The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
I. David Goldman - One of the best experts on this subject based on the ideXlab platform.
-
The proton-coupled Folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral Folate deficiency of infancy: Hereditary Folate malabsorption.
Molecular Aspects of Medicine, 2016Co-Authors: Rongbao Zhao, Srinivas Aluri, I. David GoldmanAbstract:Abstract The proton-coupled Folate transporter (PCFT-SLC46A1) is the mechanism by which Folates are absorbed across the brush-border membrane of the small intestine. The transporter is also expressed in the choroid plexus and is required for transport of Folates into the cerebrospinal fluid. Loss of PCFT function, as occurs in the autosomal recessive disorder “hereditary Folate malabsorption” (HFM), results in a syndrome characterized by severe systemic and cerebral Folate deficiency. Folate-receptor alpha (FRα) is expressed in the choroid plexus, and loss of function of this protein, as also occurs in an autosomal recessive disorder, results solely in “cerebral Folate deficiency” (CFD), the designation for this disorder. This paper reviews the current understanding of the functional and structural properties and regulation of PCFT, an electrogenic proton symporter, and contrasts PCFT properties with those of the reduced Folate carrier (RFC), an organic anion antiporter, that is the major route of Folate transport to systemic tissues. The clinical characteristics of HFM and its treatment, based upon the thirty-seven known cases with the clinical syndrome, of which thirty have been verified by genotype, are presented. The ways in which PCFT and FRα might interact at the level of the choroid plexus such that each is required for Folate transport from blood to cerebrospinal fluid are considered along with the different clinical presentations of HFM and CFD.
-
Identification of Tyr residues that enhance Folate substrate binding and constrain oscillation of the proton-coupled Folate transporter (PCFT-SLC46A1)
American Journal of Physiology-cell Physiology, 2015Co-Authors: Michele Visentin, Rongbao Zhao, Ersin Selcuk Unal, Mitra Najmi, Andras Fiser, I. David GoldmanAbstract:The proton-coupled Folate transporter (PCFT) mediates intestinal Folate absorption and transport of Folates across the choroid plexus. This study focuses on the role of Tyr residues in PCFT functio...
-
The proton-coupled Folate transporter: physiological and pharmacological roles.
Current Opinion in Pharmacology, 2013Co-Authors: Rongbao Zhao, I. David GoldmanAbstract:Recent studies have identified the proton-coupled Folate transporter (PCFT) as the mechanism by which Folates are absorbed across the apical brush-border membrane of the small intestine and across the basolateral membrane of the choroid plexus into the cerebrospinal fluid. Both processes are defective when there are loss-of-function mutations in this gene as occurs in the autosomal recessive disorder hereditary Folate malabsorption. Because this transporter functions optimally at low pH, antiFolates are being developed that are highly specific for PCFT in order to achieve selective delivery to malignant cells within the acidic environment of solid tumors. PCFT has a spectrum of affinities for Folates and antiFolates that narrows and increases at low pH. Residues have been identified that play a role in Folate and proton binding, proton coupling, and oscillation of the carrier between its conformational states.
-
Biological Role, Properties, and Therapeutic Applications of the Reduced Folate Carrier (RFC-SLC19A1) and the Proton-Coupled Folate Transporter (PCFT-SLC46A1)
Targeted Drug Strategies for Cancer and Inflammation, 2011Co-Authors: Larry H Matherly, Ndeye Diop-bove, I. David GoldmanAbstract:The mechanisms by which Folates are transported across cell membranes have been an area of research interest for nearly five decades. Major transport systems include the facilitative carriers, the reduced Folate carrier (RFC) and the proton-coupled Folate transporter (PCFT), and the high affinity Folate receptors (FRs) α and β which transport Folates by endocytosis. RFC is the major transport system in mammalian cells and tissues for Folate cofactors and clinically relevant antiFolate drugs including methotrexate, raltitrexed, pemetrexed, and pralatrexate. PCFT was identified in 2006 as the mechanism by which Folates are transported across the apical brush border of the proximal small intestine. Whereas both PCFT and RFC are widely expressed in tumors, PCFT differs from RFC in its acidic pH optimum which favors transport at the low pH commonly found in the hypoxic microenvironment of solid tumors. Reflecting tumor-specific patterns of expression and/or function, recent studies have focused on the identification of Folate-targeted therapeutics with selective transport by PCFT and FRs over RFC. The goal is to circumvent RFC and the potentially toxic consequences of drug transport by RFC in normal tissues. RFC in tumor cells can also influence the pharmacologic activity of PCFT and FR-selective agents by transporting physiological Folates which compete for polyglutamylation and binding to intracellular targets. This review focuses on the facilitative pathways of (anti)Folate transport, including RFC (SLC19A1) and PCFT (SLC46A1) in relation to their molecular properties, and their physiological and pharmacological roles.
