Thiamine#History

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 (TPP), 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.{{cite book | doi = 10.1016/B978-0-12-378630-2.00102-X | chapter = Biochemistry of Thiamine and Thiamine Phosphate Compounds | title = Encyclopedia of Biological Chemistry | year = 2013 | vauthors = Bettendorff L, Wins P | pages = 202–9 | isbn = 9780123786319 }}

{{Main|Thiamine deficiency}}

Well-known disorders caused by thiamine deficiency include beriberi, Wernicke–Korsakoff syndrome, optic neuropathy, Leigh's disease, African seasonal ataxia (or Nigerian seasonal ataxia), and central pontine myelinolysis.{{Cite book|title=Thiamine Deficiency and Associate Clinical Disorders| vauthors = McCandless D |publisher=Humana Press|year=2010|isbn=978-1-60761-310-7|location=New York, NY|pages=157–9}} Symptoms include malaise, weight loss, irritability and confusion.{{cite book | veditors = Mahan LK, Escott-Stump S |title=Krause's food, nutrition, & diet therapy |edition=10th |location=Philadelphia |publisher=W.B. Saunders Company |year=2000 |isbn=978-0-7216-7904-4 }}{{cite book | vauthors = Combs Jr GF |title=The Vitamins: Fundamental Aspects in Nutrition and Health |edition=3rd |location=Ithaca, NY |publisher=Elsevier Academic Press |year=2008 |isbn=978-0-12-183493-7 }}{{cite journal | vauthors = Smith TJ, Johnson CR, Koshy R, Hess SY, Qureshi UA, Mynak ML, Fischer PR | title = Thiamine deficiency disorders: a clinical perspective | journal = Annals of the New York Academy of Sciences | volume = 1498 | issue = 1 | pages = 9–28 | date = August 2021 | pmid = 33305487 | pmc = 8451766 | doi = 10.1111/nyas.14536 | bibcode = 2021NYASA1498....9S }}

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.{{cite journal | vauthors = Katta N, Balla S, Alpert MA | title = Does Long-Term Furosemide Therapy Cause Thiamine Deficiency in Patients with Heart Failure? A Focused Review | journal = The American Journal of Medicine | volume = 129 | issue = 7 | pages = 753.e7–753.e11 | date = July 2016 | pmid = 26899752 | doi = 10.1016/j.amjmed.2016.01.037 | doi-access = free }}{{cite journal | vauthors = Gomes F, Bergeron G, Bourassa MW, Fischer PR | title = Thiamine deficiency unrelated to alcohol consumption in high-income countries: a literature review | journal = Annals of the New York Academy of Sciences | volume = 1498 | issue = 1 | pages = 46–56 | date = August 2021 | pmid = 33576090 | doi = 10.1111/nyas.14569 | pmc = 8451800 | bibcode = 2021NYASA1498...46G }}

Image:Thiamine monophosphate coloured.svg

Five natural thiamine phosphate derivatives are known: thiamine monophosphate (ThMP), thiamine pyrophosphate (TPP), thiamine triphosphate (ThTP), adenosine thiamine diphosphate (AThDP) and adenosine thiamine triphosphate (AThTP). They are involved in many cellular processes.{{cite journal | vauthors = Fitzpatrick TB, Chapman LM | title = The importance of thiamine (vitamin B₁) in plant health: From crop yield to biofortification | journal = The Journal of Biological Chemistry | volume = 295 | issue = 34 | pages = 12002–13 | date = August 2020 | pmid = 32554808 | pmc = 7443482 | doi = 10.1074/jbc.REV120.010918 | doi-access = free }} 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.{{cite journal | vauthors = Mkrtchyan G, Aleshin V, Parkhomenko Y, Kaehne T, Di Salvo ML, Parroni A, Contestabile R, Vovk A, Bettendorff L, Bunik V | title = Molecular mechanisms of the non-coenzyme action of thiamin in brain: biochemical, structural and pathway analysis | journal = Scientific Reports | volume = 5 | page = 12583 | date = July 2015 | pmid = 26212886 | pmc = 4515825 | doi = 10.1038/srep12583 | bibcode = 2015NatSR...512583M | doi-access = free }} No physiological role is known for the monophosphate except as an intermediate in cellular conversion of thiamine to the di- and triphosphates.

{{main|thiamine pyrophosphate}}

Thiamine pyrophosphate (TPP), also called thiamine diphosphate (ThDP), participates as a coenzyme in metabolic reactions, including those in which polarity inversion takes place.{{Cite journal |vauthors=Boluda CJ, Juncá C, Soto E, de la Cruz D, Peña A |date=13 December 2019 |title=Umpolung in reactions catalyzed by thiamine pyrophosphate dependent enzymes |url=https://revistas.intec.edu.do/index.php/cienacli/article/view/1578 |journal=Ciencia, Ambiente y Clima |language=es |volume=2 |issue=2 |pages=27–42 |doi=10.22206/cac.2019.v2i2.pp27-42 |s2cid=213836801 |issn=2636-2333 |doi-access=free |access-date=1 December 2022 |archive-date=1 December 2022 |archive-url=https://web.archive.org/web/20221201152253/https://revistas.intec.edu.do/index.php/cienacli/article/view/1578 |url-status=live }} Its synthesis is catalyzed by the enzyme thiamine diphosphokinase according to the reaction thiamine + ATP → TPP + AMP (EC 2.7.6.2). However, recent findings reveal that uridine 5′-triphosphate (UTP), rather than ATP, is the preferred substrate for TPP synthesis in cells, with TPK1 showing a ~10-fold higher affinity for UTP.{{cite journal | vauthors = Sahu U, Villa E, Reczek CR, Zhao Z, O'Hara BP, Torno MD, Mishra R, Shannon WD, Asara JM, Gao P, Shilatifard A, Chandel NS, Ben-Sahra I | title = Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis | journal = Science | volume = 383 | issue = 6690 | pages = 1484–1492 | date = March 2024 | pmid = 38547260 | doi = 10.1126/science.adh2771 | pmc = 11325697 | bibcode = 2024Sci...383.1484S }} TPP is a coenzyme for several enzymes that catalyze the transfer of two-carbon units and in particular the dehydrogenation (decarboxylation and subsequent conjugation with coenzyme A) of 2-oxoacids (alpha-keto acids). The mechanism of action of TPP as a coenzyme relies on its ability to form an ylide.{{cite journal | vauthors = Ciszak EM, Korotchkina LG, Dominiak PM, Sidhu S, Patel MS | title = Structural basis for flip-flop action of thiamin pyrophosphate-dependent enzymes revealed by human pyruvate dehydrogenase | journal = The Journal of Biological Chemistry | volume = 278 | issue = 23 | pages = 21240–46 | date = June 2003 | pmid = 12651851 | doi = 10.1074/jbc.M300339200 | doi-access = free | hdl = 2060/20030106063 | hdl-access = free }} Examples include:

