β-Carboline Alkaloids from Galianthe ramosa Inhibit Malate Synthase from Paracoccidioides spp.

Abstract

As part of our continuing chemical and biological analyses of Rubiaceae species from Cerrado, we isolated novel alkaloids 1 and 2, along with known compounds epicatechin, ursolic acid, and oleanolic acid, from Galianthe ramosa. Alkaloid 2 inhibited malate synthase from the pathogenic fungus Paracoccidioides spp. This enzyme is considered an important molecular target because it is not found in humans. Molecular docking simulations were used to describe the interactions between the alkaloids and malate synthase.

Key words

Galianthe ramosa - Rubiaceae - indole alkaloids - malate synthase - Paracoccidioides spp.

• References

• 1 Restrepo A, Mc Eween JG, Castaneda E. The habitat of Paracoccidioides brasiliensis: how far from solving the riddle?. Med Mycol 2001; 39: 233-241
• 2 Bernard G, Kavakama J, Mendes-Giannini MJM, Kono A, Duarte AJ, Shikanai-Yasuda MA. Contribution to the natural history of paracocidioidomycosis: identification of primary pulmonary infection in the severe acute form of the disease – a case report. Clinical Infection Disease 2005; 40: 1-4
• 3 Shikanai-Yasuda MA, Queiroz-Telles F, Mendes RP, Colombo AL, Moretti ML. Consenso em Paracoccidioidomycosis. Rev Soc Bras Med Trop 2006; 39: 297-310
• 4 Nunura RJ, Salazar MD, Vásquez LT, Endo GS, Rodríguez FA, Zerpa LR. Paracoccidioidomicosis and multidrug-resistant tuberculosis (TBC-MDR) in patient coinfected with HIV and hepatitis C. Rev Chil Infectol 2010; 27: 551-555
• 5 Bellissimo-Rodrigues F, Vitali LH, Martinez R. Serological diagnosis of paracoccidioidomycosis in HIV-coinfected patients. Mem Inst Oswaldo Cruz 2010; 105: 904-907
• 6 McKinney JD, Höner zu Bentrup K, Muñoz-Elías EJ, Miczak A, Chen B, Chan WT, Swenson D, Sacchettini JC, Jacobs jr. WR, Russell DG. Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 2000; 406: 735-738
• 7 Lorenz MC, Fink GR. Life and death in a macrophage: role of the glyoxylate cycle in virulence. Eukaryotic Cell 2002; 1: 657-662
• 8 Lorenz MC, Bender JA, Fink GR. Transcriptional response of Candida albicans upon internalization by macrophages. Eukaryotic Cell 2004; 3: 1076-1087
• 9 Rude TH, Toffaletti DL, Cox GM, Perfect JR. Relationship of the glyoxylate pathway to the pathogenesis of Cryptococcus neoformans . Infect Immun 2002; 70: 5684-5694
• 10 Thines ER, Webwer RW, Talbot NJ. MAP kinase and protein kinase A-dependent mobilization of triacylglycerol and glycogen during appreorium turgor generation by Magnoporth grisea . Plant Cell 2000; 12: 1703-1708
• 11 Bastos KP, Bailão AM, Borges CL, Faria FP, Felipe MS, Silva MG, Martins WS, Fiuza RB, Pereira M, Soares CMA. The transcriptome analysis of early morphogenesis in Paracoccidioides brasiliensis mycelium reveals novel and induced genes potentially associated to the dimorphic process. BMC Microbiology 2007; 7: 29
• 12 Costa M, Borges CL, Bailão AM, Meirelles GV, Mendonça YA, Dantas SF, de Faria FP, Felipe MS, Molinari-Madlum EEWI, Mendes-Giannini MJ, Fiuza RB, Martins WS, Pereira M, Soares CMA. Transcriptome profiling of Paracoccidioides brasiliensis yeast-phase cells recovered from infected mice brings new insights into fungal response upon host interaction. Microbiology 2007; 153: 4194-4207