-
Membrane transporters and Folate homeostasis: intestinal absorption and transport into systemic compartments and tissues.
Expert Reviews in Molecular Medicine, 2009Co-Authors: Rongbao Zhao, Larry H Matherly, I. David GoldmanAbstract:: Members of the family of B9 vitamins are commonly known as Folates. They are derived entirely from dietary sources and are key one-carbon donors required for de novo nucleotide and methionine synthesis. These highly hydrophilic molecules use several genetically distinct and functionally diverse transport systems to enter cells: the reduced Folate carrier, the proton-coupled Folate transporter and the Folate receptors. Each plays a unique role in mediating Folate transport across epithelia and into systemic tissues. The mechanism of intestinal Folate absorption was recently uncovered, revealing the genetic basis for the autosomal recessive disorder hereditary Folate malabsorption, which results from loss-of-function mutations in the proton-coupled Folate transporter gene. It is therefore 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 the major Folate transporters, with a brief consideration of their impact on the pharmacological activities of antiFolates.
Rongbao Zhao - One of the best experts on this subject based on the ideXlab platform.
-
The proton-coupled Folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral Folate deficiency of infancy: Hereditary Folate malabsorption.
Molecular Aspects of Medicine, 2016Co-Authors: Rongbao Zhao, Srinivas Aluri, I. David GoldmanAbstract:Abstract The proton-coupled Folate transporter (PCFT-SLC46A1) is the mechanism by which Folates are absorbed across the brush-border membrane of the small intestine. The transporter is also expressed in the choroid plexus and is required for transport of Folates into the cerebrospinal fluid. Loss of PCFT function, as occurs in the autosomal recessive disorder “hereditary Folate malabsorption” (HFM), results in a syndrome characterized by severe systemic and cerebral Folate deficiency. Folate-receptor alpha (FRα) is expressed in the choroid plexus, and loss of function of this protein, as also occurs in an autosomal recessive disorder, results solely in “cerebral Folate deficiency” (CFD), the designation for this disorder. This paper reviews the current understanding of the functional and structural properties and regulation of PCFT, an electrogenic proton symporter, and contrasts PCFT properties with those of the reduced Folate carrier (RFC), an organic anion antiporter, that is the major route of Folate transport to systemic tissues. The clinical characteristics of HFM and its treatment, based upon the thirty-seven known cases with the clinical syndrome, of which thirty have been verified by genotype, are presented. The ways in which PCFT and FRα might interact at the level of the choroid plexus such that each is required for Folate transport from blood to cerebrospinal fluid are considered along with the different clinical presentations of HFM and CFD.
-
Identification of Tyr residues that enhance Folate substrate binding and constrain oscillation of the proton-coupled Folate transporter (PCFT-SLC46A1)
American Journal of Physiology-cell Physiology, 2015Co-Authors: Michele Visentin, Rongbao Zhao, Ersin Selcuk Unal, Mitra Najmi, Andras Fiser, I. David GoldmanAbstract:The proton-coupled Folate transporter (PCFT) mediates intestinal Folate absorption and transport of Folates across the choroid plexus. This study focuses on the role of Tyr residues in PCFT functio...
-
The proton-coupled Folate transporter: physiological and pharmacological roles.
