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The molecular identity and characterization of a Proton-Coupled Folate Transporter—PCFT; biological ramifications and impact on the activity of pemetrexed—12 06 06

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Abstract

Membrane transport of folates is essential for the survival of all mammalian cells and transport of antifolates is an important determinant of antifolate activity. While a major focus of attention has been on transport mediated by the reduced folate carrier and folate receptors, a very prominent carrier-mediated folate transport activity has been recognized for decades with a low-pH optimum and substrate specificity distinct from that of the reduced folate carrier which operates most efficiently at neutral pH. This low-pH transporter represents the mechanism by which folates are absorbed in the small intestine and it is also widely expressed in other human tissues and solid tumors. Recently, this laboratory discovered the molecular identity of this transporter which is genetically unrelated to the reduced folate carrier. This transporter is proton-coupled, electrogenic, and manifests a substrate specificity that is similar to that of the low-pH transport activity previously described in mammalian cells. The key role this transporter plays in intestinal folate absorption has been confirmed by the demonstration of a mutation in this gene in the rare autosomal recessive disorder, hereditary folate malabsorption. This article reviews (1) the characteristics and prevalence of the low-pH folate transport activity, (2) its relationship to, and properties of, the recently identified Proton-Coupled Folate Transporter (PCFT), (3) the physiological and pharmacological roles of this transporter, particularly with respect to pemetrexed, and (4) the historical controversy, now resolved, on the mechanism of intestinal folate absorption.

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Abbreviations

MTX:

methotrexate

5-methylTHF:

5-methyltetrahydrofolate

5-formylTHF:

5-formyltetrahydrofolate

RFC:

reduced folate carrier

FR:

folate receptor

PCFT:

Proton-Coupled Folate Transporter

HFM:

hereditary folate malabsorption

CSF:

cerebrospinal fluid

CNS:

central nervous system

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  1. Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA

    Rongbao Zhao & I. David Goldman

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  1. Rongbao Zhao
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Zhao, R., Goldman, I.D. The molecular identity and characterization of a Proton-Coupled Folate Transporter—PCFT; biological ramifications and impact on the activity of pemetrexed—12 06 06. Cancer Metastasis Rev 26, 129–139 (2007). https://doi.org/10.1007/s10555-007-9047-1

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