A single amino acid difference within the folate transporter encoded by the murine RFC-1 gene selectively alters its interaction with folate analogues. Implications for intrinsic antifolate resistance and directional orientation of the transporter within the plasma membrane of tumor cells.

The Journal of Biological Chemistry
K RoyF M Sirotnak

Abstract

The apparent Km, but not Vmax, for influx of methotrexate (MTX) mediated through the plasma membrane of S180 cells by the one-carbon, reduced folate transporter as well as the KD for binding to the transporter were 4-fold higher than in L1210 cells correlating with the greater intrinsic resistance of the former to this folate analogue. In contrast, no difference was observed between each cell type with regard to efflux of [3H]MTX mediated by this same transporter in ATP-depleted cells. The difference in influx Km in the case of this 10-methyl substituted N1O analogue of folic acid was not seen with more effective permeants, such as the unsubstituted N1O aminopterin or C1O analogues. Thus, values for influx Km for aminopterin, which were 1-1.2 microM in each cell type, increased as a result of substitution at N1O (MTX) 3-fold in L1210 cells but 12-fold in S180 cells. Nucleotide sequencing of reverse transcriptase-polymerase chain reaction-generated cDNA and of polymerase chain reaction-generated genomic DNA identified a single nucleotide difference between each cell type at +890 within exon 3 of the RFC-1 gene. This was in the form of a G (L1210 cells) to A (S180 cells) transition. Codon 297, the site of this transition, encodes...Continue Reading

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Mar 24, 2000·The Biochemical Journal·H SadlishW F Flintoff
Aug 17, 1999·Annual Review of Nutrition·F M Sirotnak, B Tolner
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May 26, 2006·Yi chuan xue bao = Acta genetica Sinica·Yuan-Xi FengSong-Bin Fu
Jul 21, 2012·PloS One·Evan S HillWilliam N Frost
Aug 12, 2003·The Journal of Biological Chemistry·Wayne F FlintoffHeather Sadlish
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May 29, 1999·The Journal of Biological Chemistry·P L Ferguson, W F Flintoff
May 29, 2000·Biochimica Et Biophysica Acta·R ZhaoI D Goldman

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