Current Opinion in Pharmacology, 2013Co-Authors: Rongbao Zhao, I. David GoldmanAbstract:Recent studies have identified the proton-coupled Folate transporter (PCFT) as the mechanism by which Folates are absorbed across the apical brush-border membrane of the small intestine and across the basolateral membrane of the choroid plexus into the cerebrospinal fluid. Both processes are defective when there are loss-of-function mutations in this gene as occurs in the autosomal recessive disorder hereditary Folate malabsorption. Because this transporter functions optimally at low pH, antiFolates are being developed that are highly specific for PCFT in order to achieve selective delivery to malignant cells within the acidic environment of solid tumors. PCFT has a spectrum of affinities for Folates and antiFolates that narrows and increases at low pH. Residues have been identified that play a role in Folate and proton binding, proton coupling, and oscillation of the carrier between its conformational states.
-
augmentation of reduced Folate carrier mediated Folate antiFolate transport through an antiport mechanism with 5 aminoimidazole 4 carboxamide riboside monophosphate
Molecular Pharmacology, 2012Co-Authors: Michele Visentin, Rongbao Zhao, David I GoldmanAbstract:5-Aminoimidazole-4-carboxamide riboside (AICAR), an agent with diverse pharmacological properties, augments transport of Folates and antiFolates. This report further characterizes this phenomenon and defines the mechanism by which it occurs. Exposure of HeLa cells to AICAR resulted in augmentation of methotrexate, 5-formyltetrahydroFolate, and 5-methyltetrahydroFolate initial rates and net uptake in cells that express the reduced Folate carrier (RFC). This did not occur in cells that express only the proton-coupled Folate transporter and accumulated Folates by this mechanism. Transport stimulation correlated with the accumulation of 5-aminoimidazole-4-carboxamide ribotide monophosphate (ZMP), the monophosphate derivative of AICAR, within cells as established by liquid chromatography. When ZMP formation was blocked with 5-iodotubercidin, an inhibitor of adenosine kinase, Folate transport stimulation by AICAR was absent. When cells first accumulated ZMP and were then exposed to 5-iodotubercidin or AICAR-free buffer, the ZMP level markedly decreased and Folate transport stimulation was abolished. Extracellular ZMP inhibited RFC-mediated Folate influx, and the presence of intracellular ZMP correlated with inhibition of Folate efflux. The data indicate that intracellular ZMP trans-stimulates Folate influx and inhibits Folate efflux, which, together, produce a marked augmentation in the net cellular Folate level. This interaction among ZMP, Folates, and RFC, a Folate/organic phosphate antiporter, is consistent with a classic exchange reaction. The transmembrane gradient for one transport substrate (ZMP) drives the uphill transport of another (Folate) via a carrier used by both substrates, a phenomenon intrinsic to the energetics of RFC-mediated Folate transport.
-
mechanisms of membrane transport of Folates into cells and across epithelia
Annual Review of Nutrition, 2011Co-Authors: Rongbao Zhao, Michele Visentin, Ndeye Diopbove, David I GoldmanAbstract:Until recently, the transport of Folates into cells and across epithelia has been interpreted primarily within the context of two transporters with high affinity and specificity for Folates, the reduced Folate carrier and the Folate receptors. However, there were discrepancies between the properties of these transporters and characteristics of Folate transport in many tissues, most notably the intestinal absorption of Folates, in terms of pH dependency and substrate specificity. With the recent cloning of the proton-coupled Folate transporter (PCFT) and the demonstration that this transporter is mutated in hereditary Folate malabsorption, an autosomal recessive disorder, the molecular basis for this low-pH transport activity is now understood. This review focuses on the properties of PCFT and briefly addresses the two other Folate-specific transporters along with other facilitative and ATP-binding cassette (ABC) transporters with Folate transport activities. The role of these transporters in the vectorial transport of Folates across epithelia is considered.
David I Goldman - One of the best experts on this subject based on the ideXlab platform.
