• The low-pH activity and the structural specificity of PCFT (high affinity for folic acid, and low affinity for PT523 - a non-polyglutamable analog of aminopterin) distinguishes this transporter functionally from the other major folate transporter, the reduced folate carrier (optimal activity at pH 7.4, very low affinity for folic acid and very high affinity for PT523), another member (SLC19A1) of the superfamily of solute transporters. (wikipedia.org)
  • Reduced folate carrier is constitutively expressed on immune cells, including the non-proliferating macrophages. (turkupetcentre.net)
  • In normal cells, folates are taken in through the reduced folate carrier (RFC) or proton-coupled folate transporter (PCFT), which are membrane-spanning proteins that facilitate bidirectional transportation of reduced folate across the plasma membrane and endosome membranes [ 1 ]. (biomedcentral.com)
  • 10 Pralatrexate is designed to have a higher affinity for the reduced folate carrier, a protein that is overexpressed in malignant cells and is upregulated by oncogenes. (drugbank.com)
  • 9 Compared to methotrexate, pralatrexate binds to the reduced folate carrier protein-1 (RFC-1) for cellular uptake with 10-times the affinity and is a more potent substrate for FPGS. (drugbank.com)
  • Pralatrexate is a folate analog metabolic inhibitor that competitively inhibits dihydrofolate reductase (DHFR) selectively in cancer cells overexpressing the reduced folate carrier protein-1 (RFC-1). (drugbank.com)
  • The physiological role of PCFT is known based upon the phenotype of subjects with loss-of-function mutations of this gene - the rare autosomal hereditary disorder, hereditary folate malabsorption (HFM). (wikipedia.org)
  • SLC46A1) was discovered in 2006 as the principal mechanism by which folates are absorbed in the intestine and the causal basis for hereditary folate malabsorption (HFM). (duq.edu)
  • The proton-coupled folate transporter (PCFT) is ubiquitously expressed in solid tumors to which it delivers antifolates, particularly pemetrexed, into cancer cells. (aspetjournals.org)
  • Studies of PCFT-mediated transport, to date, have focused exclusively on the influx of folates and antifolates. (aspetjournals.org)
  • This article addresses the impact of PCFT on concentrative transport, critical to the formation of the active polyglutamate congeners, and at pH levels relevant to the tumor microenvironment. (aspetjournals.org)
  • An HeLa-derived cell line was employed, in which folate-specific transport was mediated exclusively by PCFT. (aspetjournals.org)
  • The major parameter of studies on PCFT-mediated transport has been the rate of transport into cells (influx). (aspetjournals.org)
  • PCFT-mediated transport into cells is optimal at pH 5.5. (wikipedia.org)
  • A variety of organic anions inhibit PCFT-mediated transport at extremely high ratio of inhibitor to folate, the most potent are sulfobromophthalein, p-aminobenzylglutamate, and sulfathalazine. (wikipedia.org)
  • PCFT mRNA was reported to be increased in folate-deficient mice. (wikipedia.org)
  • However, it is unclear as to the extent that PCFT contributes to folate transport across these epithelia. (wikipedia.org)
  • PCFT was initially reported to be a low-affinity heme transporter. (wikipedia.org)
  • However, a role for PCFT in heme and iron homeostasis is excluded by the observation that humans or mice with loss-of-function PCFT mutations are not iron or heme deficient and the anemia, and all other systemic consequences of the loss of this transporter, are completely corrected with high-dose oral, or low-dose, parenteral folate. (wikipedia.org)
  • This stimulated interest in using PCFT for cytotoxic drug targeting, taking advantage of the substantial levels of PCFT transport and acidic pH conditions commonly associated with tumors. (duq.edu)
  • Areas covered: We summarize the literature from 2006 to 2022 that explores the role of PCFT in the intestinal absorption of dietary folates and its role in HFM and as a transporter of folates and antifolates such as pemetrexed (Alimta) in relation to cancer. (duq.edu)
  • We provide the rationale for the discovery of a new generation of targeted pyrrolo[2,3-d]pyrimidine antifolates with selective PCFT transport and inhibitory activity toward de novo purine biosynthesis in solid tumors. (duq.edu)
  • This laboratory lately recognized a novel proton-coupled folate transporter (PCFT) that mediates intestinal folate absorption and transport of folates into the central nervous system. (inacj.com)
  • Therapy with 5-aza-2′-deoxycytidine resulted in a considerable restoration of transport and PCFT mRNA expression and small however vital decreases in methylation within the promoter area. (inacj.com)
  • In addition to RFC and PCFT, a limited number of cells express folate receptors (FRs) that can mediate unidirectional transportation of folates into cells. (biomedcentral.com)
  • Influx has a Km range of 0.5 to 3µM for most folates and antifolates at pH 5.5. (wikipedia.org)
  • RFC1 is the major target for antifolate drugs in cancer chemotherapy because of its abundance, but antifolates usually target also other folate transporters. (turkupetcentre.net)