• 13 Derengowski LS, Tavares AH, Silva S, Procópio LS, Felipe MS, Silva-Pereira I. Upregulation of glyoxylate cycle genes upon Paracoccidioides brasiliensis internalization by murine macrophages and in vitro nutritional stress condition. Med Mycol 2008; 46: 125-134
• 14 Goldman GH, dos Reis Marques E, Duarte Ribeiro DC, de Souza Bernardes LA, Quiapin AC, Vitorelli PM, Savoldi M, Semighini CP, de Oliveira RC, Nunes LR, Travassos LR, Puccia R, Batista WL, Ferreira LE, Moreira JC, Bogossian AP, Tekaia F, Nobrega MP, Nobrega FG, Goldman MH. EST analysis of the human pathogen Paracoccidioides brasiliensis yeast phase: identification of putative homologues of Candida albicans virulence/pathogenicity genes. Eukaryot Cell 2003; 2: 34-48
• 15 Figueiredo PO, Garcez FR, Matos MFC, Perdomo RT, Queiroz LMM, Pott A, Garcez AJS, Garcez WS. A new cytotoxic b-carboline alkaloid from Galianthe thalictroides . Planta Med 2011; 77: 1852-1854
• 16 El-Razek AMH. NMR assignments of four catechi epimers. Asian J Chem 2007; 19: 4867-4872
• 17 Kim D, Han K, Chung I. Triterpenoids from the flower of Campis grandiflora K. Schum. as human acyl-CoA: cholesterol acyltransferase inhibitors. Arch Pharm Res 2005; 28: 550-556
• 18 Anstrom DM, Kallio K, Remington SJ. Structure of the Escherichia coli malate synthase G pyruvate: acetylcoenzyme A abortive ternary complex at 1.95 Å resolution. Protein Sci 2003; 12: 1822-1832
• 19 Munir E, Takefumi H, Mikio S. Purification and characterization of malate synthase from the glucose-grown wood-rotting basidiomycete Fomitopsis palustris . Biosci Biotechmol Biochem 2002; 66: 576-581
• 20 Clinical Laboratory Standard Institute. Reference method for broth dilution antifungal susceptibility testing of filamentous fungi (M38-A2). 2nd. edition. Wayne: Clinical Laboratory Standard Institute (CLSI); 2008
• 21 de Paula e Silva AC, Oliveira HC, Silva JF, Sangalli-Leite F, Scorzoni L, Fusco-Almeida AM, Mendes-Giannini MJ. Microplate alamarBlue assay for Paracoccidioides susceptibility testing. J Clin Microbiol 2013; 51: 1250-1252
• 22 Roucourt B, Minnebo N, Augustijns P, Hertveldt K, Volckaert G, Lavigne R. Biochemical characterization of malate synthase G of P. aeruginosa . BMC Biochemistry 2009; 10: 1471-2091
• 23 Ornston LN, Ornston MK. Regulation of glyoxylate metabolism in Escherichia coli K-12. J Bacteriol 1969; 98: 1098-1108
• 24 Beeckmans S, Khan AS, Kanarek L, Van Driessche E. Ligand binding on to maize (Zea mays) malate synthase: a structural study. Biochem J 1994; 303: 413-421
• 25 Eswar N, Johr B, Mirkovic N, Fiser A, Ilyn VA, Pierper U, Stuart AC, Martin Renom MA, Madhusudan MS, Yerkovich B. Tools for comparative protein structure modeling and analysis. Nucleic Acids Res 2003; 31: 3375-3380
• 26 Colovos C, Yeates TO. Verification of protein structures: Patterns of nonbonded atomic interactions. Protein Science 1993; 2: 1511-1519
• 27 Lovell SC, Davis IW, Arendall WB, De Bakker PIW, Word JM, Prisant MG, Richardson JS, Richardson DC. Structure validation by Cα geometry: Φ, Ψ and Cβ deviation. Proteins: Struct, Funct, Bioinf 2003; 50: 437-450
