Thiamin can be phosphorylated to TPP in most tissues (Zhao, Gao, and Goldman, 20011 by thiamin pyrophosphokinase (EC2.7.6.2). This enzyme converts free thiamin and TMP to TPP and TTP In brain and other tissues a significant proportion of TPP is phosphorylated again to TTP by thiamin-diphosphate kinase (EC2.7.4. IS) in an ATP-dependent reaction. Some investigators (Shioda etal.. 1993) reported that adenosylatc kinase (EC2.7.4.3) facilitates transphosphorylation (TPP + A DP <->AMP + TTP). but this (hiding has been disputed by others (Bettendorff el al.. 1993). Both these enzymes are unusual in that they require creatine as cofactors (Shikata et al.. 1986; Shikata et ai. 1989). Thiamin-diphosphate kinase may also require glucose as an activating factor (Nishino et ai. 19X3).

A broad array of enzymes in various tissues dephosphorylatc the thiamin phosphates. Magnesium-dependent thiamin triphosphatase (EC3.6.1,28). which generates TPP from TTP, is present in many tissues, both as cytosolic and membrane-bound form. TPP in mitochondria can be hydrolyzed by a heterodimene isoenzyme of acid phosphatase (EC3.1.3.2). Thiamin pyrophosphatase, which converts TTP to TMP. could be a modified form of type B nucleoside diphosphatase(EC3.6,1 6) in the (iolgi apparatus. Additional less specific phosphatases also act on thiamin phosphates.

Thiamin can be metabolized to thiamin acetate, thiamin sulfide, pyrimidinc car-boxvlic acid, thiazole acetate, 2-methyI -4-am i no-5-formylaminomethyIpyrimidine. thiochromc and other compounds (Pearson and Darby, 1967; White et ai. 1970), but the exact nature or location of the involved metabolic processes in not well understood. It has been suggested that some of these compounds mav be absorbed after intestinal bacteria have acted on thiamin or its dcrivates. but the exact nature and location of the involved reactions remains to be clarified.


Acid \ phosphatase

Thiamin pyro- 1 phosphofcinase (Mg)

Thiamin monoptiosphale (TMPl

Thiamin pyrophos phatase

Thiamin pyrophosphate (TPP)

Adenylate kinase (Mg. creatine)

TPP kinase (Mg, creatine, glucose)

Thiamin tri-phosphatase (Mg)

Thiamin tnphosphate (TTP)

Figur* 1G.10 Thiamin met abolit m


Typically about 30 mg thiamin are stored in an adult, half of it in muscle, less in liver and kidney. The biological half-life of thiamin is 9-18 days (Ariaey-Nejad et al.. 1970).

About SO" i. of total body thiamin is TPP (mostly bound to pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase in mitochondria). 10% is TTP. smaller amounts are present as free thiamin andTMP ( McCormick. 2000).


At high thiamin Intakes most of the excess is rapidly excreted with urine (Davis et r//.. 1984), very little with bile. A mean creatinine thiamin renal clearance ratio of 2.4 indicates that the thiamin excess is actively excreted. At low to moderate concentrations. on the other hand, recovery of intact thiamin from primary liltrate in the proximal tubule is very effective due to mechanisms very similar to those responsible for iniestinal absorption. A thiamin/H+ antiportcr with a I: I stoichiometric ratio in the brush border recovers filtered thiamin (Gastaldi et a!.. 2000), and an ATP-driven thiamin carrier completes transport across the ba so lateral membrane. All diuretics appear to increase thiamin losses with urine (Suter and Vetter, 2000).

Most thiamin losses w ith urine arc in the form ofpyrimidine carboxyltc acid, thin/ole acetic acid, or thiamin acetic acid, and a considerable number ofadditional minor metabolites (White et ui. 1970).


Thiamin homeostasis is maintained both at the level of intestinal absorption and of renal tubular recovery, both of which are lightly limited. Expression of the thiamin transporter gene is induced by the p53 tumor suppressor (Lo et al.. 20011 and regulated via intracellular ealeium/calcmodulin signaling (Said et at., 2001). Export of both TMP and I PP from extraintestinal tissues by the reduced folate carrier (SLC19AI) is likely to limit concentrations and thereby contribute to the maintenance of homeostasis (Zhao, Gao. Wang et al.. 2001).


Only five enzymes have been identified so far that have a strict thiamin requirement. All of them uscTPP coordinated with magnesium as a cofactor. Additional actions of thiamin, especially as TTP in brain, appear to be similarly essential, but have not yet been completely characterized.

Transketolases: (EC2.2.1.11 is needed for glucose metabolism \ia the pentose-phosphate pathway, the only pathway that generates significant amounts of NADPH. Two distinct genes are now known to encode proteins with activ itv. Alternative splicing of the more recently discovered one, transketolase 2 (Coy et al.. 1996). gives rise to different isoforms in brain and heart. Decreased activity of this enzyme may contribute to the Wernicke Korsakoff syndrome observed in alcohol abusers (see below i. The transketolase 2 gene locus is immediately adjacent to the protein-coding regions of the retina color pigment genes on the X chromosome (Hanna et al., 1997). which might suggest a particular importance for vision. Pyruvate dehydrogenase: This key enzyme (EC3.1.3.43) of glucose metabolism is embedded in the mitochondrial matrix and contains multiple copies of three distinct moieties: E1, E2, and E3. TPP is associated with E1,

Alpha-ketoglutarate dehydrogenase: f his enzyme (EC of the tricarboxylic acid cycle consists of three distinct moieties: El. E2. E3; TPP is associated w ith EI. The enzyme probably also participates in the breakdown of tryptophan, lysine, and hydroxy lysine,

Branchedchain alpha-keto acid dehydrogenase: This enzyme w ith the systematic name 3-methy 1-2-oxobutanoate dehydrogenase (EC comprises three distinct sub-units, El (with TPP bound to Ilis292), E2. and E3. The enzyme is needed for the catubolism of the branched-chain amino acids valine, isoleucine. and leucine.

