Antifolate proton coupled folate transporter. Medical search. Frequent questions

Synthesis and biological activity of a novel series of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitors of purine biosynthesis with selectivity for high affinity folate receptors and the proton-coupled folate transporter over the reduced folate carrier for cellular entry. (karmanos.org)
My research interest has been on structural and functional studies on physiologically and pharmacologically important folate membrane transporters, including human reduced folate carrier (hRFC) and the human proton-coupled folate transporter (hPCFT). (wayne.edu)
Posttranscriptional regulation of the human reduced folate carrier as a novel adaptive mechanism in response to folate excess or deficiency. (wayne.edu)
Reduced folate carrier is constitutively expressed on immune cells, including the non-proliferating macrophages. (turkupetcentre.net)
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)
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)

Currently available antifolates are transported via reduced folate career (RFC) as well as Folate receptors (FRs) and/or Proton coupled folate transporter (PCFT). (duq.edu)
More recently, I started to turn a portion of my research interest toward discovery and development of new folate-based therapeutics for cancer and other diseases that selectively use high affinity folate receptors and/or hPCFT without substrate activity for hRFC. (wayne.edu)
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)
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)
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)

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)
An HeLa-derived cell line was employed, in which folate-specific transport was mediated exclusively by PCFT. (aspetjournals.org)
Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder caused by loss-of-function mutations in the proton-coupled folate transporter (PCFT) gene, resulting in systemic folate deficiency and impaired delivery of folate to the brain. (wikipedia.org)
citation needed] The molecular basis for HFM was established in 2006 with the identification of the proton-coupled folate transporter (PCFT) as the mechanism of intestinal absorption of folates and the detection of loss-of-function mutations in this transporter in subjects with a clinical diagnosis of HFM. (wikipedia.org)
It is the pH gradient present across the apical brush-border membrane of the proximal jejunum, where PCFT is highly expressed, that drives intestinal folate absorption. (wikipedia.org)
As indicated above, PCFT is also expressed at the basolateral membrane of ependymal cells of the choroid plexus where it presumably plays a role in transport of folates into the CSF. (wikipedia.org)
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)
Taken collectively, promoter silencing via methylation and gene copy loss accounted for the lack of PCFT exercise in antifolate-resistant HeLa R1-11 cells. (inacj.com)
Exploiting the site specificity of FRs and/or the acidic pH specificity of PCFT, the goal of developing targeted antifolate agents could be achieved. (duq.edu)
The inhibitory potencies for 5 and 7 exceeded those for the classical antifolates MTX PMX and PDX toward the PCFT-and FR-expressing CHO sublines (Table 1). (crispr-reagents.com)
Proton-coupled folate transporter (PCFT, SLC46A1) is mainly located in the upper (acidic) part of the intestine , renal tubules, and also elsewhere in the body, also in several solid tumours . (turkupetcentre.net)

Hypermethylation of the human proton-coupled folate transporter (SLC46A1) minimal transcriptional regulatory area in an antifolate-resistant HeLa cell line. (inacj.com)

In last few decades many folate analogs have been discovered and several compounds are successfully being used as anticancer agents. (duq.edu)
To investigate the role of side chain aromatic group in the folate analogs, phenyl, fluorophenyl and furan groups have been placed in the linker region. (duq.edu)
This was a landmark discovery in the folate transport field with particular ramifications to therapeutic uses of cytotoxic folate analogs for cancer. (wayne.edu)

Extensive clinical studies established that HFM is due to (i) impaired intestinal absorption of folates and (ii) impaired transport of folates across the blood-choroid plexus-cerebrospinal fluid (CSF) barrier. (wikipedia.org)
When a modest dose of a folate is given by mouth, there is impaired intestinal folate absorption without other signs of malabsorption. (wikipedia.org)
In subjects with HFM it is very difficult indeed, rarely possible, to bring the CSF folate level into the normal range even with substantial doses of parenteral folate HFM must be distinguished from cerebral folate deficiency (CFD)- a syndrome in which there is normal intestinal folate absorption, without systemic folate deficiency, but a decrease in CSF folate levels. (wikipedia.org)
Intestinal bacteria synthesize and utilize folates. (turkupetcentre.net)
Folate hydrolase 1 (FOLH1, PSMA , GCPII) frees folate in the duodenal brush border cells, helping its intestinal absorption. (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)

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 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)
It is conceivable that FRs are useful when folate supply is low or when rapid cell growth requires elevated uptake of folate. (biomedcentral.com)

Methotrexate (MTX), pemetrexed (PMX), raltitrexed (RTX): are a few examples of classical antifolates that are currently in clinical use. (duq.edu)
Currently, clinically used classical antifolates suffer from this disadvantage because there is no way to selectively transport them into malignant cells. (duq.edu)

In addition, I am also interested in molecular homology modeling these facilitative folate transporters. (wayne.edu)

Targeting non-squamous non-small cell lung cancer via the proton-coupled folate transporter with 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates. (wayne.edu)

Because RFC is ubiquitous in the human body, the dose limiting toxicity is unavoidable for an antifolate if it is a substrate for RFC. (duq.edu)

