[Frontiers In Bioscience, Landmark, 24, 1024-1036, March 1, 2019]
Characterization of structural requirement for binding of gigantol and aldose reductase
TABLE OF CONTENTS
We previously reported that gigantol extracted from Caulis Dendrobii has significant therapeutic benefits for the treatment of galactosemic cataracts through its ability to inhibit aldose reductase (AR) activity. In this study, we identified the binding sites and structurally characterized the interaction between gigantol and AR, to understand the mechanism (s) of the effects of gigantol on cataracts. Gigantol was found to be protective against diabetic cataracts (DC) in rats induced by streptozotocin. Molecular docking predicted the binding sites between AR and gigantol to be residues Trp111, His110, Tyr48 and Trp20. Mutation of each of these residues led to a significant reduction in AR activity. Cold-spray ionization mass spectrometry measurements showed that the binding of gigantol to AR is concentration-dependent and that the maximum stoichiometric ratio of non-covalent bonding is 1:24.4. pH and temperature did not influence the interaction. Taken together, we provide further mechanistic evidence of the beneficial effects of gigantol on DC.
1. S. Huang, Y. Zheng, P. J. Foster, W. Huang and M. He: Prevalence and causes of visual impairment in Chinese adults in Urban Southern China. Arch Ophthalmol,127(10),1362-1367(2009)
2. A. S. Bessa, A. M. Ragab, R. A. Nassra, D. P. Piñero and M. S. Shaheen: Expression levels of aldose reductase enzyme, vascular endothelial growth factor, and intercellular adhesion molecule-1 in the anterior lens capsule of diabetic cataract patients. J Cataract Refract Surg,44(12),1431-1435(2018)
3. I. Dedov, O. Maslova, Y. Suntsov, L. Bolotskaia, T. Milenkaia and L. Besmertnaia: Prevalence of diabetic retinopathy and cataract in adult patients with type 1 and type 2 diabetes in Russia. Rev Diabet Stud,6,124-129(2009)
4. S.Wu, N.Tong, LPan, X.H Jiang, Y.A. Li, M.L Guo and H.H. Li: Retrospective Analyses of Potential Risk Factors for Posterior Capsule Opacification after Cataract Surgery. J Ophthalmol. 9089285 (2018)..
5. C. V. Ton and T.H.C.Tran:Incidence of posterior capsular opacification requiring Nd:YAG capsulotomy after cataract surgery and implantation of enVista® MX60 IOL. J Fr Ophtalmol.41(10),899-903(2018)
6. I. M. Wormstone: Posterior capsule opacification: a cell biological perspective. Exp Eye Res,74(3),337-347 (2002)
7. F. Tian, L. Dong, Y. Zhou, Y. Shao, W. Li, H. Zhang and F. Wang: Rapamycin-Induced apoptosis in HGF-stimulated lens epithelial cells by AKT/mTOR, ERK and JAK2/STAT3 pathways. Int J Mol Sci,15(8),13833-13848(2014)
8. A. B. Reddy, R. Tammali, R. Mishra, S. Srivastava, S. K. Srivastava and K. V. Ramana: A1dose reductase deficiency protects sugar-induced lens opacification in rats. Chem Biol Interact,191,346-350(2011)
9. A. Gul, M. A. Rahman and S. N. Hasnain: Role of fructose concentration on cataractogenesis in senile diabetic and non-diabetic patients. Graefes Arch Clin Exp Ophthalmol,47,809-814(2009)
10. D.Ganesh, K Torigoe, M.Kumano-Kuramochi, S.Machida and T. Kobori:Microplate-Based Assay for Screening of Advanced Glycation End Products Binding to Its Receptor. Anal Sci, (2019)
11. G. J. Zablocki, P. A. Ruzycki, M. A. Overturf, S. Palla, G. B. Reddy and J. M. Petrash: Aldose reductase-meduated induction of epithelium-to-mesenchymal transition (EMT) in lens. Chem Biol Interact,191,351-356(2011)
12. S.K.Srivastava, U.C.Yadav, A.B.Reddy, A.Saxena, R.Tammali, M.Shoeb, N.H.Ansari, A.Bhatnagar, M.JPetrash, S.Srivastava and K.V.Ramana:Aldose reductase inhibition suppresses oxidative stress-induced inflammatory disorders. Chem Biol Interact,191(1-3):330-8(2011).