Branchcd-ehain alpha-keto acid dehydrogenase and pyruvate dehydrogenase also cleave alpha-ketobutyrate (from L-threonine and homocysteine metabolism) into CO; and priopionyl-CoA (Paxton et al.. 1986; Pettit and Reed I98X),

Phytanic acid metabolism: Alpha-oxidation of 3-methyl fatty acids such as phytanic acid (Foulen et al.. 1099) involves as the third step a reaction catalyzed by the TPP-dependent enzyme 2-hydroxyphytanoyI-CoA lyase (no lit' number assigned). Brain function: TTP appears to be important for brain function, possibly by participating in the function of maxi-Cl channels (chloride channels of large unitary conductance). Deficiency due to genetic causes during early fetal development or infancy may cause progressive degeneration of the cerebral cortex 11 .atircnce and Cavanagh. 1968). Leigh syndrome is character)zed by the degeneration and focal necrosis of gray matter, and capillary proliferation in the brain stem. Reduced production ofTTP. possibly through inhibition of adenosine triphosphate-thiamin diphosphate phospho-ryltransferase has been suggested as a causative factor, pointing to the critical importance of this thiamin metabolite.

Severe confusion and agitation characterizes Wernicke Korsakoff syndrome. It is seen most often in chronic alcohol abusers and usually responds welt to thiamin administration. Working memory of alcohol abusers in a detoxification program appeared to improve in a dose-dependent manner with intramuscular injection of thiamin (Ambrose et al., 2001).

Mitochondria: A facilitating rote of thiamin for mitochondrial function has been suggested (Sato et id.. 2000).


Ambrose ML. Bowden SC. Wliclan (i. Thiamin treatment and working memory function pf alcohol-de pendent people; preliminary findings. He Clin Exj> Pes 200l;25; 112-16

Ariaey-Nejad MR. Balaghi M, Baker FM. Säuberlich HE. Thiamin metabolism in man.

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Dutta B.HuangW.MoleroM,KekudaR, LeibachFH,Dcvoe LD.GanapathyV,PrasadPD. Cloning of the human thiamine transporter, a member of the folate transporter family. J Biol Chem 1999;274:31925-9 Fleming JC. Steinkamp MP. Kawatsuji R.Tartagllni F. Pinkus JL, PinkusGS, Fleming MI), Neufeld LJ. Characterization of a murine high-affinity thiamine transporter. Slcl9a2. Mol Genet Metah 2001;74:273-80 Food and Nutrition Board. Institute of Medicine. Dietary Reference Intakes for thiamin, riboflavin, niacin, vitamin B6. folate, vitamin BI2, pantothenic acid biotin. and choline. National Academy Press. Washington, DC. 1498. pp.58 86: 480 I Foulon V. Anionenkov VD. C'roes k. Waelkens E. Mannaerts (iP. Van Veldhoven PP. Casteels M. Purification, molecular cloning, and expression of 2-hydroxyphylanoyl-CoA lyase, a peroxisomal thiamine pyrophosphate-dependent enzyme that catalyzes the carbon-carbon bond cleavage during alpha-oxidation of 3-methy I-branched fatty acids. Pmc Natl Acad of Sei USA 1999:96:10039 44 Gastaldi G, Cova E. Vcrri A. Lalbrenza U. Faelli A. Ruidi G. Transport of thiamin m rat renal brush border membrane vesicles. Kidney lnt 2000:57:2043 54 Gregory JF 3rd. Bioavailability of thiamin. Eur J Clin Nutr 1997;5l:S34 S37 Hanna MC. Plans .IT. Kirkness EF. Identification ofa gene within the tandem array of red anil green color pigment genes. Genomics 1997:43:3H4 6 Haves KC, Hegstcd DM. Toxicity of the vitamins. In Toxicants Occurring Naturally in Faints. Food and Nutrition Board, National Research Council. National Academy Press. Washington, DC. 1973,pp.235-53 kang YS. Terasaki T. Ohnishi T. Tsuji A. In vivo and in vitro evidence for a common carrier mediated transport of choline and basic drugs through the blood brain barrier. JPharmacobio-Dynamics 1990:13:353 60 Labay V, Raz T. Baron D. Mandel H. Williams I). Barrett T. Szargcl R. McDonald L. Shalata A, Nosaka k. Gregory S. Cohen V Mutations in SLCT9A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes melhtus and deafness. Nature Genet 1999;22:300-4 Laforenza L. (iastaldi G, Rindi G. Thiamine outflow from the enterocyte: a study using basolateral membrane vesicles from rat intestine. JPhysiol (Land) 1993; 468:401 -12 Laforenza U, Patrinin C. Alvisi C. Faelli A. Licandro A. Rindi ti. Thiamine uptake in human intestinal biopsy specimens, including observations from a patient with acute thiamine deficiency. Am J Clin Nutr 1997;66:320-6 Laurence KM, Cavanagh JB. Progressive degeneration of the cerebral cortex in infancy.

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