In Silico Docking of Vitamin E Isomers on Transport Proteins

Author(s): Nurul Syeefa Zulkiflee, Siti Amilia Awang, Woo Xian Ming, Muhammad Fauzan Wira’i Kamilan, M Yuveneshwari Mariappan, Tan Jen Kit*

Journal Name: Current Computer-Aided Drug Design

Volume 16 , Issue 4 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: Vitamin E is comprised of α, β, γ and δ-tocopherols (Ts) and α, β, γ and δ- tocotrienols (T3s). Vitamin E has neuroprotective antioxidant, anti-cancer, and cholesterol-lowering effects. Intracellular trafficking of these isomers remains largely unknown, except for αT which is selectively transported by αT transfer protein (αTTP).

Objective: This study aimed to determine the binding of vitamin E isomers on transport proteins using in silico docking.

Methods: Transport proteins were selected using AmiGo Gene Ontology tool based on the same molecular function annotation as αTTP. Protein structures were obtained from the Protein Data Bank. Ligands structures were obtained from ZINC database. In silico docking was performed using SwissDock.

Results and Discussion: A total of 6 transport proteins were found: SEC14-like protein 2, glycolipid transfer protein (GLTP), pleckstrin homology domain-containing family A member 8, collagen type IV alpha-3-binding protein, ceramide-1-phosphate transfer protein and afamin. Compared with other transport proteins, αTTP had the highest affinities for all isomers except βT3. Binding order of vitamin E isomers toward αTTP was γT > βT > αT > δT > αT3 > γT3 > δT3 > βT3. GLTP had a higher affinity for tocotrienols than tocopherols. βT3 bound stronger to GLTP than αTTP.

Conclusion: αTTP remained as the most preferred transport protein for most of the isomers. The binding affinity of αT toward αTTP was not the highest than other isomers suggested that other intracellular trafficking mechanisms of these isomers may exist. GLTP may mediate the intracellular transport of tocotrienols, especially βT3. Improving the bioavailability of these isomers may enhance their beneficial effects to human.

Keywords: Tocopherols, tocotrienols, carrier proteins, molecular docking simulation, αTTP, GLTP.

