STRUCTURAL COMPARISON OF PROKARYOTIC AND EUKARYOTIC FOLATE TRANSPORTERS BY COMPUTATIONAL APPROACH

Deepa Agarwal; Alok Jha

doi:10.22159/ajpcr.2018.v11s2.28511

Authors

Deepa Agarwal Department of Biotechnology and Life Science, Institute of Biomedical Education and Research, Mangalayatan University, Beswan, Aligarh, Uttar Pradesh, India.
Alok Jha Department of Biotechnology and Life Science, Institute of Biomedical Education and Research, Mangalayatan University, Beswan, Aligarh, Uttar Pradesh, India.

DOI:

https://doi.org/10.22159/ajpcr.2018.v11s2.28511

Keywords:

Human folate transporters, Plasmodium folate transporter, Streptococcus folate transporter, Structural study, Software

Abstract

Objective: In silico approach has particularly drawn attention in providing a realistic representation needed to understand the fundamental molecular structure of a transporter. The importance of folate metabolism and role in the internalization of antifolates in eukaryotes have been studied extensively, but the structural study of folate transporters in Homo sapiens (HFT), Plasmodium falciparum (PFT), and Streptococcus sp. (SFT) is still lacking. This study was conducted to study and compare the structures of prokaryotic and eukaryotic folate transporters.

Methods: HFT, PFT, and SFT were queried using blast and sequences were retrieved using National Center for Biotechnology and Information (NCBI) databases. This was superseded by structural and functional prediction of transporters. The structure has been generated using Swiss model which was visualized using PyMol and validated by Procheck and ERRAT analysis along with the values of different secondary structures mapping to diverse sections of the Ramachandran plot. The structural and functional comparison was performed by PROSO, ProFunc, TM Score, Porewalker, TMHMM, and Protscale.

Result: All the parameters for structural comparison suggest that H. sapiens folate transporter is 16.67% and 17.72% identical to Plasmodium and Streptococcus whereas Plasmodium is 21.59% identical to Streptococcus. The evaluation of transmembrane helices and hydrophobicity resulted in the presence of 1, 4, and 12 membrane-spanning segments with predicted US, UDUD, and UDS as pore shape in Plasmodium, Streptococcus, and humans.

Conclusion: Such folate receptors are the main targets for the specific conveyance of antifolates. The differences found between these species may offer possibilities for the development of new drugs in future.Â

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References

Bates CJ. FOLIC ACID, Properties and determination A2-caballero, Benjamin. Encyclopedia of Food Sciences and Nutrition. 2nd ed. Boston, MA: Academic Press; 2003. p. 2559-64.

Salcedo-Sora JE, Ochong E, Beveridge S, Johnson D, Nzila A, Biagini GA, et al. The molecular basis of folate salvage in Plasmodium falciparum: Characterisation of two folate transporters. J Biol Chem 2011;286:44659-68.

Shane B. Folylpolyglutamate synthesis and role in the regulation of one-carbon metabolism. Vitam Horm 1989;45:263-335.

Burckhardt G, Wolff NA. Structure of renal organic anion and cation transporters. Am J Physiol Rena Physiol 2000;278:F853-66.

Matherly LH, Goldman DI. Membrane transport of folates. Vitam Horm 2003;66:403-56.

Matherly LH, Hou Z, Deng Y. Human reduced folate carrier: Translation of basic biology to cancer etiology and therapy. Cancer Metastasis Rev 2007;26:111-28.

Desmoulin SK, Hou Z, Gangjee A, Matherly LH. The human proton coupled folate transporter: Biology and therapeutic applications to cancer. Cancer Biol Ther 2012;13:1355-73.

Zhao R, Goldman ID. The molecular identity and characterization of a proton-coupled folate transporter-PCFT; biological ramifications and impact on the activity of pemetrexed. Cancer Metastasis Rev 2007;26:129-39.

Elnakat H, Ratnam M. Distribution, functionality and gene regulation of folate receptor isoforms: Implications in targeted therapy. Adv Drug Deliv Rev 2004;56:1067-84.

Rijnboutt S, Jansen G, Posthuma G, Hynes JB, Schornagel JH, Strous GJ. Endocytosis of GPI-linked membrane folate receptor-alpha. J Cell Biol 1996;132:35-47.

Wang L, Cherian C, Desmoulin SK, Polin L, Deng Y, Wu J, et al. Synthesis and antitumor 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. J Med Chem 2010;53:1306-8.

Altschul SF, Madden TL, SchÃ¤ffer AA, Zhang J, Zhang Z, Miller W, et al. Gapped BLAST and PSI-BLAST: A new generation of protein database search programs. Nucleic Acids Res 1997;25:3389-402.

Schwede T, Kopp J, Guex N, Peitsch MC. SWISS-MODEL: An automated protein homology-modeling server. Nucleic Acids Res 2003;31:3381-5.

Laskowski RA, MacArthur MW, Moss DS, Thornton JM. PROCHECK - A program to check the stereochemical quality of protein structures. J Appl Cryst 1993;6:283-91.

Zhang L, Skolnick J. What should the Z-score of native protein structures be? Protein Sci Publ Protein Soc 1998;7:1201-7.

Ramachandran GN, Ramakrishnan C, Sasisekharan V. Stereochemistry of polypeptide chain configurations. J Mol Biol 1996;7:95-9.

Gasteiger E, Hoogland C, Gattiker A, Duvaud S, Wilkins MR, Appel RD, et al. Protein identification and analysis tools on the ExPASy server. In: Walker JM, editor. The Proteomics Protocols Handbook. Totowa, NJ: Humana Press; 2005. p. 571-607.

Krogh A, Larsson B, Von Heijne G, Sonnhammer EL. Predicting transmembrane protein topology with a hidden Markov model: Application to complete genomes. J Mol Biol 2001;305:567-80.

Laskowski RA, Watson JD, Thornton JM. ProFunc: A server for predicting protein function from 3D structure. Nucleic Acids Res 2005;33:W89-93.

Tan KP, Nguyen TB, Patel S, Varadarajan R, Madhusudhan MS. Depth: A web server to compute depth, cavity sizes, detect potential small-molecule ligand-binding cavities and predict the pKa of ionizable residues in proteins. Nucleic Acids Res 2013;41:314-21.

Pellegrini-Calace M, Maiwald T, Thornton JM. PoreWalker: A novel tool for the identification and characterization of channels in transmembrane proteins from their three-dimensional structure. PLoS Comput Biol 2009;5:1000440.

Ujwal R, Cascio D, Colletier JP, Faham S, Zhang J, Toro L. The crystal structure of mouse VDAC1 at 2.3Ã… resolution reveals mechanistic insights into metabolite gating. Proc Natl Acad Sci 2008;105:406-9.

Bhattacharya D, Nowotny J, Cao R, Cheng J. 3D Refine: An interactive web server for efficient protein structure refinement. Nucleic Acids Res 2016;44:406-9.

Gelly JC, Joseph AP, Srinivasan N, de Brevern AG. iPBA: A tool for protein structure comparison using sequence refinement. Nucleic Acids Res 2011;39:18-23.

Porollo A, Meller J. Prediction-based fingerprints of protein-protein interaction proteins: Structure. Funct Bionformatics 2007;66:630-45.