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Human Folate Receptor
Human folate receptors (FR-alpha, FR-beta, FR-gamma) are cysteine-rich glycoproteins at the cell surface [2]. These receptors are expressed at very low levels in most tissues, but are expressed at higher levels in numerous cancer cells to meet the folate demand of the rapidly dividing cells under low folate conditions [2]. FR-alpha is displayed on the apical surface of polarized epithelial cells, particularly in the proximal tubule cells of the kidney and choroid plexus [3]. FR-beta is expressed in the latter stages of normal myelopoiesis and in the placenta, spleen, and thymus [3]. The FR-gamma receptors are expressed in the spleen, thymus, and bone marrow [3].
Folic acid is an essential vitamin that was developed in the 1940s to treat anemia, it is converted to naturally occurring metabolites by dihydrofolate reductase and can act as a dietary supplement for these folates [3]. Folates are necessary in the cells of eukaryotes for single carbon transfer reactions, and multiple steps in nucleotide synthesis [3]. Folic acid and its reduced derivatives are transported via facilitative transporters and via a family of glycosylphosphatidylinositol (GPI)-anchored receptors with limited expression profiles that are most generally described as folate receptors [3].
Function
Folates are one-carbon donors for the synthesis of purines and thymidine, which are both essential components of nucleic acids [3]. This means that they are indirectly used for the methylation of DNA, proteins, and lipids[3]. The three subtypes of folate receptors that were previously mentioned (FR-alpha, FR-beta, FR-gamma) also play a role in other happenings in the human body. They mediated folate uptake in cells through endocytosis[3]. The endosome's acidic environment promotes the release of these folate receptors, which is then transported into the cell's cytoplasm by a proton-coupled folate transporter[3]. Expression of the folate cells however, is restricted to cells that are important for embryonic development which do include the placental and neural tubes, among other things[3]. In the human body, FR-alpha is the most widely expressed but is still low in normal tissues with higher levels of expression in many rapidly dividing tumors[3]. Folate receptors also have gene encoding functions. Human folate receptor-alpha has been implicated in folate transcytosis in the kidney and delivery into the central nervous system[3]. Human folate receptors beta and gamma gene encoding functions are unclear when expressed normally except is is known that the beta subtype is capable of delivering folate and folate-derived molecules into activated macrophages or certain leukemic cells[3].
Relevance
Structural highlights
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