Sen, C.K.; Khanna, S.; Roy, S. Tocotrienols: Vitamin E beyond tocopherols. Life Sci., 2006, 78(18), 2088-2098.
[] [PMID: 16458936]
Comitato, R.; Ambra, R.; Virgili, F. Tocotrienols: A family of molecules with specific biological activities. Antioxidants, 2017, 6(4), 93.
[] [PMID: 29156559]
Tan, J-K.; Then, S-M.; Mazlan, M.; Raja Abdul Rahman, R.N.Z.; Jamal, R.; Wan Ngah, W.Z. Gamma-tocotrienol acts as a BH3 mimetic to induce apoptosis in neuroblastoma SH-SY5Y cells. J. Nutr. Biochem., 2016, 31, 28-37.
[] [PMID: 27133421]
Khanna, S.; Roy, S.; Slivka, A.; Craft, T.K.; Chaki, S.; Rink, C.; Notestine, M.A.; DeVries, A.C.; Parinandi, N.L.; Sen, C.K. Neuroprotective properties of the natural vitamin E alpha-tocotrienol. Stroke, 2005, 36(10), 2258-2264.
[] [PMID: 16166580]
Wu, S-J.; Liu, P-L.; Ng, L-T. Tocotrienol-rich fraction of palm oil exhibits anti-inflammatory property by suppressing the expression of inflammatory mediators in human monocytic cells. Mol. Nutr. Food Res., 2008, 52(8), 921-929.
[] [PMID: 18481320]
Deng, L.; Ding, Y.; Peng, Y.; Wu, Y.; Fan, J.; Li, W.; Yang, R.; Yang, M.; Fu, Q. γ-Tocotrienol protects against ovariectomy-induced bone loss via mevalonate pathway as HMG-CoA reductase inhibitor. Bone, 2014, 67, 200-207.
[] [PMID: 25019595]
Reboul, E. Vitamin E bioavailability: mechanisms of intestinal absorption in the spotlight. Antioxidants, 2017, 6(4), 95.
[] [PMID: 29165370]
Schmölz, L.; Birringer, M.; Lorkowski, S.; Wallert, M. Complexity of vitamin E metabolism. World J. Biol. Chem., 2016, 7(1), 14-43.
[] [PMID: 26981194]
Fairus, S.; Nor, R.M.; Cheng, H.M.; Sundram, K. Postprandial metabolic fate of tocotrienol-rich vitamin E differs significantly from that of α-tocopherol. Am. J. Clin. Nutr., 2006, 84(4), 835-842.
[] [PMID: 17023711]
Khanna, S.; Patel, V.; Rink, C.; Roy, S.; Sen, C.K. Delivery of orally supplemented α-tocotrienol to vital organs of rats and tocopherol-transport protein deficient mice. Free Radic. Biol. Med., 2005, 39(10), 1310-1319.
[] [PMID: 16257640]
Meng, X.Y.; Zhang, H.X.; Mezei, M.; Cui, M. Molecular docking: a powerful approach for structure-based drug discovery. Curr Comput Aided Drug Des, 2011, 7(2), 146-157.
[] [PMID: 21534921]
Ferreira, L.G.; Dos Santos, R.N.; Oliva, G.; Andricopulo, A.D. Molecular docking and structure-based drug design strategies. Molecules, 2015, 20(7), 13384-13421.
[] [PMID: 26205061]
Grosdidier, A.; Zoete, V.; Michielin, O. SwissDock, a protein-small molecule docking web service based on EADock DSS. Nucleic Acids Res., 2011, 39, 270-277.
Ashburner, M.; Ball, C.A.; Blake, J.A.; Botstein, D.; Butler, H.; Cherry, J.M.; Davis, A.P.; Dolinski, K.; Dwight, S.S.; Eppig, J.T.; Harris, M.A.; Hill, D.P.; Issel-Tarver, L.; Kasarskis, A.; Lewis, S.; Matese, J.C.; Richardson, J.E.; Ringwald, M.; Rubin, G.M.; Sherlock, G. The gene ontology consortium. Gene ontology: tool for the unification of biology. Nat. Genet., 2000, 25(1), 25-29.
[] [PMID: 10802651]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The protein data bank. Nucleic Acids Res., 2000, 28(1), 235-242.
[] [PMID: 10592235]
Christen, M.; Marcaida, M.J.; Lamprakis, C.; Aeschimann, W.; Vaithilingam, J.; Schneider, P.; Hilbert, M.; Schneider, G.; Cascella, M.; Stocker, A. Structural insights on cholesterol endosynthesis: Binding of squalene and 2,3-oxidosqualene to supernatant protein factor. J. Struct. Biol., 2015, 190(3), 261-270.
[] [PMID: 25987292]
Samygina, V.R.; Popov, A.N.; Cabo-Bilbao, A.; Ochoa-Lizarralde, B.; Goni-de-Cerio, F.; Zhai, X.; Molotkovsky, J.G.; Patel, D.J.; Brown, R.E.; Malinina, L. Enhanced selectivity for sulfatide by engineered human glycolipid transfer protein. Structure, 2011, 19(11), 1644-1654.
[] [PMID: 22078563]
Ochoa-Lizarralde, B.; Gao, Y-G.; Popov, A.N.; Samygina, V.R.; Zhai, X.; Mishra, S.K.; Boldyrev, I.A.; Molotkovsky, J.G.; Simanshu, D.K.; Patel, D.J.; Brown, R.E.; Malinina, L. Structural analyses of 4-phosphate adaptor protein 2 yield mechanistic insights into sphingolipid recognition by the glycolipid transfer protein family. J. Biol. Chem., 2018, 293(43), 16709-16723.
[] [PMID: 30206120]
Simanshu, D.K.; Kamlekar, R.K.; Wijesinghe, D.S.; Zou, X.; Zhai, X.; Mishra, S.K.; Molotkovsky, J.G.; Malinina, L.; Hinchcliffe, E.H.; Chalfant, C.E.; Brown, R.E.; Patel, D.J. Non-vesicular trafficking by a ceramide-1-phosphate transfer protein regulates eicosanoids. Nature, 2013, 500(7463), 463-467.
[] [PMID: 23863933]