13. C. J. Bulpitt, Y. Li, P. F. Bulpitt and J. Wang: The use of orchids in Chinese medicine. J R Soc Med,100,558-563(2007)
14. W.P.Zheng, Y.P.Tang, F.Zhi and Lou FC.:Dihydroayapin, a new coumarin compound from Dendrobium densiflorum. J Asian Nat Prod Res,2(4):301-304.(2000)
15. J. M. Hu, J. J. Chen, H. Yu, Y. X. Zhao and J. Zhou: Five new compounds from Dendrobium longicornu. Planta Med,74,535-9(2008)
16. N.Petpiroon, B.Sritularak and Chanvorachote P: Phoyunnanin E inhibits migration of non-small cell lung cancer cells via suppression of epithelial-to-mesenchymal transition and integrin αv and integrin β3. BMC Complement Altern Med., 17 (1):553. (2017)
17. P. Klongkumnuankarn, K. Busaranon, P.Chanvorachote, B.Sritularak, V.Jongbunprasert and K.Likhitwitayawuid: Cytotoxic and Antimigratory Activities of Phenolic Compounds from Dendrobium brymerianum.Evid Based Complement Alternat Med, 350410 (2015)
18. L.Qian, G.Ding, Q.Zhou, Z.Feng, X.Ding, S.Gu, Y.Wang, X.Li and B.Chu: Molecular authentication of Dendrobium loddigesii Rolfe by Amplification Refractory Mutation System (ARMS). Planta Med, 74 (4):470-3 (2008).
19. M. Déciga-Campos, J. F. Palacios-Espinosa, A. Reyes-Ramírez and R. Mata: Antinociceptive and anti-inflammatory effects of compounds isolated from Scaphyglottis livida and Maxillaria densa. J Ethnopharmacol, 114,161-8 (2007)
20. S. Estrada-Soto, R. Mata, J. J. López-Guerrero, R. Villalobos-Molina and R. Mata: Endothelium-independent relaxation of aorta rings by two stilbenoids from the orchids Scaphyglottis livida. Fitoterapia,77, 236-239(2006)
21. S.Charoenrungruang, P.Chanvorachote, B.Sritularak and V. Pongrakhananon: Gigantol, a bibenzyl from Dendrobium draconis, inhibits the migratory behavior of non-small cell lung cancer cells. J Nat Prod, 77 (6):1359-66. (2014).
22. H. Fang, X. Hu, M. Wang, W. Wan, Q. Yang, X. Sun, Q. Gu, X. Gao, Z. Wang, L. Gu, C. Y. Oliver Chen and X. Wei: Anti-osmotic and antioxidant activities of gigantol from Dendrobium aurantiacum var. denneanum against cataractogenesis in galactosemic rats. J Ethnopharmacol,172,238-246(2015)
23. P. Suryanarayana, M. Saraswat, T. Mrudula, T. P. Krishna, K. Krishnaswamy and G. B. Reddy: Curcumin and turmeric delay streptozotocin-induced diabetic cataract in rats. Invest Ophthalmol Vis Sci,46(6),2092-9(2005).
24. S.B.Kim, S.H.Hwang, Z.Wang, J.M.Yu and S.S.Lim: Rapid Identification and Isolation of Inhibitors of Rat Lens Aldose Reductase and Antioxidant in Maackia amurensis. Biomed Res Int, 4941825 (2017).
25. T.Y.Song,N.C.Yang, C.L.Chen and T.L.V.Thi: Protective Effects and Possible Mechanisms of Ergothioneine and Hispidin against Methylglyoxal-Induced Injuries in Rat Pheochromocytoma Cells. Oxid Med Cell Longev. 2017, 1-10 (2017).
