Carrier-mediated membrane transport of folates in mammalian cells.
Mediated internalization of folates is required for cellular macromolecular biosynthesis. Multiple carrier-mediated mechanisms have been identified that can fulfill this role in a variety of mammalian cell types, including neoplastic cells, with and without proliferative potential. The absorption of dietary folates also relies on the function of a carrier-mediated system in mature luminal epithelium of small intestine. The various carrier-mediated systems can be distinguished by their preferences for various folate compounds as permeants as well as by differences in temperature and pH dependence. The widely studied one-carbon, reduced-folate transport system is mediated by a transporter encoded by the newly discovered RFC-1 (reduced-folate carrier) gene. The characteristics of this gene in rodent and human cells are similar, consistent with the close similarity between these species of folate transport mediated by this transporter. However, differences occur in the form of tissue-specific expression, alternate splicing, and 5' end mRNA heterogeneity, as well as in promoter utilization regulating transcription. RFC-1 gene expression also appears to regulate luminal epithelial cell folate absorption in small intestine. However, the properties of RFC-1-mediated folate transport in these cells is anomalous when compared with that seen in nonabsorptive cell types. Detailed mechanisms as to the regulation of RFC-1 transcription are now emerging along with other information on structure and function of the transporter and its alteration following mutation.
Sirotnak
F M
FM
Program in Molecular Pharmacology and Experimental Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. sirotnaf@mskcc.org
Tolner
B
B
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D005492:Folic Acid / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics; D026901:Membrane Transport Proteins; D008969:Molecular Sequence Data
D002352:Carrier Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C120043:SLC19A2 protein, human; D005492:Folic Acid