• Present in most species
• pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase (also called α-ketoglutarate dehydrogenase)
• branched-chain α-keto acid dehydrogenase
• 2-hydroxyphytanoyl-CoA lyase
• transketolase
• Present in some species:
• pyruvate decarboxylase (in yeast)
• several additional bacterial enzymes

The enzymes transketolase, pyruvate dehydrogenase (PDH), and 2-oxoglutarate dehydrogenase (OGDH) are important in carbohydrate metabolism. PDH links glycolysis to the citric acid cycle. OGDH catalyzes the overall conversion of 2-oxoglutarate (alpha-ketoglutarate) 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 (ATP), which is the main energy transfer molecule for the cell. In the nervous system, PDH is also involved in the synthesis of myelin and the neurotransmitter acetylcholine.{{cite book | vauthors = Butterworth RF | chapter = Thiamin | veditors = Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ | title = Modern Nutrition in Health and Disease | edition = 10th | location = Baltimore | publisher = Lippincott Williams & Wilkins | date = 2006 }}

File:Thiamine triphosphate coloured.svg

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.{{cite journal | vauthors = Makarchikov AF, Lakaye B, Gulyai IE, Czerniecki J, Coumans B, Wins P, Grisar T, Bettendorff L | title = Thiamine triphosphate and thiamine triphosphatase activities: from bacteria to mammals | journal = Cellular and Molecular Life Sciences | volume = 60 | issue = 7 | pages = 1477–88 | date = July 2003 | pmid = 12943234 | doi = 10.1007/s00018-003-3098-4 | s2cid = 25400487 | pmc = 11146050 }} In Escherichia coli, it is implicated in the response to amino acid starvation.

AThDP exists in small amounts in vertebrate liver, but its role remains unknown.{{cite journal |vauthors=Bettendorff L |title=Update on Thiamine Triphosphorylated Derivatives and Metabolizing Enzymatic Complexes |journal=Biomolecules |volume=11 |issue=11 |date=November 2021 |page=1645 |pmid=34827643 |pmc=8615392 |doi=10.3390/biom11111645 |doi-access=free }}

AThTP is present in E. coli, where it accumulates as a result of carbon starvation. In this bacterium, AThTP may account for up to {{Percentage|20}} of total thiamine. It also exists in lesser amounts in yeast, roots of higher plants and animal tissue.

{{See also|Prenatal vitamins}}

During pregnancy, thiamine is sent to the fetus via the placenta. Pregnant women have a greater requirement for the vitamin than other adults, especially during the third trimester. Pregnant women with hyperemesis gravidarum are at an increased risk of thiamine deficiency due to losses when vomiting.{{cite journal | vauthors = Oudman E, Wijnia JW, Oey M, van Dam M, Painter RC, Postma A | title = Wernicke's encephalopathy in hyperemesis gravidarum: A systematic review | journal = European Journal of Obstetrics, Gynecology, and Reproductive Biology | volume = 236 | pages = 84–93 | date = May 2019 | pmid = 30889425 | doi = 10.1016/j.ejogrb.2019.03.006 | hdl = 1874/379566 | s2cid = 84184482| hdl-access = free }} In lactating women, thiamine is delivered in breast milk even if it results in thiamine deficiency in the mother.{{cite journal | vauthors = Butterworth RF | date = December 2001 |title=Maternal thiamine deficiency: still a problem in some world communities | journal = The American Journal of Clinical Nutrition | volume = 74 |issue=6 | pages = 712–3 | doi = 10.1093/ajcn/74.6.712 | pmid = 11722950 | doi-access = free }}

Thiamine is important not only for mitochondrial membrane development, but also for synaptic membrane function.{{cite journal | vauthors = Kloss O, Eskin NA, Suh M | title = Thiamin deficiency on fetal brain development with and without prenatal alcohol exposure | journal = Biochemistry and Cell Biology | volume = 96 | issue = 2 | pages = 169–77 | date = April 2018 | pmid = 28915355 | doi = 10.1139/bcb-2017-0082 | hdl = 1807/87775 | hdl-access = free }} It has also been suggested that a deficiency hinders brain development in infants and may be a cause of sudden infant death syndrome.{{cite journal | vauthors = Lonsdale D | title = A review of the biochemistry, metabolism and clinical benefits of thiamin(e) and its derivatives | journal = Evidence-Based Complementary and Alternative Medicine | volume = 3 | issue = 1 | pages = 49–59 | date = March 2006 | pmid = 16550223 | pmc = 1375232 | doi = 10.1093/ecam/nek009 }}

The US National Academy of Medicine updated the Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for thiamine in 1998. The EARs for thiamine for women and men aged 14 and over are 0.9 mg/day and 1.1 mg/day, respectively; the RDAs are 1.1 and 1.2 mg/day, respectively. RDAs are higher than EARs to provide adequate intake levels for individuals with higher than average requirements. The RDA during pregnancy and for lactating females is 1.4 mg/day. For infants up to the age of 12 months, the Adequate Intake (AI) is 0.2–0.3 mg/day and for children aged 1–13 years the RDA increases with age from 0.5 to 0.9 mg/day.

