name furfural comes from the Latin word , meaning bran, referring to its usual source....
is catalyzed by thiamine through a relatively stable carbene
Carbene
In chemistry, a carbene is a molecule containing a neutral carbon atom with a valence of two and two unshared valence electrons. The general formula is RR'C:, but the carbon can instead be double-bonded to one group. The term "carbene" may also merely refer to the compound H2C:, also called...
(an organic molecule containing unbonded valence electrons pairs at a carbon center). This reaction, studied in 1957 by R. Breslow
Ronald Breslow
Ronald C. D. Breslow is an American chemist from Rahway, New Jersey. He is currently University Professor at Columbia University, where he is based in the Department of Chemistry and affiliated with the Departments of Biological Sciences and Pharmacology; he has also been on the faculty of its...
, was the first evidence for the existence of persistent carbene
Persistent carbene
A persistent carbene is a type of carbene demonstrating particular stability. The best-known examples are diaminocarbenes with the general formula 2C:, where the 'R's are various functional groups...
s.