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Rongbao Zhao - One of the best experts on this subject based on the ideXlab platform.
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Folate and thiamine transporters mediated by facilitative carriers (SLC19A1-3 and SLC46A1) and folate receptors.
Molecular aspects of medicine, 2013Co-Authors: Rongbao Zhao, I David GoldmanAbstract:The reduced folate carrier (RFC, SLC19A1), thiamine transporter-1 (ThTr1, SLC19A2) and thiamine transporter-2 (ThTr2, SLC19A3) evolved from the same family of solute carriers. SLC19A1 transports folates but not thiamine. SLC19A2 and SLC19A3 transport thiamine but not folates. SLC19A1 and SLC19A2 deliver their substrates to systemic tissues; SLC19A3 mediates intestinal thiamine absorption. The proton-coupled folate transporter (PCFT, SLC46A1) is the mechanism by which folates are absorbed across the apical-brush-border membrane of the proximal small intestine. Two folate receptors (FOLR1 and FOLR2) mediate folate transport across epithelia by an endocytic process. Folate transporters are routes of delivery of drugs for the treatment of cancer and inflammatory diseases. There are autosomal recessive disorders associated with mutations in genes encoded for SLC46A1 (hereditary folate malabsorption), FOLR1 (cerebral folate deficiency), SLC19A2 (thiamine-responsive megaloblastic anemia), and SLC19A3 (biotin-responsive basal ganglia disease).
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slc19a3 encodes a second thiamine transporter thtr2
Biochimica et Biophysica Acta, 2001Co-Authors: Arun Rajgopal, Antoinette Edmondnson, David I Goldman, Rongbao ZhaoAbstract:Abstract Recently, a new family of facilitative carriers has been cloned consisting of the reduced folate (SLC19A1) and the thiamine (SLC19A2) transporters. Despite a high level of sequence identity and similarity there is essentially no functional overlap between these carriers. The former transports folates and the latter thiamine. In this paper we describe the function of SLC19A3, another member of this transporter family most recently cloned, after transient transfection of the cDNA into HeLa cells. Uptake of [ 3 H]thiamine, but not of methotrexate nor folic acid, was enhanced in SLC19A3 transfectants relative to vector control. Similarly, in the transfectants thiamine transport increased with an increase in pH with peak activity at pH ∼7.5. While [ 3 H]thiamine uptake was markedly inhibited by nonlabeled thiamine it was not inhibited by several organic cations in 100-fold excess. Hence this carrier has a high degree of specificity for vitamin B 1 . The data indicate that SLC19A3 has the characteristics of SLC19A2 (ThTr1) and represents a second thiamine transporter (ThTr2) in this family of facilitative carriers.
Puttur D Prasad - One of the best experts on this subject based on the ideXlab platform.
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slc19 the folate thiamine transporter family
Pflügers Archiv: European Journal of Physiology, 2004Co-Authors: Vadivel Ganapathy, Sylvia B. Smith, Puttur D PrasadAbstract:The SLC19 gene family of solute carriers is a family of three transporter proteins with significant structural similarity, transporting, however, substrates with different structure and ionic charge. The three members of this gene family are expressed ubiquitously and mediate the transport of two important water-soluble vitamins, folate and thiamine. The concentrative transport of substrates mediated by the members of this gene family is energized by transcellular H+/OH− gradient. SLC19A1 is expressed at highest levels in absorptive cells where it is located in a polarized manner either in the apical or basal membrane, depending on the cell type. It mediates the transport of reduced folate and its analogs, such as methotrexate, which are anionic at physiological pH. SLC19A2 is expressed ubiquitously and mediates the transport of thiamine, a cation at physiological pH. SLC19A3 is also widely expressed and is capable of transporting thiamine. This review summarizes the current knowledge on the structural, functional, molecular and physiological aspects of the SLC19 gene family.
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SLC19: the folate/thiamine transporter family
Pflügers Archiv: European Journal of Physiology, 2003Co-Authors: Vadivel Ganapathy, Sylvia B. Smith, Puttur D PrasadAbstract:The SLC19 gene family of solute carriers is a family of three transporter proteins with significant structural similarity, transporting, however, substrates with different structure and ionic charge. The three members of this gene family are expressed ubiquitously and mediate the transport of two important water-soluble vitamins, folate and thiamine. The concentrative transport of substrates mediated by the members of this gene family is energized by transcellular H+/OH− gradient. SLC19A1 is expressed at highest levels in absorptive cells where it is located in a polarized manner either in the apical or basal membrane, depending on the cell type. It mediates the transport of reduced folate and its analogs, such as methotrexate, which are anionic at physiological pH. SLC19A2 is expressed ubiquitously and mediates the transport of thiamine, a cation at physiological pH. SLC19A3 is also widely expressed and is capable of transporting thiamine. This review summarizes the current knowledge on the structural, functional, molecular and physiological aspects of the SLC19 gene family.
De Jesus Df - One of the best experts on this subject based on the ideXlab platform.