-
augmentation of reduced Folate carrier mediated Folate antiFolate transport through an antiport mechanism with 5 aminoimidazole 4 carboxamide riboside monophosphate
Molecular Pharmacology, 2012Co-Authors: Michele Visentin, Rongbao Zhao, David I GoldmanAbstract:5-Aminoimidazole-4-carboxamide riboside (AICAR), an agent with diverse pharmacological properties, augments transport of Folates and antiFolates. This report further characterizes this phenomenon and defines the mechanism by which it occurs. Exposure of HeLa cells to AICAR resulted in augmentation of methotrexate, 5-formyltetrahydroFolate, and 5-methyltetrahydroFolate initial rates and net uptake in cells that express the reduced Folate carrier (RFC). This did not occur in cells that express only the proton-coupled Folate transporter and accumulated Folates by this mechanism. Transport stimulation correlated with the accumulation of 5-aminoimidazole-4-carboxamide ribotide monophosphate (ZMP), the monophosphate derivative of AICAR, within cells as established by liquid chromatography. When ZMP formation was blocked with 5-iodotubercidin, an inhibitor of adenosine kinase, Folate transport stimulation by AICAR was absent. When cells first accumulated ZMP and were then exposed to 5-iodotubercidin or AICAR-free buffer, the ZMP level markedly decreased and Folate transport stimulation was abolished. Extracellular ZMP inhibited RFC-mediated Folate influx, and the presence of intracellular ZMP correlated with inhibition of Folate efflux. The data indicate that intracellular ZMP trans-stimulates Folate influx and inhibits Folate efflux, which, together, produce a marked augmentation in the net cellular Folate level. This interaction among ZMP, Folates, and RFC, a Folate/organic phosphate antiporter, is consistent with a classic exchange reaction. The transmembrane gradient for one transport substrate (ZMP) drives the uphill transport of another (Folate) via a carrier used by both substrates, a phenomenon intrinsic to the energetics of RFC-mediated Folate transport.
-
mechanisms of membrane transport of Folates into cells and across epithelia
Annual Review of Nutrition, 2011Co-Authors: Rongbao Zhao, Michele Visentin, Ndeye Diopbove, David I GoldmanAbstract:Until recently, the transport of Folates into cells and across epithelia has been interpreted primarily within the context of two transporters with high affinity and specificity for Folates, the reduced Folate carrier and the Folate receptors. However, there were discrepancies between the properties of these transporters and characteristics of Folate transport in many tissues, most notably the intestinal absorption of Folates, in terms of pH dependency and substrate specificity. With the recent cloning of the proton-coupled Folate transporter (PCFT) and the demonstration that this transporter is mutated in hereditary Folate malabsorption, an autosomal recessive disorder, the molecular basis for this low-pH transport activity is now understood. This review focuses on the properties of PCFT and briefly addresses the two other Folate-specific transporters along with other facilitative and ATP-binding cassette (ABC) transporters with Folate transport activities. The role of these transporters in the vectorial transport of Folates across epithelia is considered.
-
identification of an intestinal Folate transporter and the molecular basis for hereditary Folate malabsorption
Cell, 2006Co-Authors: Michaela Jansen, Rongbao Zhao, Antoinette Sakaris, Shrikanta Chattopadhyay, Eugenia Tsai, Claudio Sandoval, Myles H Akabas, David I GoldmanAbstract:Summary Folates are essential nutrients that are required for one-carbon biosynthetic and epigenetic processes. While Folates are absorbed in the acidic milieu of the upper small intestine, the underlying absorption mechanism has not been defined. We now report the identification of a human proton-coupled, high-affinity Folate transporter that recapitulates properties of Folate transport and absorption in intestine and in various cell types at low pH. We demonstrate that a loss-of-function mutation in this gene is the molecular basis for hereditary Folate malabsorption in a family with this disease. This transporter was previously reported to be a lower-affinity, pH-independent heme carrier protein, HCP1. However, the current study establishes that a major function of this gene product is proton-coupled Folate transport required for Folate homeostasis in man, and we have thus amended the name to PCFT/HCP1.