  • These subjects have two major abnormalities: (i) severe systemic folate deficiency and (ii) a defect in the transport of folates from blood across the choroid plexus into the CSF with very low CSF folate levels even when the blood folate level is corrected or supranormal. (wikipedia.org)
  • In the liver OATs mediate the uptake of folic acid and release into the bile, enabling the extensive enterohepatic circulation of folates. (turkupetcentre.net)
  • Folate receptors FRα and FRβ bind folate and its reduced forms, and are important in folate tissue uptake, and FRα especially in renal reabsorption. (turkupetcentre.net)
  • It is conceivable that FRs are useful when folate supply is low or when rapid cell growth requires elevated uptake of folate. (biomedcentral.com)
  • 12 This reaction both increases cellular retention of pralatrexate for extended drug action and impedes the uptake of folate, also a substrate of FPGS, to further inhibit folate metabolism in cancer cells. (drugbank.com)
  • The high-affinity folate binding protein (FBP) exists in humans in four isoforms, folate receptors (FRα and FRβ, or FOLR1 and FOLR2) that are attached to the outer cell surface by glycosyl-phosphatidyl-inositol (GPI) link, and FRγ (FOLR3) that is a secretory protein, and expressed at much lower levels than FRα and FRβ. (turkupetcentre.net)
  • Among the four isoforms of FRs identified (α, β, γ, and δ), α and β isoforms of FR are glycosylphosphatidylinositol (GPI)-anchored proteins with two N-glycosylation sites, and both have high affinity (K D of approximately 1 nM) for folate [ 2 ]. (biomedcentral.com)
  • 12 Folate is a water-soluble vitamin required for DNA synthesis and maintenance as well as DNA, RNA, and protein methylation. (drugbank.com)
  • As cancer cells are rapidly replicating, they require a lot of folates to accommodate an accelerated cell division and DNA and protein modification for cellular transformation. (drugbank.com)
  • Due to its anti-folate activity, pralatrexate's main toxicity is manifested as mucositis that can require dose interruption or reduction 10 , 13 . (drugbank.com)
  • Unlike folate-drug conjugates, m909 selectively binds to FRβ, does not recognize FRα, and has at least one effector function. (biomedcentral.com)
  • Because m909 does not compete with folate for receptor binding, it can be used with folate-drug conjugates in a combination therapy. (biomedcentral.com)
  • Pralatrexate is a folate analog that inhibits folate metabolism, thus impeding the synthesis of amino acids and nucleic acid. (drugbank.com)
  • Biology and therapeutic applications of the proton-coupled folate tran" by Larry H. Matherly, Mathew Schneider et al. (duq.edu)
  • Folates are molecules that have a pteridine ring that can be reduced or oxidized, a para-aminobenzoic acid (PABA) linker that together with the pteridine ring binds 1C units, and a variable chain length polyglutamate tail that serves to localize the molecule within the cell. (turkupetcentre.net)
  • Folylpoly-γ-glutamate synthetase (FPGS) catalyzes the addition of multiple glutamates to THF, and is needed for retaining folates intracellularly. (turkupetcentre.net)
  • 9 Additionally, pralatrexate also competes for enzymatic processing by folyopolyglutamate synthase (FPGS)with folate to increase cellular retention. (drugbank.com)
  • Multidrug resistance-associated proteins (MRPs) and organic anion transporters (OATs) transport folates in addition to many other substrates, mostly in epithelial tissues. (turkupetcentre.net)
  • Conjugation of proteins and liposomes to folate does not necessarily prevent the receptor-mediated endocytosis, and this can be utilized in delivery of therapeutic macromolecules into cells ( Leamon and Low, 1991 ). (turkupetcentre.net)
  • Folates are hydrophilic molecules and anions at physiological pH, and therefore do not diffuse well across cell membranes. (turkupetcentre.net)
  • it is expressed ubiquitously in mammalian tissues, including intestinal and colonic epithelia, basolateral membrane of renal proximal tubules, and blood-brain barrier , and although usually it is considered to be a facilitative transporter, in case of negatively charged folates it can work strongly against concentration gradient. (turkupetcentre.net)
  • Folate receptor beta (FRβ) is only detectable in placenta and limited to some hematopoietic cells of myeloid lineage in healthy people. (biomedcentral.com)
  • There is a prominent low-pH folate transport activity in the cells and/or membrane vesicles derived from these tissues which, in some cases, has been shown to be indicative of a proton-coupled folate transport process. (wikipedia.org)
  • The augmentation of intracellular pH, when cells are in a HEPES buffer, should be taken into consideration in studies that encompass all proton-coupled transporter families. (aspetjournals.org)
  • m909 did not compete with folate for the binding to FRβ on cells. (biomedcentral.com)
  • m909 was not only able to select FRβ positive, activated macrophages from synovial fluid cells of arthritis patients as efficiently as folate, but also able to mediate ADCC in FRβ positive cells. (biomedcentral.com)
  • Residues have been identified that play a role in proton-coupling, proton binding, folate binding and oscillation of the carrier between its conformational states. (wikipedia.org)