The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intakes (PRIs) instead of RDAs, and Average Requirements instead of EARs. For women (including those pregnant or lactating), men and children the PRI is 0.1 mg thiamine per megajoule (MJ) of energy in their diet. As the conversion is 1 MJ = 239 kcal, an adult consuming 2390 kilocalories ought to be consuming 1.0 mg thiamine. This is slightly lower than the US RDA.{{cite web| title = Overview on Dietary Reference Values for the EU population as derived by the EFSA Panel on Dietetic Products, Nutrition and Allergies| year = 2017| url = https://www.efsa.europa.eu/sites/default/files/assets/DRV_Summary_tables_jan_17.pdf| url-status = live| archive-url = https://web.archive.org/web/20170828082247/https://www.efsa.europa.eu/sites/default/files/assets/DRV_Summary_tables_jan_17.pdf| archive-date = 28 August 2017}}

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.

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.

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.{{cite web |url=https://www.gpo.gov/fdsys/pkg/FR-2016-05-27/pdf/2016-11867.pdf |title=Federal Register May 27, 2016 Food Labeling: Revision of the Nutrition and Supplement Facts Labels. FR page 33982. |url-status=live |archive-url=https://web.archive.org/web/20160808164651/https://www.gpo.gov/fdsys/pkg/FR-2016-05-27/pdf/2016-11867.pdf |archive-date=8 August 2016 }}{{cite web | title=Daily Value Reference of the Dietary Supplement Label Database (DSLD) | website=Dietary Supplement Label Database (DSLD) | url=https://www.dsld.nlm.nih.gov/dsld/dailyvalue.jsp | access-date=6 February 2022 | archive-date=7 April 2020 | archive-url=https://web.archive.org/web/20200407073956/https://dsld.nlm.nih.gov/dsld/dailyvalue.jsp | url-status=dead }}

Thiamine is found in a wide variety of processed and whole foods, including lentils, peas, whole grains, pork, and nuts.{{cite web|url=https://ndb.nal.usda.gov/ndb/nutrients/report/nutrientsfrm?max=25&offset=0&totCount=0&nutrient1=404&nutrient2=&nutrient3=&subset=1&fg=13&fg=20&fg=1&fg=15&fg=9&fg=16&fg=12&fg=10&fg=5&sort=c&measureby=g|title=Thiamin content per 100 grams; select food subset, abridged list by food groups|publisher=United States Department of Agriculture, Agricultural Research Service, USDA Branded Food Products Database v.3.6.4.1|date=17 January 2017|access-date=27 January 2017 |url-status=dead |archive-url= https://web.archive.org/web/20170202054051/https://ndb.nal.usda.gov/ndb/nutrients/report/nutrientsfrm?max=25&offset=0&totCount=0&nutrient1=404&nutrient2=&nutrient3=&subset=1&fg=13&fg=20&fg=1&fg=15&fg=9&fg=16&fg=12&fg=10&fg=5&sort=c&measureby=g |archive-date=2 February 2017}} A typical daily prenatal vitamin product contains around 1.5 mg of thiamine.{{cite journal | vauthors = Kominiarek MA, Rajan P | title = Nutrition Recommendations in Pregnancy and Lactation | journal = The Medical Clinics of North America | volume = 100 | issue = 6 | pages = 1199–215 | date = November 2016 | pmid = 27745590 | pmc = 5104202 | doi = 10.1016/j.mcna.2016.06.004 }}

{{main|Food fortification}}

Some countries require or recommend fortification of grain foods such as wheat, rice or maize (corn) because processing lowers vitamin content.{{Cite web|url=https://www.ffinetwork.org/from-nutritionists-faq?rq=riboflavin|publisher=Food Fortification Initiative|title=What nutrients are added to flour and rice in fortification?|date=2021|access-date=8 October 2021|archive-date=8 October 2021|archive-url=https://web.archive.org/web/20211008135516/https://www.ffinetwork.org/from-nutritionists-faq?rq=riboflavin|url-status=live}} 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.{{cite web|url=https://fortificationdata.org/map-number-of-nutrients/|title=Map: Count of Nutrients In Fortification Standards|website=Global Fortification Data Exchange|access-date=11 October 2021|archive-date=11 April 2019|archive-url=https://web.archive.org/web/20190411123853/https://fortificationdata.org/map-number-of-nutrients/|url-status=live}} An additional 18 countries have a voluntary fortification program. For example, the Indian government recommends 3.5 mg/kg for "maida" (white) and "atta" (whole wheat) flour.{{cite web |url=https://fssai.gov.in/upload/advisories/2018/03/5a97968275a36206.pdf |title=Direction under Section 16(5) of Foods Safety and Standards Act, 2006 regarding Operationalisation of Food Safety & Standards (Fortification of Foods) Regulations, 2017 relating to standards for fortification of food |date=19 May 2017 |website=Food Safety & Standards Authority of India (FSSAI) |access-date=1 February 2022 |archive-date=17 December 2021 |archive-url=https://web.archive.org/web/20211217054313/https://www.fssai.gov.in/upload/advisories/2018/03/5a97968275a36206.pdf |url-status=live }}