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loss of function mutation in thiamine transporter 1 in a family with autosomal dominant diabetes
Diabetes, 2019Co-Authors: Prapaporn Jungtrakoon, Patinut Buranasupkajorn, De Jesus Df, Jun Shirakawa, M GuptaAbstract:Solute Carrier Family 19 Member 2 ( SLC19A2 ) encodes thiamine transporter 1 (THTR1), which facilitates thiamine transport across the cell membrane. SLC19A2 homozygous mutations have been described as a cause of thiamine-responsive megaloblastic anemia (TRMA), an autosomal recessive syndrome characterized by megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Here we describe a loss-of-function SLC19A2 mutation (c.A1063C: p.Lys355Gln) in a family with early-onset diabetes and mild TRMA traits transmitted in an autosomal dominant fashion. We show that SLC19A2 deficient β-cells are characterized by impaired thiamine uptake, which is not rescued by overexpression of the p.Lys355Gln mutant protein. We further demonstrate that SLC19A2 deficit causes impaired insulin secretion in conjunction with mitochondrial dysfunction, loss of protection against oxidative stress, and cell cycle arrest. These findings link SLC19A2 mutations to autosomal dominant diabetes and suggest a role of SLC19A2 in β-cell function and survival.
Rafael Artuch - One of the best experts on this subject based on the ideXlab platform.
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op6 2631 decreased free thiamine in cerebro spinal fluid and fibroblasts is a sensitive marker of thiamine transporter 2 deficiency in leigh syndrome patients
European Journal of Paediatric Neurology, 2015Co-Authors: J Ortigoza D Escobar, Mercedes Casado, J A Mayr, Alfonso Ribes, Angela Arias, Mercedes Serrano, Mireia Tondo, Niklas Darin, Marta Moleroluis, Rafael ArtuchAbstract:Objectives Thiamine transporter-2 (hTHTR2) deficiency due to SLC19A3 mutations is a potentially reversible cause of Leigh syndrome for which no biochemical markers are currently available. Our aim was to assess the sensitivity of thiamine quantification in cerebrospinal fluid (CSF) and fibroblasts from patients with Leigh encephalopathy and SLC19A3 defects as compared with other causes of Leigh syndrome. Methods Thiamine vitamers (free-thiamine, thiamine monophosphate (TMP) and thiamine diphosphate (TDP)) were analyzed by HPLC-fluorescence detection in whole-blood and cerebrospinal fluid (CSF) samples from 106 and 38 paediatric controls, respectively. Results were compared with patients with Leigh syndrome due to SLC19A3 defects (N=6) and mitochondrial respiratory chain defects (N=9). In all but one SLC19A3 patient, samples were collected before thiamine supplementation. Thiamine vitamers were also analyzed by HPLC in fibroblasts from SLC19A3 patients (N=3) and patients with other metabolic defects (N=6). Results A negative correlation between thiamine isoforms and age was detected in whole-blood and CSF, thus three reference intervals were established for free-thiamine and two intervals for TMP and TDP. Free-thiamine was severely reduced in five non-treated SLC19A3 patients CSF, but not TMP and TPP. The SLC19A3 patient under thiamine supplementation showed thiamine values above reference range. Nine Leigh patients with mitochondrial defects showed normal o slightly reduced values for CSF thiamine. In SLC19A3 patient's fibroblasts, a reduction in free-thiamine was detected as compared with control sample. These values normalized after thiamine was added to the culture medium. Conclusion SLC19A3 patients show a profound deficiency of free-thiamine in the CSF that allows their identification from other causes of Leigh syndrome. SLC19A3 is essential to maintain CSF thiamine homeostasis and to prevent brain damage. Thiamine overload can supply the SLC19A3 defect and restore thiamine values in fibroblasts and CSF, probably by an alternative transport system.
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OP6 – 2631: Decreased free-thiamine in cerebro spinal fluid and fibroblasts is a sensitive marker of thiamine transporter 2 deficiency in Leigh syndrome patients
European Journal of Paediatric Neurology, 2015Co-Authors: J.d. Ortigoza Escobar, Marta Molero-luis, Mercedes Casado, J A Mayr, Alfonso Ribes, Angela Arias, Mercedes Serrano, Mireia Tondo, Niklas Darin, Rafael ArtuchAbstract:Objectives Thiamine transporter-2 (hTHTR2) deficiency due to SLC19A3 mutations is a potentially reversible cause of Leigh syndrome for which no biochemical markers are currently available. Our aim was to assess the sensitivity of thiamine quantification in cerebrospinal fluid (CSF) and fibroblasts from patients with Leigh encephalopathy and SLC19A3 defects as compared with other causes of Leigh syndrome. Methods Thiamine vitamers (free-thiamine, thiamine monophosphate (TMP) and thiamine diphosphate (TDP)) were analyzed by HPLC-fluorescence detection in whole-blood and cerebrospinal fluid (CSF) samples from 106 and 38 paediatric controls, respectively. Results were compared with patients with Leigh syndrome due to SLC19A3 defects (N=6) and mitochondrial respiratory chain defects (N=9). In all but one SLC19A3 patient, samples were collected before thiamine supplementation. Thiamine vitamers were also analyzed by HPLC in fibroblasts from SLC19A3 patients (N=3) and patients with other metabolic defects (N=6). Results A negative correlation between thiamine isoforms and age was detected in whole-blood and CSF, thus three reference intervals were established for free-thiamine and two intervals for TMP and TDP. Free-thiamine was severely reduced in five non-treated SLC19A3 patients CSF, but not TMP and TPP. The SLC19A3 patient under thiamine supplementation showed thiamine values above reference range. Nine Leigh patients with mitochondrial defects showed normal o slightly reduced values for CSF thiamine. In SLC19A3 patient's fibroblasts, a reduction in free-thiamine was detected as compared with control sample. These values normalized after thiamine was added to the culture medium. Conclusion SLC19A3 patients show a profound deficiency of free-thiamine in the CSF that allows their identification from other causes of Leigh syndrome. SLC19A3 is essential to maintain CSF thiamine homeostasis and to prevent brain damage. Thiamine overload can supply the SLC19A3 defect and restore thiamine values in fibroblasts and CSF, probably by an alternative transport system.
