Sandbox Reserved 1591

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Revision as of 04:00, 4 December 2021

This Sandbox is Reserved from September 14, 2021, through May 31, 2022, for use in the class Introduction to Biochemistry taught by User:John Means at the University of Rio Grande, Rio Grande, OH, USA. This reservation includes 5 reserved sandboxes (Sandbox Reserved 1590 through Sandbox Reserved 1594).

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You may include any references to papers as in: the use of JSmol in Proteopedia ^[1] or to the article describing Jmol ^[2] to the rescue.

1 Human Folate Receptor
2 Function
3 Applications
4 Structural highlights

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].

Applications

Many cancers highly express the alpha folate receptor, therefore resulting in becoming an important target for receptor-mediated chemotherapy ^[3]. Folate receptor targeted therapies are expected to be effective in treatment of many types of cancers and inflammatory diseases^[4]. Alpha folate receptors are overexpressed in nonmucinous adenocarcinomas of the ovary, uterus, breast, cervix, kidney, and colon ^[4]. Beta human folate receptors expression is increased in certain leukemias, its also increased in cells that are involved in the pathogenesis of rheumatoid arthritis and other conditions such as psoriasis and Crohn's disease^[4].

Structural highlights

The folate receptor is a glycoprotein which binds the vitamin folic acid and its analogues. Alpha folate receptors have three predicted (N47, N139, and N179)^[5]. Glycosylation is a structural feature of all three isoforms of the human folate receptor ^[5]. At least on of the core glycosylated residues is necessary for the synthesis of FRα in its active conformation ^[5].

This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

References

↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
↑ ^2.0 ^2.1 ^2.2 Chen C, Ke J, Zhou XE, Yi W, Brunzelle JS, Li J, Yong EL, Xu HE, Melcher K. Structural basis for molecular recognition of folic acid by folate receptors. Nature. 2013 Jul 14. doi: 10.1038/nature12327. PMID:23851396 doi:10.1038/nature12327
↑ ^3.00 ^3.01 ^3.02 ^3.03 ^3.04 ^3.05 ^3.06 ^3.07 ^3.08 ^3.09 ^3.10 ^3.11 ^3.12 ^3.13 ^3.14 Wibowo AS, Singh M, Reeder KM, Carter JJ, Kovach AR, Meng W, Ratnam M, Zhang F, Dann CE 3rd. Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition. Proc Natl Acad Sci U S A. 2013 Sep 17;110(38):15180-8. doi:, 10.1073/pnas.1308827110. Epub 2013 Aug 9. PMID:23934049 doi:10.1073/pnas.1308827110
↑ ^4.0 ^4.1 ^4.2 Wibowo AS, Singh M, Reeder KM, Carter JJ, Kovach AR, Meng W, Ratnam M, Zhang F, Dann CE 3rd. Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition. Proc Natl Acad Sci U S A. 2013 Sep 17;110(38):15180-8. doi:, 10.1073/pnas.1308827110. Epub 2013 Aug 9. PMID:23934049 doi:10.1073/pnas.1308827110
↑ ^5.0 ^5.1 ^5.2 Roberts SJ, Petropavlovskaja M, Chung KN, Knight CB, Elwood PC. Role of individual N-linked glycosylation sites in the function and intracellular transport of the human alpha folate receptor. Arch Biochem Biophys. 1998 Mar 15;351(2):227-35. doi: 10.1006/abbi.1997.0551. PMID:9515058 doi:http://dx.doi.org/10.1006/abbi.1997.0551

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 Many cancers highly express the alpha folate receptor, therefore resulting in becoming an important target for receptor-mediated chemotherapy <ref name="Wibowo"/>. Folate receptor targeted therapies are expected to be effective in treatment of many types of cancers and inflammatory diseases<ref name="Cancer">PMID: 23934049</ref>. Alpha folate receptors are overexpressed in nonmucinous adenocarcinomas of the ovary, uterus, breast, cervix, kidney, and colon <ref name="Cancer"/>. Beta human folate receptors expression is increased in certain leukemias, its also increased in cells that are involved in the pathogenesis of rheumatoid arthritis and other conditions such as psoriasis and Crohn's disease<ref name="Cancer"/>.
 == Structural highlights ==
-<scene name='82/824636/N-glycosylation_sites/1'>N-glycosylation sites</scene>
+The folate receptor is a glycoprotein which binds the vitamin folic acid and its analogues. Alpha folate receptors have three predicted <scene name='82/824636/N-glycosylation_sites/1'>N-glycosylation sites</scene> (N47, N139, and N179)<ref name="Structure">PMID: 9515058</ref>. Glycosylation is a structural feature of all three isoforms of the human folate receptor <ref name="Structure"/>. At least on of the core glycosylated residues is necessary for the synthesis of FRα in its active conformation <ref name="Structure"/>.
 This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

Sandbox Reserved 1591

From Proteopedia

Revision as of 04:00, 4 December 2021

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Contents

Human Folate Receptor

Function

Applications

Structural highlights

References

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