Thiamine biosynthesis occurs in bacteria, some protozoans, plants, and fungi.{{cite journal | vauthors = Webb ME, Marquet A, Mendel RR, Rébeillé F, Smith AG | title = Elucidating biosynthetic pathways for vitamins and cofactors | journal = Natural Product Reports | volume = 24 | issue = 5 | pages = 988–1008 | date = October 2007 | pmid = 17898894 | doi = 10.1039/b703105j }}{{cite journal | vauthors = Begley TP, Chatterjee A, Hanes JW, Hazra A, Ealick SE | title = Cofactor biosynthesis--still yielding fascinating new biological chemistry | journal = Current Opinion in Chemical Biology | volume = 12 | issue = 2 | pages = 118–25 | date = April 2008 | pmid = 18314013 | pmc = 2677635 | doi = 10.1016/j.cbpa.2008.02.006 }} 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 (ThiC), an enzyme in the radical SAM superfamily of iron–sulfur proteins, which use S-adenosyl methionine as a cofactor.{{cite web |url=https://biocyc.org/META/NEW-IMAGE?type=PATHWAY&object=THISYN-PWY&detail-level=2 |title=Pathway: superpathway of thiamine diphosphate biosynthesis I |vauthors=Caspi R |publisher=MetaCyc Metabolic Pathway Database |date=14 September 2011 |access-date=1 February 2022 |archive-date=1 February 2022 |archive-url=https://web.archive.org/web/20220201111017/https://biocyc.org/META/NEW-IMAGE?type=PATHWAY&object=THISYN-PWY&detail-level=2 |url-status=live }}{{cite book |chapter=Atlas of the Radical SAM Superfamily: Divergent Evolution of Function Using a "Plug and Play" Domain |title=Radical SAM Enzymes |series=Methods in Enzymology |year=2018 |vauthors=Holliday GL, Akiva E, Meng EC, Brown SD, Calhoun S, Pieper U, Sali A, Booker SJ, Babbitt PC |volume=606 |pages=1–71 |pmid=30097089 |pmc=6445391 |isbn=9780128127940 |doi=10.1016/bs.mie.2018.06.004}}

:File:Pyrimidine biosynthesis.svg

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.{{cite journal | vauthors = Chatterjee A, Hazra AB, Abdelwahed S, Hilmey DG, Begley TP | title = A "radical dance" in thiamin biosynthesis: mechanistic analysis of the bacterial hydroxymethylpyrimidine phosphate synthase | journal = Angewandte Chemie | volume = 49 | issue = 46 | pages = 8653–6 | date = November 2010 | pmid = 20886485 | pmc = 3147014 | doi = 10.1002/anie.201003419 }}{{cite journal | vauthors = Mehta AP, Abdelwahed SH, Fenwick MK, Hazra AB, Taga ME, Zhang Y, Ealick SE, Begley TP | title = Anaerobic 5-Hydroxybenzimidazole Formation from Aminoimidazole Ribotide: An Unanticipated Intersection of Thiamin and Vitamin B₁₂ Biosynthesis | journal = Journal of the American Chemical Society |volume = 137 |issue = 33 | pages = 10444–7 |date = August 2015 |pmid = 26237670 |pmc = 4753784 |doi = 10.1021/jacs.5b03576 }}

The thiazole ring is formed in a reaction catalysed by thiazole synthase (EC 2.8.1.10). The ultimate precursors are 1-deoxy-D-xylulose 5-phosphate, 2-iminoacetate and a sulfur carrier protein called ThiS. An additional protein, ThiG, is also required to bring together all the components of the ring at the enzyme active site.{{cite journal | vauthors = Begley TP | title = Cofactor biosynthesis: an organic chemist's treasure trove | journal = Natural Product Reports | volume = 23 | issue = 1 | pages = 15–25 | date = February 2006 | pmid = 16453030 | doi = 10.1039/b207131m }}

:File:Thiamine biosynthesis.svg

Image:TPP riboswitch pdb-2hoj.png 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 (ThMP + ATP → TPP + ADP). In most bacteria and in eukaryotes, ThMP is hydrolyzed to thiamine and then pyrophosphorylated to TPP by thiamine diphosphokinase (thiamine + ATP → TPP + AMP).{{cite web |url=https://biocyc.org/META/NEW-IMAGE?type=PATHWAY&object=THISYNARA-PWY |title=Pathway: superpathway of thiamine diphosphate biosynthesis III (eukaryotes) |vauthors=Caspi R |publisher=MetaCyc Metabolic Pathway Database |date=23 September 2011 |access-date=14 November 2022 |archive-date=14 November 2022 |archive-url=https://web.archive.org/web/20221114142838/https://biocyc.org/META/NEW-IMAGE?type=PATHWAY&object=THISYNARA-PWY |url-status=live }}

The biosynthetic pathways are regulated by riboswitches.{{cite book | vauthors = Bettendorff L | title = Present Knowledge in Nutrition, Eleventh Edition | chapter = Thiamine | veditors = Marriott BP, Birt DF, Stallings VA, Yates AA | publisher = Academic Press (Elsevier) | year = 2020 | location = London, United Kingdom | pages = 171–88 | isbn = 978-0-323-66162-1 }} 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.{{cite journal | vauthors = Bocobza SE, Aharoni A | title = Switching the light on plant riboswitches | journal = Trends in Plant Science | volume = 13 | issue = 10 | pages = 526–33 | date = October 2008 | pmid = 18778966 | doi = 10.1016/j.tplants.2008.07.004 | bibcode = 2008TPS....13..526B }}

