The complex interplay between ligand binding and conformational structure of the folate binding protein (folate receptor): Biological perspectives

Holm, Jan; Bruun, Sander; Hansen, Steen Ingemann

doi:10.1016/j.bbapap.2015.06.009

Cited by 7 publications

(3 citation statements)

References 73 publications

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“…Fully oxidized folic acid, currently particularly relevant in the context of the development of folic acid-conjugated drugs (see below), is bound with an even higher affinity (K D < 1 nM) by FRα [26]. Binding of free folates to this receptor leads to cell membrane invagination, endosomal acidification, ligand release, and recycling of the receptor to the outer leaflet [27]. FRα cycles between an acid labile, surface accessible, ligand binding conformation, and an acid resistant, internalized, ligand releasing conformation, remaining membrane-bound throughout [26].…”

Section: Mechanisms Of Folate Tubular Reabsorptionmentioning

confidence: 99%

Renal Reabsorption of Folates: Pharmacological and Toxicological Snapshots

et al. 2019

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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.

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Section: Mechanisms Of Folate Tubular Reabsorptionmentioning

confidence: 99%

Renal Reabsorption of Folates: Pharmacological and Toxicological Snapshots

et al. 2019

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“…All forms of the protein have molecular weights around 30 kDa. Soluble FBP, present at 1–2 nM concentrations in human serum and other body fluids and 100 nM concentrations in milk, − is believed to be a mixture of FR-γ and FR-α that has undergone cleavage of the GPI anchor. X-ray crystal structures of FA-bound FR-α and FA-bound FR-β were recently reported. , In the studies reported here, we employed bovine FBP (bFBP) isolated from milk.…”

Section: Introductionmentioning

confidence: 99%

Substrate-Triggered Exosite Binding: Synergistic Dendrimer/Folic Acid Action for Achieving Specific, Tight-Binding to Folate Binding Protein

Chen¹,

Dongen²,

Merzel³

et al. 2016

Biomacromolecules

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Polymer-ligand conjugates are designed to bind proteins for applications as drugs, imaging agents, and transport scaffolds. In this work, we demonstrate a folic acid (FA)-triggered exosite binding of a generation five poly(amidoamine) (G5 PAMAM) dendrimer scaffold to bovine folate binding protein (bFBP). The protein exosite is a secondary binding site on the protein surface, separate from the FA binding pocket, to which the dendrimer binds. Exosite binding is required to achieve the greatly enhanced binding constants and protein structural change observed in this study. The G5Ac-COG-FA1.0 conjugate bound tightly to bFBP, was not displaced by a 28-fold excess of FA, and quenched roughly 80% of the initial fluorescence. Two-step binding kinetics were measured using the intrinsic fluorescence of the FBP tryptophan residues to give a KD in the low nanomolar range for formation of the initial G5Ac-COG-FA1.0/FBP* complex, and a slow conversion to the tight complex formed between the dendrimer and the FBP exosite. The extent of quenching was sensitive to the choice of FA-dendrimer linker chemistry. Direct amide conjugation of FA to G5-PAMAM resulted in roughly 50% fluorescence quenching of the FBP. The G5Ac-COG-FA, which has a longer linker containing a 1,2,3-triazole ring, exhibited an ∼80% fluorescence quenching. The binding of the G5Ac-COG-FA1.0 conjugate was compared to poly(ethylene glycol) (PEG) conjugates of FA (PEGn-FA). PEG2k-FA had a binding strength similar to that of FA, whereas other PEG conjugates with higher molecular weight showed weaker binding. However, no PEG conjugates gave an increased degree of total fluorescence quenching.

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“…In human, FR exists in multiple isoforms such as FR-α, FR-β, FR-δ, and FR-γ. Only FR-α and FR-β possess GPI anchors, which aid easy recognition by FA in a sensor [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Highly Sensitive Electrochemical Biosensor Using Folic Acid-Modified Reduced Graphene Oxide for the Detection of Cancer Biomarker

et al. 2021

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The detection of cancer biomarkers in the early stages could prevent cancer-related deaths significantly. Nanomaterials combined with biomolecules are extensively used in drug delivery, imaging, and sensing applications by targeting the overexpressed cancer proteins such as folate receptors (FRs) to control the disease by providing earlier treatments. In this investigation, biocompatible reduced graphene oxide (rGO) nanosheets combined with folic acid (FA)-a vitamin with high bioaffinity to FRs-is utilized to develop an electrochemical sensor for cancer detection. To mimic the cancer cell environment, FR-β protein is used to evaluate the response of the rGO-FA sensor. The formation of the rGO-FA nanocomposite was confirmed through various characterization techniques. A glassy carbon (GC) electrode was then modified with the obtained rGO-FA and analyzed via differential pulse voltammetry (DPV) for its specific detection towards FRs. Using the DPV technique, the rGO-FA-modified electrode exhibited a limit of detection (LOD) of 1.69 pM, determined in a linear concentration range from 6 to 100 pM. This excellent electrochemical performance towards FRs detection could provide a significant contribution towards future cancer diagnosis. Moreover, the rGO-FA sensing platform also showed excellent specificity and reliability when tested against similar interfering biomolecules. This rGO-FA sensor offers a great promise to the future medical industry through its highly sensitive detection towards FRs in a fast, reliable, and economical way.

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The complex interplay between ligand binding and conformational structure of the folate binding protein (folate receptor): Biological perspectives

Cited by 7 publications

References 73 publications

Renal Reabsorption of Folates: Pharmacological and Toxicological Snapshots

Renal Reabsorption of Folates: Pharmacological and Toxicological Snapshots

Substrate-Triggered Exosite Binding: Synergistic Dendrimer/Folic Acid Action for Achieving Specific, Tight-Binding to Folate Binding Protein

Highly Sensitive Electrochemical Biosensor Using Folic Acid-Modified Reduced Graphene Oxide for the Detection of Cancer Biomarker

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