Membrane transporters and folate homeostasis: intestinal absorption and transport into systemic compartments and tissues

Abstract

Folates, the generic term for the family of B vitamins, are derived entirely from dietary sources, and are key one-carbon donors required for de novo nucleotide and methionine synthesis. These highly hydrophilic molecules utilize genetically distinct and functionally diverse transport systems to enter cells: the reduced folate carrier (RFC), the proton-coupled folate transporter (PCFT), and the folate receptors. Each plays a unique role in mediating folate transport across epithelia and into systemic tissues. With the recent discovery of the mechanism of intestinal folate absorption, and the clarification of the genetic basis for the autosomal recessive disorder, hereditary folate malabsorption, involving loss-of-function mutations in PCFT protein, it is now possible to piece together how these folate transporters contribute, both individually and collectively, to folate homeostasis in humans. This review focuses on the physiological roles of these major folate transporters with a brief consideration of their impact on the pharmacological activities of antifolates.

Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition

“…All crystallization experiments were carried out in the Indiana University METACyt Crystallization Automation Facility. Results shown in this report for the P6 5 and P1 crystal forms of apo-hFRα are derived from work performed at beamline 19BM at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source. Argonne is operated by UChicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research under Contract DE-AC02-06CH11357.…”

“…Folates are necessary in eukaryotic cells for single carbon transfer reactions, notably the conversion of homocysteine to methionine and a multitude of steps in de novo nucleotide synthesis (2)(3)(4)(5). Folic acid and its reduced derivatives, including 5-methyltetrahydrofolate and 10-formyltetrahydrofolate, are transported via two widely expressed facilitative transporters, the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT), and via a family of glycosyl-phosphatidylinositol (GPI)-anchored receptors with limited expression profiles generally described as folate receptors (FRs) (3)(4)(5)(6)(7). For >60 y, folate analogs that inhibit intracellular folate-using enzymes, termed antifolates, have been developed to treat a variety of cancer types and inflammatory diseases (8)(9)(10)(11)(12)(13)(14).…”

Identification and Functional Impact of Homo-oligomers of the Human Proton-coupled Folate Transporter

“…Three primary transport routes are involved in folate internalization, including the reduced folate carrier (RFC), 4 the proton-coupled folate transporter (PCFT), and the folate receptors. These transporters differ in terms of mechanism, and each system typically plays a unique role in mediating folate transport across epithelia and into systemic tissues (2).…”

“…Although proton-coupled, this transporter is also func-tional at more physiologic pH, at which it retains appreciable affinity for pemetrexed (16), a newer antifolate currently approved for treating mesothelioma and non-squamous, nonsmall cell lung cancer (17)(18)(19). In addition to proximal small intestine, PCFT is expressed in other normal tissues, such as liver and kidney, which do not experience low pH conditions (2). In terms of cancer, a prominent low pH transport route was identified in 29 of 32 human solid tumor cell lines (20), and abundant hPCFT transcripts were detected by real-time PCR in a large cohort (n ϭ 53) of human tumor sublines from an assortment of lineages (21).…”

Incrimination of Heterogeneous Nuclear Ribonucleoprotein E1 (hnRNP-E1) as a Candidate Sensor of Physiological Folate Deficiency

“…High affinity folate receptors (FR), 2 which were first introduced to the biomedical literature 30 years ago (2), are critical for the cellular uptake of 5-methyltetrahydrofolate in several human (normal and cancer) cells (3). Among three human FR (FR-␣, FR-␤, and FR-␥), the FR-␣ are ubiquitous and physiologically relevant for proper development of the neural tube and neural crest (4,5), for hematopoiesis (6), for transplacental maternal-to-fetal folate transport (7), for cerebral folate transport (8), and for renal conservation of folates (3,9,10).…”