:File:Thiamine synthesis.svg

In the first total synthesis in 1936, ethyl 3-ethoxypropanoate was treated with ethyl formate to give an intermediate dicarbonyl compound which when reacted with acetamidine formed a substituted pyrimidine. Conversion of its hydroxyl group to an amino group was carried out by nucleophilic aromatic substitution, first to the chloride derivative using phosphorus oxychloride, followed by treatment with ammonia. The ethoxy group was then converted to a bromo derivative using hydrobromic acid. In the final stage, thiamine (as its dibromide salt) was formed in an alkylation reaction using 4-methyl-5-(2-hydroxyethyl)thiazole.{{cite journal | vauthors = Tylicki A, Łotowski Z, Siemieniuk M, Ratkiewicz A | title = Thiamine and selected thiamine antivitamins - biological activity and methods of synthesis | journal = Bioscience Reports | volume = 38 | issue = 1 | date = February 2018 | pmid = 29208764 | pmc = 6435462 | doi = 10.1042/BSR20171148 | doi-access = free }}{{rp|7}}{{cite journal | vauthors = Eggersdorfer M, Laudert D, Létinois U, McClymont T, Medlock J, Netscher T, Bonrath W | title = One hundred years of vitamins-a success story of the natural sciences | journal = Angewandte Chemie | volume = 51 |issue = 52 |pages = 12960–90 |date = December 2012 |pmid = 23208776 | doi = 10.1002/anie.201205886 }}

File:Grewe diamine.svg

Merck & Co. adapted the 1936 laboratory-scale synthesis, allowing them to manufacture thiamine in Rahway in 1937. However, an alternative route using the intermediate Grewe diamine (5-(aminomethyl)-2-methyl-4-pyrimidinamine), first published in 1937,{{cite journal | doi = 10.1039/JR9370000364 | title = 73. Aneurin. Part VII. A synthesis of aneurin | year = 1937 | vauthors = Todd AR, Bergel F | journal = Journal of the Chemical Society (Resumed) | page = 364 }} was investigated by Hoffman La Roche and competitive manufacturing processes followed. Efficient routes to the diamine have continued to be of interest.{{cite journal | doi = 10.1021/acs.oprd.1c00253 | title = Fully Continuous Flow Synthesis of 5-(Aminomethyl)-2-methylpyrimidin-4-amine: A Key Intermediate of Vitamin B1 |year = 2021 |vauthors = Jiang M, Liu M, Huang H, Chen F |journal=Organic Process Research & Development | volume = 25 | issue = 10 | pages = 2331–7 |s2cid = 242772232 }} In the European Economic Area, thiamine is registered under REACH regulation and between 100 and 1,000 tonnes per annum are manufactured or imported there.{{cite web | url = https://echa.europa.eu/substance-information/-/substanceinfo/100.000.583 | access-date = 11 May 2022 | title = Substance Infocard | website = echa.europa.eu | archive-date = 20 April 2021 | archive-url = https://web.archive.org/web/20210420023445/https://echa.europa.eu/substance-information/-/substanceinfo/100.000.583 | url-status = live }}

Many vitamin B₁ analogues, such as Benfotiamine, fursultiamine, and sulbutiamine, are synthetic derivatives of thiamine. Most were developed in Japan in the 1950s and 1960s as forms that were intended to improve absorption compared to thiamine.{{cite book | vauthors = Bettendorff L | veditors = Zempleni J, Suttie JW, Gregory JF, Stover PJ | title = Handbook of vitamins | date = 2014 | publisher = CRC Press | location = Hoboken | isbn=9781466515574 | pages = 267–324 | edition = 5th | chapter = Chapter 7 - Thiamine }} Some are approved for use in some countries as a drug or non-prescription dietary supplement for treatment of diabetic neuropathy or other health conditions.{{cite journal | vauthors = Zaheer A, Zaheer F, Saeed H, Tahir Z, Tahir MW |title=A Review of Alternative Treatment Options in Diabetic Polyneuropathy | journal = Cureus |volume = 13 |issue = 4 |at = e14600 |date = April 2021 |pmid = 34040901 | pmc = 8139599 | doi = 10.7759/cureus.14600 |doi-access=free }}{{cite book | vauthors = McCarty MF, Inoguchi T | veditors = Pasupuleti VK, Anderson JW | title = Nutraceuticals, glycemic health and type 2 diabetes | date = 2008 |publisher = Wiley-Blackwell/IFT Press |location=Ames, Iowa | isbn = 9780813804286 |page = 213 | edition = 1st | chapter-url = https://books.google.com/books?id=9FvCD-a32VMC&pg=PA213 | chapter = 11. Targeting Oxidant Stress as a Strategy for Preventing Vascular Complications of Diabetes and Metabolic Syndrome }}{{cite journal | vauthors = Lonsdale D | title = Thiamine tetrahydrofurfuryl disulfide: a little known therapeutic agent | journal = Medical Science Monitor | volume = 10 | issue = 9 | pages = RA199–203 | date = September 2004 | pmid = 15328496 | url = http://www.medscimonit.com/fulltxt.php?ICID=11763 | access-date = 17 July 2022 | archive-date = 25 September 2012 | archive-url = https://web.archive.org/web/20120925220433/http://www.medscimonit.com/fulltxt.php?ICID=11763 | url-status = live }}

In the upper small intestine, thiamine phosphate esters present in food are hydrolyzed by alkaline phosphatase enzymes.{{cite book|doi=10.1016/B978-0-323-66162-1.00010-X |chapter=Thiamine |title=Present Knowledge in Nutrition |date=2020 |pages=171–188 |isbn=978-0-323-66162-1 | vauthors = Bettendorff L }} At low concentrations (<2 μmol l−1), the absorption process is carrier-mediated. At higher concentrations, absorption also occurs via passive diffusion. Active transport can be inhibited by alcohol consumption or by folate deficiency.

