Cloning and Functional Expression of a cDNA Encoding a Mammalian Sodium-dependent Vitamin Transporter Mediating the Uptake of Pantothenate, Biotin, and Lipoate

Prasad, Puttur D.; Wang, Haiping; Kekuda, Ramesh; Fujita, Takuya; Fei, You Jun; Devoe, Lawrence D.; Leibach, Frederick H.; Ganapathy, Vadivel

doi:10.1074/jbc.273.13.7501

Cited by 209 publications

(118 citation statements)

References 24 publications

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“…5B). Thus far, our results do not indicate whether this Na ϩ uptake is substrate-coupled or is a ''Na ϩ leak'' similar to that typically observed among of all of the previously characterized members of the SLC5 family (22)(23)(24). However, our findings provide direct functional data that SLC5A8 encodes a sodium transporter and is therefore highly likely to be a bona fide member of the SLC5 family of sodium solute symporters.…”

Section: Slc5a8 Encodes a Functional Sodiumcontrasting

confidence: 52%

“…Both molecular homology and functional data suggest that SLC5A8 functions as a sodium solute symporter. There are 109 currently known members of the sodium solute symporter family, which functions to cotransport sodium coupled to solutes as diverse as iodine (NIS͞SLC5A5), glucose (SGLT1͞SLC5A1;SGLT2͞SLC5A2), inositol (SMIT͞ SLC5A3), and water-soluble vitamins (SMVT͞SLC5A6) (22)(23)(24). Elucidating the putative solute cotransported by SLC5A8 may provide both insight into the mechanism of SLC5A8 growth suppression and leads for potential development of novel agents useful for colon neoplasia prevention and treatment.…”

Section: Discussionmentioning

confidence: 99%

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SLC5A8 , a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers

Myeroff

Smiraglia

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

264

254

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We identify a gene, SLC5A8, and show it is a candidate tumor suppressor gene whose silencing by aberrant methylation is a common and early event in human colon neoplasia. Aberrant DNA methylation has been implicated as a component of an epigenetic mechanism that silences genes in human cancers. Using restriction landmark genome scanning, we performed a global search to identify genes that would be aberrantly methylated at high frequency in human colon cancer. From among 1,231 genomic NotI sites assayed, site 3D41 was identified as methylated in 11 of 12 colon cancers profiled. Site 3D41 mapped to exon 1 of SLC5A8, a transcript that we assembled. In normal colon mucosa we found that SLC5A8 exon 1 is unmethylated and SLC5A8 transcript is expressed. In contrast, SLC5A8 exon 1 proved to be aberrantly methylated in 59% of primary colon cancers and 52% of colon cancer cell lines. SLC5A8 exon 1 methylated cells were uniformly silenced for SLC5A8 expression, but reactivated expression on treatment with a demethylating drug, 5-azacytidine. Transfection of SLC5A8 suppressed colony growth in each of three SLC5A8-deficient cell lines, but showed no suppressive effect in any of three SLC5A8-proficient cell lines. SLC5A8 exon 1 methylation is an early event, detectable in colon adenomas, and in even earlier microscopic colonic aberrant crypt foci. Structural homology and functional testing demonstrated that SLC5A8 is a member of the family of sodium solute symporters, which are now added as a class of candidate colon cancer suppressor genes.colon cancer

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Section: Slc5a8 Encodes a Functional Sodiumcontrasting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

SLC5A8 , a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers

Myeroff

Smiraglia

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

264

254

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“…The first is a transporter for the uptake of biotin through the plasma membrane. Although different biotin transporters have been proposed in different species, only one has been confirmed by cDNA cloning (3,4). The sodiumdependent multivitamin transporter (SMVT) transports biotin, pantothenic acid, and lipoic acid and is characterized by a seemingly high K m for biotin (5,6).…”

mentioning

confidence: 99%

Paradoxical Regulation of Biotin Utilization in Brain and Liver and Implications for Inherited Multiple Carboxylase Deficiency

Pacheco‐Alvarez

Solorzano–Vargas

Gravel

et al. 2004

Journal of Biological Chemistry

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Holocarboxylase synthetase (HCS) catalyzes the biotinylation of five carboxylases in human cells, and mutations of HCS cause multiple carboxylase deficiency (MCD). Although HCS also participates in the regulation of its own mRNA levels, the relevance of this mechanism to normal metabolism or to the MCD phenotype is not known. In this study, we show that mRNA levels of enzymes involved in biotin utilization, including HCS, are down-regulated during biotin deficiency in liver while remaining constitutively expressed in brain. We propose that this mechanism of regulation is aimed at sparing the essential function of biotin in the brain at the expense of organs such as liver and kidney during biotin deprivation. In MCD, it is possible that some of the manifestations of the disease may be associated with downregulation of biotin utilization in liver because of the impaired activity of HCS and that high dose biotin therapy may in part be important to overcoming the adverse regulatory impact in such organs.

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“…Here, biotin transport was quantified using a physiological concentration of [ 3 H]biotin (475 pM) in the presence or absence of putative BTD inhibitors (0.5 mM) as described [31]; the K m of biotin transporters is in the low micromolar range [32]. Human Jurkat cells were used for biotin transport studies [33].…”

Section: Biotin Transportmentioning

confidence: 99%

Biotinyl-methyl 4-(amidomethyl)benzoate is a competitive inhibitor of human biotinidase

Kobza¹,

Chaiseeda²,

Sarath³

et al. 2008

The Journal of Nutritional Biochemistry

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M.; and Zempleni, Janos, "Biotinyl-methyl 4-(amidomethyl)benzoate is a competitive inhibitor of human biotinidase" (2008 Abstract Posttranslational modification of histones by biotinylation can be catalyzed by both biotinidase (BTD) and holocarboxylase synthetase. Biotinylation of histones is an important epigenetic mechanism to regulate gene expression, DNA repair, and chromatin remodeling. The role of BTD in histone biotinylation is somewhat ambiguous, given that BTD also catalyzes removal of the biotin tag from histones. Here, we sought to develop BTD inhibitors for future studies of the role of BTD in altering chromatin structure. We adopted an existing colorimetric BTD assay for use in a novel 96-well plate format to permit high-throughput screening of potential inhibitors. Biotin analogs were chemically synthesized and tested for their ability to inhibit human BTD. Seven of these compounds inhibited BTD by 26-80%. Biotinyl-methyl 4-(amidomethyl)benzoate had the largest effect on BTD, causing an 80% inhibition at 1 mM concentration. Enzyme kinetics studies were conducted to determine V max , K m and K i for the seven inhibitors; kinetics were consistent with the hypothesis that biotinyl-methyl 4-(amidomethyl)benzoate and the other compounds acted by competitive inhibition of BTD. Finally, biotinyl-methyl 4-(amidomethyl) benzoate did not affect biotin transport in human cells, suggesting specificity in regard to biotin-related processes.

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Cloning and Functional Expression of a cDNA Encoding a Mammalian Sodium-dependent Vitamin Transporter Mediating the Uptake of Pantothenate, Biotin, and Lipoate

Abstract: Previous studies have shown that a Na

Cited by 209 publications

References 24 publications

SLC5A8 , a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers

SLC5A8 , a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers

Paradoxical Regulation of Biotin Utilization in Brain and Liver and Implications for Inherited Multiple Carboxylase Deficiency

Biotinyl-methyl 4-(amidomethyl)benzoate is a competitive inhibitor of human biotinidase

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