Inhibitors of bacterial folate synthesis can be used as antibiotics. (turkupetcentre.net)

In the liver OATs mediate the uptake of folic acid and release into the bile, enabling the extensive enterohepatic circulation of folates. (turkupetcentre.net)
FRδ (Juno, FOLR4) does not bind folic acid or reduced folates. (turkupetcentre.net)
Folate (folic acid or vitamin B9) is essential for the biosynthesis of nucleotide bases and for many other methylation reactions. (biomedcentral.com)

Unlike folate-drug conjugates, m909 selectively binds to FRβ, does not recognize FRα, and has at least one effector function. (biomedcentral.com)

increasing the specificity of folate-based therapeutics aimed for treating inflammation or tumours. (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)

Because m909 does not compete with folate for receptor binding, it can be used with folate-drug conjugates in a combination therapy. (biomedcentral.com)

Affected infants present within a few months after birth with failure to thrive and severe folate deficiency manifested as macrocytic anemia and developmental delays. (wikipedia.org)
Correction of the systemic folate deficiency, with the normalization of folate blood levels, is easily achieved with high doses of oral folates or much smaller doses of parenteral folate. (wikipedia.org)

Pralatrexate is a folate analog that inhibits folate metabolism, thus impeding the synthesis of amino acids and nucleic acid. (drugbank.com)

Structural determinants of human proton-coupled folate transporter oligomerization: role of GXXXG motifs and identification of oligomeric interfaces at transmembrane domains 3 and 6, Biochem. (wayne.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)

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)

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)

12 Folate is a water-soluble vitamin required for DNA synthesis and maintenance as well as DNA, RNA, and protein methylation. (drugbank.com)

To circumvent this challenge with antifolate chemotherapy, it is necessary to develop agents which are selective for the cancerous tissues. (duq.edu)

Multidrug resistance-associated proteins (MRPs) and organic anion transporters (OATs) transport folates in addition to many other substrates, mostly in epithelial tissues. (turkupetcentre.net)

The properties of this transporter and its physiological and pharmacological roles were recently reviewed. (wikipedia.org)
Folates are hydrophilic molecules and anions at physiological pH, and therefore do not diffuse well across cell membranes. (turkupetcentre.net)

Under these conditions transport of a folate molecule across the cell membrane is accompanied by a sufficient number of protons to result a positive charge and current mediated by the ternary carrier complex. (wikipedia.org)
Even when the blood folate level is corrected, or far above normal, the CSF folate level remains low, consistent with impaired transport across the choroid plexus. (wikipedia.org)
It can transport both reduced and oxidized folates. (turkupetcentre.net)

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)

This antifolate gradient correlated with an alkaline intracellular pH in the former (pH 7.85), but not the latter (pH 7.39), buffer and was abolished by the protonophore carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone. (aspetjournals.org)
An antifolate chemical gradient was also detected in bicarbonate buffer at pH 6.9 versus 7.4, also suppressed by carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone. (aspetjournals.org)

Females with HFM are fertile and, if folate sufficient during pregnancy, have normal offspring. (wikipedia.org)
The normal CSF folate level in children over the first three years of life is in the 75 to 150 nM range. (wikipedia.org)
the normal blood folate levels may be protective, although for a limited time. (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)
Folate receptor beta (FRβ) is only detectable in placenta and limited to some hematopoietic cells of myeloid lineage in healthy people. (biomedcentral.com)
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)

Using the IC50 values of 4 5 7 and PMX against the transporter-specific CHO cell lines from Table 1 "selectivity ratios" for FRand FRover RFC with selectivities of 610-fold and 1890-fold respectively. (crispr-reagents.com)

Results for 5 and 7 were compared to those for 4 and to classical antifolate drugs including MTX PMX PDX and LMTX (Table 1). (crispr-reagents.com)
Folate pool reducing molecules are some of the oldest anticancer drugs. (turkupetcentre.net)

Hence, patients with HFM have very low or undetectable folate blood levels. (wikipedia.org)

One form of CFD is due to loss-of-mutations in folate receptor-α, (FRα), which transports folates via an endocytic process. (wikipedia.org)
FRα and FRβ accumulate folates via endocytotic process. (turkupetcentre.net)

Anatomy2

Organisms3

Diseases3

Chemicals and Drugs60

Analytical, Diagnostic and Therapeutic Techniques and Equipment2

Phenomena and Processes9

Information Science2

Reduced folate carrier8

Receptors5

PCFT12

SLC46A11

Analogs3

Intestinal6

High affinity1

Uptake of folate2

Classical antifolates2

Facilitative1

Pyrrolo1

Substrate1

Inhibitors1

Folic3

Selectively1

Therapeutics1

Therapeutic1

Conjugates1

Deficiency2

Metabolism1

Transmembrane1

Binds1

Toxicity1

FPGS2

Synthesis1

Selective1

Proteins1

Physiological2

Transport3

Cellular1

Gradient2

Normal3

Cells4

Cell lines1

Drugs2

Blood1

Process2