The majority of thiamine in serum is circulating bound to albumin,{{cite book|doi=10.1016/B978-0-12-801238-3.00233-6|quote=Thiamine is absorbed through the jejunum (small intestine) via two mechanisms: active transport or passive diffusion. At low concentrations (<2 μmol l−1), the process is carrier-mediated active transport. Two main thiamine transporters ThTR1 and ThTr2 are essential for absorption and the process is thought to be regulated by an intracellular calcium/calmodulin-mediated pathway and by the actual extracellular circulating concentration of thiamine itself. The majority of thiamine in serum is protein bound to albumin with over 90% contained within erythrocytes. Cellular uptake occurs by active transport and passive diffusion through thiamine transporters ThTr1 and ThTr2. |chapter=Water-Soluble Vitamins and Essential Nutrients |title=Reference Module in Biomedical Sciences |date=2014 |isbn=978-0-12-801238-3 | vauthors = Laird E, Molloy A }} with over ({{Percentage|90}}) in erythrocytes (red blood cells), and is delivered to cells with high metabolic needs—particularly those in the brain, liver, pancreas, heart, and skeletal and smooth muscles, including cardiac muscle cells. A specific binding protein called thiamine-binding protein has been identified in rat serum and is believed to be a hormone-regulated carrier protein important for tissue distribution of thiamine. Uptake of thiamine by cells of the blood and other tissues occurs via active transport and passive diffusion. Two members of the family of transporter proteins encoded by the genes SLC19A2 and SLC19A3 are capable of thiamine transport.{{cite book|doi=10.1016/B978-0-12-810387-6.00003-4 |chapter=Mitochondria, Thiamine, and Autonomic Dysfunction |title=Thiamine Deficiency Disease, Dysautonomia, and High Calorie Malnutrition |date=2017 |pages=59–103 |isbn=978-0-12-810387-6 | vauthors = Lonsdale D, Marrs C }} In some tissues, thiamine uptake and secretion appear to be mediated by a Na⁺-dependent transporter and a transcellular proton gradient.

Human storage of thiamine is about 25 to 50 mg, with the greatest concentrations in liver, skeletal muscle, heart, brain, and kidneys.{{cite journal |vauthors=Chandrakumar A, Bhardwaj A, 't Jong GW |title=Review of thiamine deficiency disorders: Wernicke encephalopathy and Korsakoff psychosis |journal=J Basic Clin Physiol Pharmacol |volume=30 |issue=2 |pages=153–162 |date=October 2018 |pmid=30281514 |doi=10.1515/jbcpp-2018-0075}}{{cite book|doi=10.1016/B978-0-12-381980-2.00010-4 |chapter=Thiamin |title=The Vitamins |date=2012 |pages=261–276 |isbn=978-0-12-381980-2 | vauthors = Combs GF }} ThMP and free (unphosphorylated) thiamine are present in plasma, milk, cerebrospinal fluid, and, it is presumed, all extracellular fluid. Unlike the highly phosphorylated forms of thiamine, ThMP and free thiamine are capable of crossing cell membranes. Calcium and magnesium have been shown to affect the distribution of thiamine in the body and magnesium deficiency has been shown to aggravate thiamine deficiency. Thiamine contents in human tissues are less than those of other species.{{cite journal | vauthors = Bettendorff L, Mastrogiacomo F, Kish SJ, Grisar T | title = Thiamine, thiamine phosphates, and their metabolizing enzymes in human brain |journal = Journal of Neurochemistry |volume = 66 |issue = 1 |pages = 250–8 | date = January 1996 |pmid = 8522961 |doi = 10.1046/j.1471-4159.1996.66010250.x | s2cid = 7161882 }} The half-life of thiamine content stored in tissues of human body is about 9-18 days, while after intake in high doses, the half-life of thiamine in circulating blood is about one to 12 hours. Additionally, thiamine pyrophosphate derived from pyrimidines supports lipid synthesis and adipogenesis, highlighting its role in energy storage and cellular differentiation.

Thiamine and its metabolites (2-methyl-4-amino-5-pyrimidine carboxylic acid, 4-methyl-thiazole-5-acetic acid, and others) are excreted principally in the urine.

The bioavailability of thiamine in foods can be interfered with in a variety of ways. Sulfites, added to foods as a preservative,{{cite book | vauthors = McGuire M, Beerman KA | title = Nutritional Sciences: From Fundamentals to Foods. | date = 2007 | location = California | publisher = Thomas Wadsworth }} will attack thiamine at the methylene bridge, cleaving the pyrimidine ring from the thiazole ring. The rate of this reaction is increased under acidic conditions. Thiamine is degraded by thermolabile thiaminases present in some species of fish, shellfish and other foods. The pupae of an African silk worm, Anaphe venata, is a traditional food in Nigeria. Consumption leads to thiamine deficiency.{{cite journal |vauthors=Nishimune T, Watanabe Y, Okazaki H, Akai H |title=Thiamin is decomposed due to Anaphe spp. entomophagy in seasonal ataxia patients in Nigeria |journal=J. Nutr. |volume=130 |pages=1625–8 |year=2000 |issue=6 |doi=10.1093/jn/130.6.1625 |pmid=10827220 |doi-access=free }} Older literature reported that in Thailand, consumption of fermented, uncooked fish caused thiamine deficiency, but either abstaining from eating the fish or heating it first reversed the deficiency.{{cite journal |vauthors=Vimokesant SL, Hilker DM, Nakornchai S, Rungruangsak K, Dhanamitta S |title=Effects of betel nut and fermented fish on the thiamin status of northeastern Thais |journal=Am J Clin Nutr |volume=28 |issue=12 |pages=1458–63 |date=December 1975 |pmid=803009 |doi=10.1093/ajcn/28.12.1458}} In ruminants, intestinal bacteria synthesize thiamine and thiaminases. The bacterial thiaminases are cell surface enzymes that must dissociate from the cell membrane before being activated; the dissociation can occur in ruminants under acidotic conditions. In dairy cows, over-feeding with grain causes subacute ruminal acidosis and increased ruminal bacteria thiaminase release, resulting in thiamine deficiency.{{cite journal |vauthors=Pan X, Nan X, Yang L, Jiang L, Xiong B |title=Thiamine status, metabolism and application in dairy cows: a review |journal=Br J Nutr |volume=120 |issue=5 |pages=491–9 |date=September 2018 |pmid=29986774 |doi=10.1017/S0007114518001666|s2cid=51606809 |doi-access=free }}