-
membrane transport of Folates
Vitamins and Hormones Series, 2003Co-Authors: Larry H Matherly, David I GoldmanAbstract:Abstract The chapter reviews the current understanding of the transport mechanisms for Folates in mammalian cells—their molecular identities and organization, tissue expression, regulation, structures, and their kinetic and thermodynamic properties. This encompasses a variety of diverse processes. Best characterized is the reduced Folate carrier, a member of the SLC19 family of facilitative carriers. But other facilitative organic anion carriers (SLC21), largely expressed in epithelial tissues, transport Folates as well. In addition to these bi-directional carrier systems are the membrane-localized Folate receptors alpha and beta, that mediate Folate uptake unidirectionally into cells via an endocytotic process. There are also several transporters, typified by the family of multidrug resistance-associated proteins, that unidirectionally export Folates from cells. There are transport activities for Folates, that function optimally at low pH, related in part to the reduced Folate carrier, with at least one activity that is independent of this carrier. The reduced Folate carrier-associated low-pH route mediates intestinal Folate transport. This review considers how these different transport processes contribute to the generation of transmembrane Folate gradients and to vectorial flows of Folates across epithelia. The role of Folate transporters in mouse development, as assessed by homologous deletion of Folate receptors and the reduced Folate carrier, is described. Much of the focus is on antiFolate cancer chemotherapeutic agents that are often model surrogates for natural Folates in transport studies. In particular, antiFolate transport mediated by the reduced Folate carrier is a major determinant of the activity of, and resistance to, these agents. Finally, many of the key in vitro findings on the properties of antiFolate transporters are now beginning to be extended to patient specimens, thus setting the stage for understanding response to these drugs in the clinical setting at the molecular level.© 2003, Elsevier Science (USA).
Michele Visentin - One of the best experts on this subject based on the ideXlab platform.
-
renal reabsorption of Folates pharmacological and toxicological snapshots
Nutrients, 2019Co-Authors: Sophia L Samodelov, Gerd A Kullakublick, Michele VisentinAbstract:Folates are water-soluble B9 vitamins that serve as one-carbon donors in the de novo synthesis of thymidylate and purines, and in the conversion of homocysteine to methionine. Due to their key roles in nucleic acid synthesis and in DNA methylation, inhibiting the Folate pathway is still one of the most efficient approaches for the treatment of several tumors. Methotrexate and pemetrexed are the most prescribed antiFolates and are mainly used in the treatment of acute myeloid leukemia, osteosarcoma, and lung cancers. Normal levels of Folates in the blood are maintained not only by proper dietary intake and intestinal absorption, but also by an efficient renal reabsorption that seems to be primarily mediated by the glycosylphosphatidylinositol- (GPI) anchored protein Folate receptor α (FRα), which is highly expressed at the brush-border membrane of proximal tubule cells. Folate deficiency due to malnutrition, impaired intestinal absorption or increased urinary elimination is associated with severe hematological and neurological deficits. This review describes the role of the kidneys in Folate homeostasis, the molecular basis of Folate handling by the kidneys, and the use of high dose folic acid as a model of acute kidney injury. Finally, we provide an overview on the development of Folate-based compounds and their possible therapeutic potential and toxicological ramifications.
-
Identification of Tyr residues that enhance Folate substrate binding and constrain oscillation of the proton-coupled Folate transporter (PCFT-SLC46A1)
American Journal of Physiology-cell Physiology, 2015Co-Authors: Michele Visentin, Rongbao Zhao, Ersin Selcuk Unal, Mitra Najmi, Andras Fiser, I. David GoldmanAbstract:The proton-coupled Folate transporter (PCFT) mediates intestinal Folate absorption and transport of Folates across the choroid plexus. This study focuses on the role of Tyr residues in PCFT functio...