Hamid M Said - One of the best experts on this subject based on the ideXlab platform.
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targeting and trafficking of the human thiamine transporter 2 in epithelial cells
Journal of Biological Chemistry, 2006Co-Authors: Veedamali S. Subramanian, Jonathan S Marchant, Hamid M SaidAbstract:Abstract Humans lack biochemical pathways for thiamine synthesis, so cellular requirements are met via specific carrier-mediated uptake pathways. Two proteins from the solute carrier SLC19A gene family have been identified as human thiamine transporters (hTHTRs), SLC19A1 (hTHTR1) and SLC19A2 (hTHTR2). Both of these transporters are co-expressed but are differentially targeted in polarized cell types that mediate vectorial thiamine transport (e.g. renal and intestinal epithelia). It is important to understand the domain structure of these proteins, namely which regions within the polypeptide sequence are important for physiological delivery to the cell surface, in order to understand the impact of clinically relevant mutations on thiamine transport. Here we have characterized the mechanisms regulating hTHTR2 distribution by using live cell imaging methods that resolve the targeting and trafficking dynamics of full-length hTHTR2, a series of hTHTR2 truncation mutants, as well as chimeras comprising the hTHTR1 and hTHTR2 sequence. We showed the following: (i) that the cytoplasmic COOH-tail of hTHTR2 is not essential for apical targeting in polarized cells; (ii) that delivery of hTHTR2 to the cell surface is critically dependent on the integrity of the transmembrane backbone of the polypeptide so that minimal truncations abrogate cell surface expression of hTHTR2; and (iii) video rate images of hTHTR2-containing intracellular vesicles displayed rapid bi-directional trafficking events to and from the cell surface impaired by microtubule-disrupting but not microfilament-disrupting agents as well as by overexpression of the dynactin subunit dynamitin (p50). Finally, we compared the behavior of hTHTR2 with that of hTHTR1 and the human reduced folate carrier (SLC19A1) to underscore commonalities in the cell surface targeting mechanisms of the entire SLC19A gene family.
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Expression and promoter analysis of SLC19A2 in the human intestine
Biochimica et Biophysica Acta, 2002Co-Authors: Jack C. Reidling, Veedamali S. Subramanian, Pradeep K Dudeja, Hamid M SaidAbstract:Abstract The molecular mechanism and regulation of the intestinal uptake process of dietary thiamine is not well understood. Previous studies have established the involvement of a carrier-mediated system for thiamine uptake in the human intestine. Recently a human thiamine transporter, SLC19A2, was cloned from a number of human tissues. Little, however, is known about expression of the SLC19A2 message along the native human gastrointestinal tract, and no analysis of its promoter in intestinal tissue is available. Therefore, the current studies were aimed at investigating the expression of SLC19A2 in the human gastrointestinal tract and at analyzing the promoter of this potential intestinal thiamine transporter. First we cloned SLC19A2 cDNA from a human intestinal cell line (Caco-2) by reverse transcriptase–polymerase chain reaction, then used this cDNA as a probe in Northern blot analysis. SLC19A2 message was found to be expressed in all gastrointestinal tissues in the following order: liver>stomach>duodenum>jejunum>colon>cecum>rectum>ileum. SLC19A2 was also expressed at the protein level in Caco-2 cells and in native human small intestine by Western blot analysis. We also cloned the 5′-regulatory region of the SLC19A2 gene and confirmed activity of its promoter following transfection into intestinal epithelial Caco-2 cells. Furthermore, we identified the minimal promoter region required for basal activity of SLC19A2 in these cells which was found to be mainly encoded in a sequence between −356 and −36, and included multiple cis -regulatory elements. Transcription initiation sites of the SLC19A2 gene in intestinal epithelial Caco-2 cells were also identified by 5′-rapid amplification of cDNA ends. These results demonstrate that SLC19A2 is expressed in various regions of the human gastrointestinal tract. In addition, the results provide the first characterization of the SLC19A2 promoter. These findings raise the possibility that SLC19A2 may play a role in the normal intestinal thiamine absorption process.
