Thiamine


Thiamine, also known as thiamin and vitamin B1, is a vitamin - an essential micronutrient for humans and animals. It is found in food and commercially synthesized to be a dietary supplement or medication. Phosphorylated forms of thiamine are required for some metabolic reactions, including the breakdown of glucose and amino acids.
Food sources of thiamine include whole grains, legumes, and some meats and fish. Grain processing removes much of the vitamin content, so in many countries cereals and flours are enriched with thiamine. Supplements and medications are available to treat and prevent thiamine deficiency and the disorders that result from it such as beriberi and Wernicke encephalopathy. They are also used to treat maple syrup urine disease and Leigh syndrome. Supplements and medications 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 on the World Health Organization's List of Essential Medicines. It is available as a generic medication, and in some countries as a non-prescription dietary supplement. In 2023, it was the 305th most commonly prescribed medication in the United States, with more than 300,000 prescriptions.

Definition

Thiamine is one of the B vitamins and is also known as vitamin B1. It is a cation that is usually supplied as a chloride salt. It is soluble in water, methanol and glycerol, but practically insoluble in less polar organic solvents. In the body, thiamine can form derivatives; the most well-characterized of which is thiamine pyrophosphate, a coenzyme in the catabolism of sugars and amino acids.
The chemical 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 stable at acidic pH, but it is unstable in alkaline solutions and from exposure to heat. It reacts strongly in Maillard-type reactions. Oxidation yields the fluorescent derivative thiochrome, which can be used to determine the amount of the vitamin present in biological samples.

Deficiency

Well-known disorders caused by thiamine deficiency include beriberi, Wernicke–Korsakoff syndrome, optic neuropathy, Leigh's disease, African seasonal ataxia, and central pontine myelinolysis. Symptoms include malaise, weight loss, irritability and confusion.
In Western countries, chronic alcoholism is a risk factor for deficiency. Also at risk are older adults, persons with HIV/AIDS or diabetes, and those who have had bariatric surgery. Varying degrees of thiamine insufficiency have been associated with the long-term use of diuretics.

Biological functions

Five natural thiamine phosphate derivatives are known: thiamine monophosphate, thiamine pyrophosphate, thiamine triphosphate, adenosine thiamine diphosphate and adenosine thiamine triphosphate. They are involved in many cellular processes. The best-characterized form is TPP, a coenzyme in the catabolism of sugars and amino acids. While its role is well-known, the non-coenzyme action of thiamine and derivatives may be realized through binding to proteins which do not use that mechanism. No physiological role is known for the monophosphate except as an intermediate in cellular conversion of thiamine to the di- and triphosphates.

Thiamine pyrophosphate



Thiamine pyrophosphate, also called thiamine diphosphate, participates as a coenzyme in metabolic reactions, including those in which polarity inversion takes place. Its synthesis is catalyzed by the enzyme thiamine diphosphokinase according to the reaction thiamine + ATP → TPP + AMP. However, recent findings reveal that uridine 5′-triphosphate, rather than ATP, is the preferred substrate for TPP synthesis in cells, with TPK1 showing a ~10-fold higher affinity for UTP. TPP is a coenzyme for several enzymes that catalyze the transfer of two-carbon units and in particular the dehydrogenation of 2-oxoacids. The mechanism of action of TPP as a coenzyme relies on its ability to form an ylide. Examples include:
The enzymes transketolase, pyruvate dehydrogenase, and 2-oxoglutarate dehydrogenase are important in carbohydrate metabolism. PDH links glycolysis to the citric acid cycle. OGDH catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO2 during the citric acid cycle. The reaction catalyzed by OGDH is a rate-limiting step in the citric acid cycle. The cytosolic enzyme transketolase is central to the pentose phosphate pathway, a major route for the biosynthesis of the pentose sugars deoxyribose and ribose. The mitochondrial PDH and OGDH are part of biochemical pathways that result in the generation of adenosine triphosphate, which is the main energy transfer molecule for the cell. In the nervous system, PDH is also involved in the synthesis of myelin and the neurotransmitter acetylcholine.

Thiamine triphosphate

ThTP is implicated in chloride channel activation in the neurons of mammals and other animals, although its role is not well understood. ThTP has been found in bacteria, fungi and plants, suggesting that it has other cellular roles. In Escherichia coli, it is implicated in the response to amino acid starvation.