From reports on two small studies conducted in Thailand, chewing slices of areca nut wrapped in betel leaves and chewing tea leaves reduced food thiamine bioavailability by a mechanism that may involve tannins.{{cite journal |vauthors=Vimokesant S, Kunjara S, Rungruangsak K, Nakornchai S, Panijpan B |title=Beriberi caused by antithiamin factors in food and its prevention |journal=Ann N Y Acad Sci |volume=378 |issue= 1|pages=123–36 |date=1982 |pmid=7044221 |doi=10.1111/j.1749-6632.1982.tb31191.x|bibcode=1982NYASA.378..123V |s2cid=40854060 }}

Bariatric surgery for weight loss is known to interfere with vitamin absorption.{{cite journal |vauthors=Nunes R, Santos-Sousa H, Vieira S, Nogueiro J, Bouça-Machado R, Pereira A, Carneiro S, Costa-Pinho A, Lima-da-Costa E, Preto J |title=Vitamin B Complex Deficiency After Roux-en-Y Gastric Bypass and Sleeve Gastrectomy-a Systematic Review and Meta-Analysis |journal=Obes Surg |volume=32 |issue=3 |pages=873–91 |date=March 2022 |pmid=34982396 |doi=10.1007/s11695-021-05783-2|s2cid=245655046 }} A meta-analysis reported that {{Percentage|27}} of people who underwent bariatric surgeries experience vitamin B₁ deficiency.{{cite journal |vauthors=Bahardoust M, Eghbali F, Shahmiri SS, Alijanpour A, Yarigholi F, Valizadeh R, Madankan A, Pouraskari AB, Ashtarinezhad B, Farokhi H, Sarafraz H, Khanafshar E |title=B1 Vitamin Deficiency After Bariatric Surgery, Prevalence, and Symptoms: a Systematic Review and Meta-analysis |journal=Obes Surg |volume=32 |issue=9 |pages=3104–12 |date=September 2022 |pmid=35776243 |doi=10.1007/s11695-022-06178-7|s2cid=250149680 }}

{{See|Vitamin#History}}

Thiamine was the first of the water-soluble vitamins to be isolated. The earliest observations in humans and in chickens had shown that diets of primarily polished white rice caused beriberi, but did not attribute it to the absence of a previously unknown essential nutrient.

In 1884, Takaki Kanehiro, a surgeon general in the Imperial Japanese Navy, rejected the previous germ theory for beriberi and suggested instead that the disease was due to insufficiencies in the diet.{{cite book | vauthors = McCollum EV | title = A History of Nutrition | location = Cambridge, Massachusetts | publisher = Riverside Press, Houghton Mifflin |date = 1957 }} Switching diets on a navy ship, he discovered that replacing a diet of white rice only with one also containing barley, meat, milk, bread, and vegetables, nearly eliminated beriberi on a nine-month sea voyage. However, Takaki had added many foods to the successful diet and he incorrectly attributed the benefit to increased protein intake, as vitamins were unknown at the time. The Navy was not convinced of the need for such an expensive program of dietary improvement, and many men continued to die of beriberi, even during the Russo-Japanese war of 1904–5. Not until 1905, after the anti-beriberi factor had been discovered in rice bran (removed by polishing into white rice) and in barley bran, was Takaki's experiment rewarded. He was made a baron in the Japanese peerage system, after which he was affectionately called "Barley Baron".

