Thiamin transporters

SMVT Sodium-dependent multivitamin transporter SVCT Sodium-dependent vitamin C transporter THTR High affinity thiamine transporter... 

Rajgopal, A., et al. SLC19A3 encodes a second thiamine transporter ThTr2. Biochim. Biophys. Acta 2001, 3537, 175-178. 

Dutta, B., et al. Cloning of the human thiamine transporter, a member of the folate transporter family. J. Biol. Chem. 1999, 274, 31925-31929. 

Non-enzymatic proteins found in both parasites and humans, but exhibiting different pharmacological profiles between the two species (e.g., thiamine transporter)... 

Amprolium (Fig. 5.7) is a vitamin IT analogue. It is a competitive antagonist of the thiamine transport mechanism. Amprolium has been used as a coccidi-ostat mainly in chickens, laying hens, turkeys, and ruminants. It is available as a soluble powder for addition to drinking water (60-240 mg/L) or as a premix, usually in combination with ethopabate and/or sulfaquinoxaline, for mixing with the feed (125-500 mg/kg feed). A withdrawal period of 3 days is required for chickens. 

Carbohydrate metabolism provides the main energy source in coccidia. Diets deficient in thiamin, riboflavin, or nicotinic acid—all cofactors in carbohydrate metabolism—result in suppression of parasitic infestation of chickens by E tenella and E acervulina. A thiamin analog, amprolium—1-[(4-amino-2-propyl-5-pyrimidinyl)-methyl]-2-picolinium chloride—has long been used as an effective anticoccidial agent in chickens and cattle with relatively low host toxicity. The antiparasitic activity of amprolium is reversible by thiamin and is recognized to involve inhibition of thiamin transport in the parasite. Unfortunately, amprolium has a rather narrow spectrum of antiparasitic activity it has poor activity against toxoplasmosis, a closely related parasitic infection. 

Genetic defects of the tissue thiamin transport protein and thiamin pyrophosphokinase cause megaloblastic anemia, presumahly as a result of impaired synthesis of pentoses for DNA synthesis from low activity of trans-ketolase (Section 6.3.2). In many cases, this megaloblastic anemia is thiamin-responsive, suggesting that the defect must be because of low af nity of either the transport protein or thiarnin pyrophosphokinase for its substrate (Neufeld et al., 2001). 

Hoyumpa AM Jr, Nichols SG, Wilson FA, and Schenker S (1977) Effect of ethanol on intestinal (Na, K)ATPase and intestinal thiamine transport in mts. Journal of Laboratory and Clinical Medicine 90,1086-95. 

Neufeld EJ, Fleming JC, Tartaglini E, and Steinkamp MP (2001) Thiamine-responsive megaloblastic anemia syndrome a disorder of high-affinity thiamine transport. Blood Cells Molecules and Diseases 27, 135-8. 

Thiamine absorption occurs primarily in the proximal small intestine by both a saturable (thiamine transporter) process at low concentration (Ipmol/L, or lower) and by simple passive diffusion beyond that, though percentage absorption diminishes with increased dose. The absorbed thiamine undergoes intracellular phosphorylation, mainly to the pyrophosphate, but at the serosal side 90% of the transferred thiamine is in the firee form. Thiamine uptake is enhanced by thiamine deficiency and reduced by thyroid hormone, diabetes, and ethanol ingestion. The gene for the specific thiamine transporter has been identified, and the transporter cloned. Thiamine is carried by the portal blood to the liver. The firee vitamin occurs in the plasma, but the coenzyme, TPP, is the primary cellular component. Approximately 30 mg is stored in the body with 80% as the pyrophosphate, 10% as triphosphate, and the rest as thiamine and its monophosphate. About half of the body stores are found in skeletal muscles, with much of the remainder in heart, liver, kidneys, and nervous tissues (including the brain, which contains most of the triphosphate). 

Fleming JC, Tartaglini E, Steinkamp MP, Schorderet DF, Cohen N, Neufeld EJ. The gene mutated in thiamine-responsive anemia with diabetes and deafiiess (TRMA) encodes a functional thiamine transporter. Nat Genet 1999 22 305-8. 

SLC19 (2) Folate/thiamine transporters FOLT, THTR Placenta, small intestine... 

ThiXYZ - transporter of HMP precursor YkoEDC - transporter of HMP precursor CytX - transporter of HMP precursor PnuT - thiamine transporter OMR - outer membrane thiamine transporter... 

SLC19 Folate/thiamine transporter 3 Methotrexate Thiamine-responsive megaloblastic anemia... 

Thiamin transporter Carbohydrate metabolism is the primary energy source in coc-cidia. Inhibition of the cellular transport of thiamin by the structurally similar agent ampro-lium leads to a deficiency of this cofactor in coccidia. 

A) Amprolium is an inhibitor of thiamin transport in eimeria species... 

Cells in culture allow much more detailed studies of mechanism than in vivo. Cultured cerebellar granule neurons were treated with amprolium, a potent inhibitor of thiamine transport. Exposure to amprolium causes apoptosis and the generation of reactive... 

The incidence of thiamine deficiency in alcoholics is 30-80% (Homewood and Bond, 1999). Factors that promote thiamine deficiency in alcoholics include poor thiamine intake, decreased activation of thiamine to thiamine pyrophosphate(TPP), decreased hepatic storage, decreased intestinal thiamine transport and impairment of thiamine absorption (see Table 14.3) (Breen et al, 1985 Hoyumpa, 1980). Although thiamine is stored in various sites, including skeletal muscles, heart, kidneys and brain, the Uver remains the main storage site. Due to the reasons cited above, hepatic thiamine content may be reduced by 73% in patients with severe, chronic alcoholic liver disease. In addition, ethanol has been shown to promote thiamine release from the liver (Hoyumpa, 1980). 

Dudeja, P.K., Tyagi, S., GUI, R., and Said, H.M. (2003). Evidence of a carrier-mediated mechanism for thiamine transport to human jejunal basolateral membrane vesicles. Dig. Dis. ScL 48 109-115. 

Thiamin transport has been nearly exclusively studied in mammalian cells. However, a few studies carried out in bacteria show that thiamin can be transported via ABC transporters. These transporters comprise a periplasmic thiamin binding protein in gram-negative bacteria such as E. coli and Salmonella typhimurium. These proteins are generally not specific for thiamin as they also bind ThMP and ThDP. Examination of the three-dimensional structure of an E. coli thiamin binding protein revealed structural similarities with thiami-nase I, suggesting a common ancestor (Soriano et al. 2008). 

Another thiamin transporter, ThTR2, is the product of the SLC19A3 gene. It transports thiamin with a very high apparent affinity = 20-100 nM). 

Thiamin-related diseases are the result of either insulficient thiamin intake (thiamin deficiency), poisoning by antithiamins, or of mutations in thiamin transporters or thiamin diphosphate-dependent enzymes. 

Mutations in thiamin transporters lead to various disorders ranging from megaloblastic thiamin-responsive anaemia to severe, sometimes lethal, encephalopathies. 

---