-
augmentation of reduced Folate carrier mediated Folate antiFolate transport through an antiport mechanism with 5 aminoimidazole 4 carboxamide riboside monophosphate
Molecular Pharmacology, 2012Co-Authors: Michele Visentin, Rongbao Zhao, David I GoldmanAbstract:5-Aminoimidazole-4-carboxamide riboside (AICAR), an agent with diverse pharmacological properties, augments transport of Folates and antiFolates. This report further characterizes this phenomenon and defines the mechanism by which it occurs. Exposure of HeLa cells to AICAR resulted in augmentation of methotrexate, 5-formyltetrahydroFolate, and 5-methyltetrahydroFolate initial rates and net uptake in cells that express the reduced Folate carrier (RFC). This did not occur in cells that express only the proton-coupled Folate transporter and accumulated Folates by this mechanism. Transport stimulation correlated with the accumulation of 5-aminoimidazole-4-carboxamide ribotide monophosphate (ZMP), the monophosphate derivative of AICAR, within cells as established by liquid chromatography. When ZMP formation was blocked with 5-iodotubercidin, an inhibitor of adenosine kinase, Folate transport stimulation by AICAR was absent. When cells first accumulated ZMP and were then exposed to 5-iodotubercidin or AICAR-free buffer, the ZMP level markedly decreased and Folate transport stimulation was abolished. Extracellular ZMP inhibited RFC-mediated Folate influx, and the presence of intracellular ZMP correlated with inhibition of Folate efflux. The data indicate that intracellular ZMP trans-stimulates Folate influx and inhibits Folate efflux, which, together, produce a marked augmentation in the net cellular Folate level. This interaction among ZMP, Folates, and RFC, a Folate/organic phosphate antiporter, is consistent with a classic exchange reaction. The transmembrane gradient for one transport substrate (ZMP) drives the uphill transport of another (Folate) via a carrier used by both substrates, a phenomenon intrinsic to the energetics of RFC-mediated Folate transport.
-
mechanisms of membrane transport of Folates into cells and across epithelia
Annual Review of Nutrition, 2011Co-Authors: Rongbao Zhao, Michele Visentin, Ndeye Diopbove, David I GoldmanAbstract:Until recently, the transport of Folates into cells and across epithelia has been interpreted primarily within the context of two transporters with high affinity and specificity for Folates, the reduced Folate carrier and the Folate receptors. However, there were discrepancies between the properties of these transporters and characteristics of Folate transport in many tissues, most notably the intestinal absorption of Folates, in terms of pH dependency and substrate specificity. With the recent cloning of the proton-coupled Folate transporter (PCFT) and the demonstration that this transporter is mutated in hereditary Folate malabsorption, an autosomal recessive disorder, the molecular basis for this low-pH transport activity is now understood. This review focuses on the properties of PCFT and briefly addresses the two other Folate-specific transporters along with other facilitative and ATP-binding cassette (ABC) transporters with Folate transport activities. The role of these transporters in the vectorial transport of Folates across epithelia is considered.
Larry H Matherly - One of the best experts on this subject based on the ideXlab platform.
-
the major facilitative Folate transporters solute carrier 19a1 and solute carrier 46a1 biology and role in antiFolate chemotherapy of cancer
Drug Metabolism and Disposition, 2014Co-Authors: Larry H Matherly, Mike R Wilson, Zhanjun HouAbstract:This review summarizes the biology of the major facilitative membrane transporters, the reduced Folate carrier (RFC) (Solute Carrier 19A1) and the proton-coupled Folate transporter (PCFT) (Solute Carrier 46A1). Folates are essential vitamins, and Folate deficiency contributes to a variety of health disorders. RFC is ubiquitously expressed and is the major Folate transporter in mammalian cells and tissues. PCFT mediates the intestinal absorption of dietary Folates and appears to be important for transport of Folates into the central nervous system. Clinically relevant antiFolates for cancer, such as methotrexate and pralatrexate, are transported by RFC, and loss of RFC transport is an important mechanism of methotrexate resistance in cancer cell lines and in patients. PCFT is expressed in human tumors, and is active at pH conditions associated with the tumor microenvironment. Pemetrexed is an excellent substrate for both RFC and PCFT. Novel tumor-targeted antiFolates related to pemetrexed with selective membrane transport by PCFT over RFC are being developed. In recent years, there have been major advances in understanding the structural and functional properties and the regulation of RFC and PCFT. The molecular bases for methotrexate resistance associated with loss of RFC transport and for hereditary Folate malabsorption, attributable to mutant PCFT, were determined. Future studies should continue to translate molecular insights from basic studies of RFC and PCFT biology into new therapeutic strategies for cancer and other diseases.