• 28 Luthy R, Bowie JU, Eisenberg D. Assessment of protein models with three-dimensional profiles. Nature 1992; 356: 83-85
• 29 Van Gusnsteren WF, Billeter SR, Eising AA, Hunenberger PJ, Kroger P, Mark AE, Scott WRP, Tironi IG. Biomolecular simulation: The GROMOS96 manual and user guide. Zurich, Groningen: Biomos b.v.; 1996
• 30 Berendsen HJC, Van der Spoel D, Van Drunen R. Gromacs: A message-passing parallel molecular dynamics implementation. Comput Phys Commun 1995; 91: 43-56
• 31 Lindahl E, Hess B, Van der Spoel D. GROMACS 3.0: a package for molecular simulation and trajectory analysis. J Mol Model 2001; 7: 306-317
• 32 Kim ND, Chun H, Park SJ, Yang JW, Kim JW, Ahn SK. Discovery of novel HCV polymerase inhibitors using pharmacophore-based virtual screening. Bioorg Med Chem Lett 2011; 21: 3329-3334
• 33 Darden T, York D, Pedersen L. Particle mesh Ewald: an N.log (N) method for Ewald sums in large systems. J Chem Phys 1993; 98: 10089-10092
• 34 Daura X, Gademann K, Jaun B, Seebach D, Van Gusteren WF, Mark EA. Peptide folding: when simulation meets experiment. Angew Chem Int 1999; 38: 236-240
• 35 Schüttelkopf AW, Van Aalten DMF. PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystal Sec D Biol Crystall 2004; 60: 1355-1363
• 36 Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comp Chem 2009; 30: 2785-2791
• 37 Volkamer A, Kuhn D, Grombacher T, Rippmann F, Rarey M. Combining global and local measures for structure-based druggability predictions. J Chem Info Model 2012; 52: 360-372
• 38 Volkamer A, Griewel A, Grombacher T, Rarey M. Analyzing the topology of active sites: on the prediction of pockets and subpockets. J Chem Info Model 2010; 50: 2041-2052
• 39 Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comp Chem 2011; 31: 455-461
• 40 Chang MW, Ayeni C, Breuer S, Torbett BE. Virtual screening for HIV protease inhibitors: a comparison of AutoDock 4 and Vina. PloS one 2010; 5: e11955
• 41 Queiroz jr. LHK, Lacerda jr. V, dos Santos RB, Greco SJ, Neto AC, Castro EVR. NMR property calculations and experimental study of the 1,6-epoxycarvone and α-epoxypinene: a comparison of models. Magn Reson Chem 2011; 49: 140-146
• 42 Oliveira KT, Lacerda jr. V, Constantino MG, Donate PM, da Silva GVJ, Brocksom TJ, Frederico D. Analysis of a cycloheptenone derivative: An experimental and theoretical approach. Spectrochim Acta A 2006; 63: 709-713
• 43 Møller C, Plesset MS. Note on an approximation treatment for many-electron systems. Phys Rev 1934; 46: 618-622
• 44 Dunning TH. Gaussian basis sets for use in correlated molecular calculations. I. The atoms boron through neon and hydrogen. J Chem Phys 1989; 90: 1007-1023
• 45 Woon D, Dunning TH. Gaussian basis sets for use in correlated molecular calculations. IV. Calculation of static electrical response properties. J Chem Phys 1995; 100: 2975-2988
• 46 Miertus S, Scrocco E, Tomasi J. Electrostatic interaction of a solute with a continuum. A direct utilization of ab initio molecular potentials for the prevision of solvent effects. Chem Phys 1981; 55: 117-129
• 47 Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ. Gaussian 09, Revision A02. Wallingford: Gaussian, Inc.; 2009