26. S. S. Lim, Y. J. Jung, S. K. Hyun, Y. S. Lee and J. S. Choi: Rat lens aldose reductase inhibitory constituents of Nelumbo nucifera stamens. Phytother Res, 20,825-830(2006)
27. H. M. Li, S. H. Hwang, B. G. Kang, J. S. Hong and S. S. Lim: Inhibitory effects of Colocasia esculenta(L.) Schott constituents on aldose reductase. Molecules, 19,13212-13224(2014)
28. A.Podjarny, R.E.Cachau, T.Schneider, M. Z.Van and A..Joachimiak: Subatomic and atomic crystallographic studies of aldose reductase: implications for inhibitor binding.Cell Mol Life Sci,61(7-8):763-73(2004)
29. A.Hassanin, Y. Kaminishi and T.Itakura : Characterization of Tilapia (Oreochromis niloticus) aldehyde reductase (AKR1A1) gene, promoter and expression pattern in benzo-a-pyrene exposed fish. Toxicol Mech Methods.27(1):36-44(2017).
30. L. Ji, L.Cheng and Z.Yang: Diosgenin, a Novel Aldose Reductase Inhibitor, Attenuates the Galactosemic Cataract in Rats. J Diabetes Res,7309816. (2017).
31. H. Steuber, M. Zentgraf, C. Gerlach, C. A. Sotriffer, A. Heine and G. Klebe: Expect the unexpected or caveat for drug designers: multiple structure determinations using aldose reductase crystals treated under varying soaking and co-crystallisation conditions. J Mol Biol, 363,174-87 (2006)
32. R. Maccari, R. Ottanà, R. Ciurleo, D. Rakowitz, B. Matuszczak, C. Laggner and T. Langer: Synthesis, induced-fit docking investigations, and in vitro aldose reductase inhibitory activity of non-carboxylic acid containing 2,4-thiazolidinedione derivatives. Bioorg Med Chem, 16, 5840-52 (2008).
33. Z. Wang, B. Ling, R. Zhang, Y. Suo, Y. Liu, Z. Yu and C.liu: Docking and molecular dynamics studies toward the binding of new natural phenolic marine inhibitors and aldose reductase. J Mol Graph Model, 28,162-9 (2009).
34. C. Koukoulitsa, F. Bailly, K. Pegklidou, V. J. Demopoulos and P. Cotelle: Evaluation of aldose reductase inhibition and docking studies of 6’-nitro and 6’,6’’-dinitrorosmarinic acids. Eur J Med Chem, 45, 1663-6 (2010) .
35. K.Sundaram, S.Endo, T.Matsunaga, N.Tanaka, A.Hara and El-Kabbani O: Structure of the His269Arg mutant of the rat aldose reductase-like protein AKR1B14 complexed with NADPH. Acta Crystallogr Sect F Struct Biol Cryst Commun., 68 (Pt 4):400-3. (2012).
36. X. Wei, D. Chen, Y. Yi, H. Qi, X. Gao, H. Fang, Q. Gu, L. Wang and L. Gu: Syringic Acid Extracted from Herba dendrobii Prevents Diabetic Cataract Pathogenesis by Inhibiting Aldose Reductase Activity. Evid Based Complement Alternat Med,426537(2012)
37. R. Maccari, R. Ciurleo, M. Giglio, M. Cappiello, R. Moschini, A. D. Corso, U. Mura and R. Ottanà: Identification of new non-carboxylic acid containing inhibitors of aldose reductase. Bioorg Med Chem, 18, 4049-4055 (2010).
38. Z.Hashim and S.Zarina: Osmotic stress induced oxidative damage: possible mechanism of cataract formation in diabetes. J Diabetes Complications.26 (4):275-9 (2012).
39. Y. Li, T. H. Huang and J. Yamahara: Salacia root, a unique Ayurvedic medicine, meets multiple targets in diabetes and obesity. Life Sci,82,1045-1049(2008)
40. G. K. Balendiran and B. Rajkumar: Fibrates inhibit aldose reductase activity in the forward and reverse reactions. Biochem Pharmacol, 70,1653-1663(2005)
41. M. Stefek, Prnova M. Soltesova, M. Majekova, C. Rechlin, A. Heine and G. Klebe: Identification of novel aldose reductase inhibitors based on carboxymethylated mercaptotriazinoindole scaffold. J Med Chem, 58 (6), 2649-2657 (2015).