-
Biological Role, Properties, and Therapeutic Applications of the Reduced Folate Carrier (RFC-SLC19A1) and the Proton-Coupled Folate Transporter (PCFT-SLC46A1)
Targeted Drug Strategies for Cancer and Inflammation, 2011Co-Authors: Larry H Matherly, Ndeye Diop-bove, I. David GoldmanAbstract:The mechanisms by which Folates are transported across cell membranes have been an area of research interest for nearly five decades. Major transport systems include the facilitative carriers, the reduced Folate carrier (RFC) and the proton-coupled Folate transporter (PCFT), and the high affinity Folate receptors (FRs) α and β which transport Folates by endocytosis. RFC is the major transport system in mammalian cells and tissues for Folate cofactors and clinically relevant antiFolate drugs including methotrexate, raltitrexed, pemetrexed, and pralatrexate. PCFT was identified in 2006 as the mechanism by which Folates are transported across the apical brush border of the proximal small intestine. Whereas both PCFT and RFC are widely expressed in tumors, PCFT differs from RFC in its acidic pH optimum which favors transport at the low pH commonly found in the hypoxic microenvironment of solid tumors. Reflecting tumor-specific patterns of expression and/or function, recent studies have focused on the identification of Folate-targeted therapeutics with selective transport by PCFT and FRs over RFC. The goal is to circumvent RFC and the potentially toxic consequences of drug transport by RFC in normal tissues. RFC in tumor cells can also influence the pharmacologic activity of PCFT and FR-selective agents by transporting physiological Folates which compete for polyglutamylation and binding to intracellular targets. This review focuses on the facilitative pathways of (anti)Folate transport, including RFC (SLC19A1) and PCFT (SLC46A1) in relation to their molecular properties, and their physiological and pharmacological roles.
-
Membrane transporters and Folate homeostasis: intestinal absorption and transport into systemic compartments and tissues.
Expert Reviews in Molecular Medicine, 2009Co-Authors: Rongbao Zhao, Larry H Matherly, I. David GoldmanAbstract:: Members of the family of B9 vitamins are commonly known as Folates. They are derived entirely from dietary sources and are key one-carbon donors required for de novo nucleotide and methionine synthesis. These highly hydrophilic molecules use several genetically distinct and functionally diverse transport systems to enter cells: the reduced Folate carrier, the proton-coupled Folate transporter and the Folate receptors. Each plays a unique role in mediating Folate transport across epithelia and into systemic tissues. The mechanism of intestinal Folate absorption was recently uncovered, revealing the genetic basis for the autosomal recessive disorder hereditary Folate malabsorption, which results from loss-of-function mutations in the proton-coupled Folate transporter gene. It is therefore 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 the major Folate transporters, with a brief consideration of their impact on the pharmacological activities of antiFolates.
-
membrane transport of Folates
Vitamins and Hormones Series, 2003Co-Authors: Larry H Matherly, David I GoldmanAbstract:Abstract The chapter reviews the current understanding of the transport mechanisms for Folates in mammalian cells—their molecular identities and organization, tissue expression, regulation, structures, and their kinetic and thermodynamic properties. This encompasses a variety of diverse processes. Best characterized is the reduced Folate carrier, a member of the SLC19 family of facilitative carriers. But other facilitative organic anion carriers (SLC21), largely expressed in epithelial tissues, transport Folates as well. In addition to these bi-directional carrier systems are the membrane-localized Folate receptors alpha and beta, that mediate Folate uptake unidirectionally into cells via an endocytotic process. There are also several transporters, typified by the family of multidrug resistance-associated proteins, that unidirectionally export Folates from cells. There are transport activities for Folates, that function optimally at low pH, related in part to the reduced Folate carrier, with at least one activity that is independent of this carrier. The reduced Folate carrier-associated low-pH route mediates intestinal Folate transport. This review considers how these different transport processes contribute to the generation of transmembrane Folate gradients and to vectorial flows of Folates across epithelia. The role of Folate transporters in mouse development, as assessed by homologous deletion of Folate receptors and the reduced Folate carrier, is described. Much of the focus is on antiFolate cancer chemotherapeutic agents that are often model surrogates for natural Folates in transport studies. In particular, antiFolate transport mediated by the reduced Folate carrier is a major determinant of the activity of, and resistance to, these agents. Finally, many of the key in vitro findings on the properties of antiFolate transporters are now beginning to be extended to patient specimens, thus setting the stage for understanding response to these drugs in the clinical setting at the molecular level.© 2003, Elsevier Science (USA).