Kudo, N.; Kumagai, K.; Matsubara, R.; Kobayashi, S.; Hanada, K.; Wakatsuki, S.; Kato, R. Crystal structures of the CERT START domain with inhibitors provide insights into the mechanism of ceramide transfer. J. Mol. Biol., 2010, 396(2), 245-251.
[] [PMID: 20036255]
Naschberger, A.; Orry, A.; Lechner, S.; Bowler, M.W.; Nurizzo, D.; Novokmet, M.; Keller, M.A.; Oemer, G.; Seppi, D.; Haslbeck, M.; Pansi, K.; Dieplinger, H.; Rupp, B. Structural evidence for a role of the multi-functional human glycopro-tein afamin in Wnt transport. Structure, 2017, 25(12), 1907-1915.e5.
[] [PMID: 29153507]
Min, K.C.; Kovall, R.A.; Hendrickson, W.A. Crystal structure of human alpha-tocopherol transfer protein bound to its ligand: implications for ataxia with vitamin E deficiency. Proc. Natl. Acad. Sci. USA, 2003, 100(25), 14713-14718.
[] [PMID: 14657365]
Irwin, J.J.; Sterling, T.; Mysinger, M.M.; Bolstad, E.S.; Coleman, R.G. ZINC: a free tool to discover chemistry for biology. J. Chem. Inf. Model., 2012, 52(7), 1757-1768.
[] [PMID: 22587354]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera--a visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-1612.
[] [PMID: 15264254]
Bankaitis, V.A.; Mousley, C.J.; Schaaf, G. The Sec14 superfamily and mechanisms for crosstalk between lipid metabolism and lipid signaling. Trends Biochem. Sci., 2010, 35(3), 150-160.
[] [PMID: 19926291]
Saito, K.; Tautz, L.; Mustelin, T. The lipid-binding SEC14 domain. Biochim. Biophys. Acta, 2007, 1771(6), 719-726.
[] [PMID: 17428729]
Mokashi, V.; Singh, D.K.; Porter, T.D. Supernatant protein factor stimulates HMG-CoA reductase in cell culture and in vitro. Arch. Biochem. Biophys., 2005, 433(2), 474-480.
[] [PMID: 15581604]
Panagabko, C.; Morley, S.; Hernandez, M.; Cassolato, P.; Gordon, H.; Parsons, R.; Manor, D.; Atkinson, J. Ligand specificity in the CRAL-TRIO protein family. Biochemistry, 2003, 42(21), 6467-6474.
[] [PMID: 12767229]
Rao, C.S.; Lin, X.; Pike, H.M.; Molotkovsky, J.G.; Brown, R.E. Glycolipid transfer protein mediated transfer of glycosphingolipids between membranes: a model for action based on kinetic and thermodynamic analyses. Biochemistry, 2004, 43(43), 13805-13815.
[] [PMID: 15504043]
Ahsan, H.; Ahad, A.; Iqbal, J.; Siddiqui, W.A. Pharmacological potential of tocotrienols: a review. Nutr. Metab. (Lond.), 2014, 11(1), 52.
[] [PMID: 25435896]
D’Angelo, G.; Polishchuk, E.; Di Tullio, G.; Santoro, M.; Di Campli, A.; Godi, A.; West, G.; Bielawski, J.; Chuang, C-C.; van der Spoel, A.C.; Platt, F.M.; Hannun, Y.A.; Polishchuk, R.; Mattjus, P.; De Matteis, M.A. Glycosphingolipid synthesis requires FAPP2 transfer of glucosylceramide. Nature, 2007, 449(7158), 62-67.
[] [PMID: 17687330]
Huang, P-H.; Chuang, H-C.; Chou, C-C.; Wang, H.; Lee, S-L.; Yang, H-C.; Chiu, H-C.; Kapuriya, N.; Wang, D.; Kulp, S.K.; Chen, C-S. Vitamin E facilitates the inactivation of the kinase Akt by the phosphatase PHLPP1. Sci. Signal., 2013, 6(267), ra19-ra19.
[] [PMID: 23512990]
Arana, L.; Gangoiti, P.; Ouro, A.; Trueba, M.; Gómez-Muñoz, A. Ceramide and ceramide 1-phosphate in health and disease. Lipids Health Dis., 2010, 9(1), 15.
[] [PMID: 20137073]
Palau, V.E.; Chakraborty, K.; Wann, D.; Lightner, J.; Hilton, K.; Brannon, M.; Stone, W.; Krishnan, K. γ-Tocotrienol induces apoptosis in pancreatic cancer cells by upregulation of ceramide synthesis and modulation of sphingolipid transport. BMC Cancer, 2018, 18(1), 564.
[] [PMID: 29769046]
Lim, Y.; Traber, M.G. Alpha-tocopherol transfer protein (α-TTP): Insights from alpha-tocopherol transfer protein knock-out mice. Nutr. Res. Pract., 2007, 1(4), 247-253.
[] [PMID: 20368946]
Hosomi, A.; Arita, M.; Sato, Y.; Kiyose, C.; Ueda, T.; Igarashi, O.; Arai, H.; Inoue, K. Affinity for α-tocopherol transfer protein as a determinant of the biological activities of vitamin E analogs. FEBS Lett., 1997, 409(1), 105-108.
[] [PMID: 9199513]
Arita, M.; Nomura, K.; Arai, H.; Inoue, K. α-tocopherol transfer protein stimulates the secretion of α-tocopherol from a cultured liver cell line through a brefeldin A-insensitive pathway. Proc. Natl. Acad. Sci. USA, 1997, 94(23), 12437-12441.
[] [PMID: 9356467]
Chung, S.; Ghelfi, M.; Atkinson, J.; Parker, R.; Qian, J.; Carlin, C.; Manor, D. Vitamin E and phosphoinositides regulate the intracellular localization of the hepatic α-tocopherol trans-fer protein. J. Biol. Chem., 2016, 291(33), 17028-17039.
[] [PMID: 27307040]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 02 September, 2020
Page: [467 - 472]
Pages: 6
DOI: 10.2174/1573409915666190614113733
Price: $65

Article Metrics

PDF: 30