42. M. P. Kumar, V. Sankeshi, R. R. Naik, P. Thirupathi, B. Das and T. N. Raju: The inhibitory effect of Isoflavones isolated from Caesalpinia pulcherrima on aldose reductase in STZ induced diabetic rats. Chem Biol Interact, 237, 18-24 (2015) .
43. S. R. Sharma and N. Sharma: Epalrestat, an aldose reductase inhibitor, in diabetic neuropathy: an Indian perspective. Ann Indian Acad Neurol, 11 (4), 231-235 (2008).
44. S.Senthilkumari, R.Sharmila, G.Chidambaranathan, A.Vanniarajan: Epalrestat, an Aldose Reductase Inhibitor Prevents Glucose-Induced Toxicity in Human Retinal Pigment Epithelial Cells In Vitro. J Ocul Pharmacol Ther, 33 (1):34-41 (2017).
45. C. Veeresham, Rao A. Rama and K. Asres: Aldose reductase inhibitors of plant origin. Phytother Res,28 (3),317-333 (2014).
46. H. N. Yoon, M. Y. Lee, J. K. Kim, H. W. Suh and S. S. Lim: Aldose reductase inhibitory compounds from Xanthium strumarium. Arch Pharm Res, 36 (9), 1090-1095 (2013)
47. J. P. Luo, Y. Y. Deng and X. Q. Zha: Mechanism of Polysaccharides from Dendrobium huoshanense on Streptozotocin-Induced Diabetic Cataract. Pharmaceutical Biology, 46,243-249 (2008).
48. H.An, Q.Zhu, W.Pei, J.Fan, Y.Liang, Y.Cui, N.Lv and Wang W: Whole Transcriptome Selection and Evaluation of Internal Reference Genes for Expression Analysis in Protocorm Development of Dendrobium officinale Kimura et Migo. PLoS One., 11(11):e0163478 (2016).
49. P.P.Singh, S.K.Aithagani, M.Yadav, V.P.Singh and R.A.Vishwakarma: Iron-catalyzed cross-coupling of electron-deficient heterocycles and quinone with organoboron species via innate C-H functionalization: application in total synthesis of pyrazine alkaloid botryllazine A. J Org Chem.78 (6):2639-48. (2013).
50. A. Ramunno, S. Cosconati, S. Sartini, V. Maglio and S. Angiuoli, V. L. Pietra, S. D. Maro, M. Giustiniano , C..L. Motta, F.D. Settimo, LMarinelli and E.Novellino: Progresses in the pursuit of aldose reductase inhibitors: the structure-based lead optimization step. Eur J Med Chem, 51,216-226 (2012).
Abbreviations: diabetic cataracts (DC), aldose reductase (AR), aldose reductase inhibitors (ARI), AR,Ala substitution at Trp20 (W20A), AR,Ala substitution at Tyr48 (Y48A), AR,Ala substitution at His110 (H110A), AR,Ala substitution at Trp111 (W111A), phosphate buffer saline (PBS), dimethyl sulfoxide (DMSO), molecular docking (MD), protein data bank (PDB), 50% inhibition of enzyme activity (IC50), transferable intermolecular potential 3 points (TIP3P), wild-type (WT), root mean square deviation (RMSD), cold spray ionization mass spetrometry (CSI-MS), Streptozotocin (STZ), Kanamycin (Kan), Dalton (Da), Nanosecond (ns), reduced nicotinamide adenine dinucleotide phosphate (NADPH), three times a day (TID), complementary DNA (cDNA), polymerase chain reaction (PCR), basic local alignment search tool (BLAST), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Michaelis-Menten constant (Km), maximum velocity (Vax)
Key Words: Binding Sites, Gigantol, Aldose Reductase, Diabetic Cataract, Site-Directed Mutagenesis, Cold-Spray Ionization Mass Spectrometry
Send correspondence to: Xiaoyong Wei, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine; School of Medicine, Hangzhou Normal University. Tel: 8618520498313, Fax: 862039358588, E-mail:email@example.com