The specific connection to grain was made in 1897 by Christiaan Eijkman, a military doctor in the Dutch East Indies, who discovered that fowl fed on a diet of cooked, polished rice developed paralysis that could be reversed by discontinuing rice polishing.{{cite journal |vauthors = Eijkman C |year = 1897 |title = Eine Beriberiähnliche Krankheit der Hühner |trans-title = A disease of chickens which is similar to beriberi |url = https://zenodo.org/record/1572089 |journal = Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin |volume = 148 |issue = 3 |pages = 523–532 |doi = 10.1007/BF01937576 |s2cid = 38445999 |access-date = 4 July 2019 |archive-date = 9 August 2020 |archive-url = https://web.archive.org/web/20200809120608/https://zenodo.org/record/1572089 |url-status = live }} 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.{{cite web|title=The Nobel Prize and the Discovery of Vitamins|url=https://www.nobelprize.org/nobel_prizes/themes/medicine/carpenter/|website=nobelprize.org|access-date=1 May 2018|archive-date=16 January 2018|archive-url=https://web.archive.org/web/20180116004953/https://www.nobelprize.org/nobel_prizes/themes/medicine/carpenter/|url-status=live}} An associate, Gerrit Grijns, correctly interpreted the connection between excessive consumption of polished rice and beriberi in 1901: He concluded that rice contains an essential nutrient in the outer layers of the grain that is removed by polishing.{{cite journal |vauthors = Grijns G |year = 1901 |title = Over polyneuritis gallinarum |trans-title = On polyneuritis gallinarum |url = https://babel.hathitrust.org/cgi/pt?id=uc1.b3748913&view=1up&seq=29 |journal = Geneeskundig Tijdschrift voor Nederlandsch-Indië (Medical Journal for the Dutch East Indies) |volume = 41 |issue = 1 |pages = 3–11 |access-date = 5 February 2020 |archive-date = 29 August 2021 |archive-url = https://web.archive.org/web/20210829084152/https://babel.hathitrust.org/cgi/pt?id=uc1.b3748913&view=1up&seq=29 |url-status = live }} 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 agricultural chemist of Tokyo Imperial University, Umetaro Suzuki, isolated a water-soluble thiamine compound from rice bran, which he named aberic acid. (He later renamed it Orizanin.) He described the compound as not only an anti-beriberi factor, but also as being essential to human nutrition; however, this finding failed to gain publicity outside of Japan, because a claim that the compound was a new finding was omitted in translation of his publication from Japanese to German.{{cite journal | title = Active constituent of rice grits preventing bird polyneuritis | journal = Tokyo Kagaku Kaishi | year = 1911 | vauthors = Suzuki U, Shimamura T | volume = 32 | pages = 4–7, 144–6, 335–58 | doi = 10.1246/nikkashi1880.32.4 | doi-access = free | url = https://www.jstage.jst.go.jp/browse/nikkashi1880/32/1/_contents | access-date = 2 May 2018 | archive-date = 21 June 2020 | archive-url = https://web.archive.org/web/20200621103704/https://www.jstage.jst.go.jp/browse/nikkashi1880/32/1/_contents | url-status = live }} 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).{{cite journal | vauthors = Funk C | title = On the chemical nature of the substance which cures polyneuritis in birds induced by a diet of polished rice | journal = The Journal of Physiology | volume = 43 | issue = 5 | pages = 395–400 | date = December 1911 | pmid = 16993097 | pmc = 1512869 | doi = 10.1113/jphysiol.1911.sp001481 }}{{cite journal | vauthors = Funk C | title = The etiology of the deficiency diseases. Beri-beri, polyneuritis in birds, epidemic dropsy, scurvy, experimental scurvy in animals, infantile scurvy, ship beri-beri, pellagra | journal = Journal of State Medicine | date = 1912 | volume = 20 | pages = 341–68 | url = https://babel.hathitrust.org/cgi/pt?id=mdp.39015069802166&view=1up&seq=351 | access-date = 5 February 2020 | archive-date = 4 July 2020 | archive-url = https://web.archive.org/web/20200704183954/https://babel.hathitrust.org/cgi/pt?id=mdp.39015069802166&view=1up&seq=351 | url-status = live }} The word "vitamine" is coined on p. 342: "It is now known that all these diseases, with the exception of pellagra, can be prevented and cured by the addition of certain preventative substances; the deficient substances, which are of the nature of organic bases, we will call "vitamines"; and we will speak of a beri-beri or scurvy vitamine, which means a substance preventing the special disease." However, Funk did not completely characterize its chemical structure. Dutch chemists, Barend Coenraad Petrus Jansen and his closest collaborator Willem Frederik Donath, went on to isolate and crystallize the active agent in 1926,{{cite journal | vauthors = Jansen BC, Donath WF | year = 1926 | title = On the isolation of antiberiberi vitamin | journal = Proc. Kon. Ned. Akad. Wet. | volume = 29 | pages = 1390–400 }} whose structure was determined by Robert Runnels Williams, in 1934. Thiamine was named by the Williams team as a portmanteau of "thio" (meaning sulfur-containing) and "vitamin". The term "vitamin" coming indirectly, by way of Funk, from the amine group of thiamine itself (although by this time, vitamins were known to not always be amines, for example, vitamin C). Thiamine was also synthesized by the Williams group in 1936.{{cite journal | doi = 10.1021/ja01299a505 | title = Synthesis of Vitamin B₁ | year = 1936 | vauthors = Williams RR, Cline JK | journal = Journal of the American Chemical Society | volume = 58 | issue = 8 |pages = 1504–5 | bibcode = 1936JAChS..58.1504W }}

Sir Rudolph Peters, in Oxford, used pigeons to understand how thiamine deficiency results in the pathological-physiological symptoms of beriberi. Pigeons fed exclusively on polished rice developed opisthotonos, a condition characterized by head retraction. If not treated, the animals died after a few days. Administration of thiamine after opisthotonos was observed led to a complete cure within 30 minutes. As no morphological modifications were seen in the brain of the pigeons before and after treatment with thiamine, Peters introduced the concept of a biochemical-induced injury.{{cite journal | vauthors = Peters RA | title = The biochemical lesion in vitamin B₁ deficiency. Application of modern biochemical analysis in its diagnosis |journal = Lancet |year = 1936 | volume = 230 | issue = 5882 |pages = 1161–4 |doi = 10.1016/S0140-6736(01)28025-8 }} In 1937, Lohmann and Schuster showed that the diphosphorylated thiamine derivative, TPP, was a cofactor required for the oxidative decarboxylation of pyruvate.{{cite journal | vauthors = Lohmann K, Schuster P |year = 1937 |title = Untersuchungen über die Cocarboxylase |journal = Biochem. Z. |volume = 294 |pages = 188–214 }}

File:Takaki Kanehiro.jpg|Takaki Kanehiro

File:Eijkman.jpg|Christiaan Eijkman

File:Portrait_of_Gerrit_Grijns_Wellcome_M0010254.jpg|Gerrit Grijns

File:Umetarosuzuki-pre1943.jpg|Umetaro Suzuki

File:Casimir_Funk_01.jpg|Casimir Funk

File:Rudolph Albert Peters.jpg|Rudolph Peters

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