ReviewFolate and thiamine transporters mediated by facilitative carriers (SLC19A1-3 and SLC46A1) and folate receptorsâ
Introduction
The folates and thiamine are members of the B family of vitamins. Both are metabolized to active forms that are poor export substrates and accumulate in cells where they sustain key metabolic reactions. Folates carry a negative charge, and thiamine a positive charge, at physiological pH (Fig. 1A). Each is transported into cells by a specific member of the SLC19 family of solute carriers with a high degree of structural specificity (Table 1). SLC19A1, the reduced folate carrier (RFC), transports folates but not thiamine; SLC19A2 (thiamine transporter 1- ThTr1) and SLC19A3 (thiamine transporter 2-ThTr2) transport thiamine but not folates. These transporters function optimally at physiological pH and are the major routes of delivery of folates and thiamine to systemic tissues. Intestinal absorption of folates is mediated by another member of the solute carrier family, SLC46A1 (Table 2), the proton-coupled folate transporter (PCFT), also required for folate transport across the blood:choroid plexus:cerebrospinal fluid barrier. Folates are also transported by an endocytic mechanism mediated by two folate membrane receptors, FOLR1 and FOLR2. SLC19A1-3 are members of the 2A.48 subfamily of the Saier âtransporter classification systemâ (http://www.tcdp.org/), while SLC46A1 is not classified in this system. The physiological roles of SLC19A2, SLC46A1, FOLR1, and to some extent SLC19A2 have been established by the autosomal recessive inherited disorders caused by loss-of-function mutations in these genes. Folate transporters also play an important role in the delivery of folate analogs to neoplastic and inflammatory cells for the treatment of cancer and inflammatory/autoimmune diseases, respectively. The recent development of diagnostic and therapeutic agents linked to folic acid, transported into malignant and immune cells via folate receptor mediated endocytosis, is a novel approach to the selective delivery of drugs to these tissues. Much of what has been learned about the mechanisms of folate transport has come from studies focused on folate analogues, in particular, methotrexate and, more recently, pemetrexed. Membrane transport of folates has been the subject of several recent reviews (Matherly et al., 2007, Matherly and Goldman, 2003, Zhao et al., 2009a, Zhao et al., 2011)
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The biological roles of folates and thiamine
The major physiological folate is 5-methyltetrahydrofolate (Fig. 1A). This is the predominant dietary form of folate, the folate absorbed in the intestine, the form in blood and delivered to mammalian tissues. The carbon at the N- 5 position is donated to homocysteine in the synthesis of methionine, yielding tetrahydrofolate to which up to eight glutamate residues are added to the Îł-carboxy of the glutamic acid moiety to form a series of polyglutamate derivatives. These are the preferred
The reduced folate carrier (RFC;SLC19A1)
Soon after methotrexate was introduced for the treatment of acute leukemia, acquired resistance emerged as a major clinical challenge. Laboratory studies identified membrane transport as an important determinant of the activity of this agent and loss of transport as an important mechanism of acquired resistance in tumor cell lines (Zhao and Goldman, 2003). At about the same time as carrier-mediated mechanisms were being identified for a variety of major biological substrates, methotrexate
Expression and function
Distinct from transport mediated by the solute carriers is folate-receptor mediated endocytosis involving two genetically distinct proteins, folate receptor-1 (FRι encoded by the FOLR1 gene) and folate-receptor-2 (FRβ encoded by the FOLR2 gene), that are functionally similar but have a different pattern of tissue expression.
FOLR1 in adult mice is expressed almost exclusively in epithelia â the apical brush border membrane of the proximal renal tubule, the apical membrane of the choroid plexus
Folate transporters
Targeted disruption of Slc46a1 in mice is embryonic lethal unless the dams are supplemented with parenteral folate. When prenatal supplementation is sufficient, normal pups can be delivered but, without further supplementation, they die within 2Â weeks due to atrophy of all hematopoietic tissues (bone marrow, liver, spleen, thymus) (Zhao et al., 2001). There is no known human counterpart. Thirty-one families have now been described with loss-of-function SLC46A1 gene mutations causing HFM (OMIM
Summation
Considerable progress has been made over the past two decades in the development of a comprehensive understanding of the mechanisms by which folates and thiamine are transported across epithelia and into human cells. Major advances were highlighted by identification of the genes encoding these vitamin transporters (Table 1, Table 2) employing diverse approaches and in diverse contexts. The impetus for cloning the SLC19A1 gene was stimulated by the observation that acquired resistance to
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Publication in part sponsored by the Swiss National Science Foundation through the National Center of Competence in Research (NCCR) TransCure, University of Bern, Switzerland; Director Matthias A. Hediger; Web: http://www.transcure.ch.