Adenosine derivatives



AThDP exists in small amounts in vertebrate liver, but its role remains unknown.
AThTP is present in E. coli, where it accumulates as a result of carbon starvation. In this bacterium, AThTP may account for up to of total thiamine. It also exists in lesser amounts in yeast, roots of higher plants and animal tissue.

Medical uses

During pregnancy, thiamine is sent to the fetus via the placenta. Pregnant women have a greater requirement for the vitamin than other adults, especially during the third trimester. Pregnant women with hyperemesis gravidarum are at an increased risk of thiamine deficiency due to losses when vomiting. In lactating women, thiamine is delivered in breast milk even if it results in thiamine deficiency in the mother.
Thiamine is important not only for mitochondrial membrane development, but also for synaptic membrane function. It has also been suggested that a deficiency hinders brain development in infants and may be a cause of sudden infant death syndrome.

Dietary recommendations

The US National Academy of Medicine updated the Estimated Average Requirements and Recommended Dietary Allowances for thiamine in 1998. The EARs for thiamine for women and men aged 14 and over are 0.9 mg/day and 1.1 mg/day, respectively; the RDAs are 1.1 and 1.2 mg/day, respectively. RDAs are higher than EARs to provide adequate intake levels for individuals with higher than average requirements. The RDA during pregnancy and for lactating females is 1.4 mg/day; a typical daily prenatal vitamin product contains around 1.5 mg of thiamine. For infants up to the age of 12 months, the Adequate Intake is 0.2–0.3 mg/day and for children aged 1–13 years the RDA increases with age from 0.5 to 0.9 mg/day.
The European Food Safety Authority refers to the collective set of information as Dietary Reference Values, with Population Reference Intakes instead of RDAs, and Average Requirements instead of EARs. For women, men and children the PRI is 0.1 mg thiamine per megajoule of energy in their diet. As the conversion is 1 MJ = 239 kcal, an adult consuming 2390 kilocalories ought to be consuming 1.0 mg thiamine. This is slightly lower than the US RDA.
Neither the National Academy of Medicine nor EFSA have set an upper intake level for thiamine, as there is no human data for adverse effects from high doses.

Safety

Thiamine is generally well tolerated and non-toxic when administered orally. There are rare reports of adverse side effects when thiamine is given intravenously, including allergic reactions, nausea, lethargy, and impaired coordination.

Labeling

For US food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value. Since 27 May 2016, the Daily Value has been 1.2 mg, in line with the RDA.

Food fortification

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

Synthesis

Biosynthesis

Thiamine biosynthesis occurs in bacteria, some protozoans, plants, and fungi. The thiazole and pyrimidine moieties are biosynthesized separately and are then combined to form ThMP by the action of thiamine-phosphate synthase.
The pyrimidine ring system is formed in a reaction catalysed by phosphomethylpyrimidine synthase, an enzyme in the radical SAM superfamily of iron–sulfur proteins, which use S-adenosyl methionine as a cofactor.
The starting material is 5-aminoimidazole ribotide, which undergoes a rearrangement reaction via radical intermediates which incorporate the blue, green and red fragments shown into the product.
The thiazole ring is formed in a reaction catalysed by thiazole synthase. The ultimate precursors are 1-deoxy-D-xylulose 5-phosphate, 2-iminoacetate and a sulfur carrier protein called ThiS. An additional protein, ThiG, is also required to bring together all the components of the ring at the enzyme active site.
Image:TPP riboswitch pdb-2hoj.png|thumb|upright|A 3D representation of the TPP riboswitch with thiamine bound
The final step to form ThMP involves decarboxylation of the thiazole intermediate, which reacts with the pyrophosphate derivative of phosphomethylpyrimidine, itself a product of a kinase, phosphomethylpyrimidine kinase.
The biosynthetic pathways differ among organisms. In E. coli and other enterobacteriaceae, ThMP is phosphorylated to the cofactor TPP by a thiamine-phosphate kinase. In most bacteria and in eukaryotes, ThMP is hydrolyzed to thiamine and then pyrophosphorylated to TPP by thiamine diphosphokinase.
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, is the only known riboswitch found in both eukaryotic and prokaryotic organisms.