Artículo

La versión final de este artículo es de uso interno. El editor solo permite incluir en el repositorio el artículo en su versión post-print. Por favor, si usted la posee enviela a
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor

Abstract:

Farnesyl pyrophosphate synthase (FPPS) catalyses the formation of a key cellular intermediate in isoprenoid metabolic pathways, farnesyl pyrophosphate, by the sequential head-to-tail condensation of two molecules of isopentenyl diphosphate (IPP) with dimethylallyl diphosphate (DMAPP). Recently, FPPS has been shown to represent an important target for the treatment of parasitic diseases such as Chagas disease and African trypanosomiasis. Bisphosphonates, pyrophosphate analogues in which the oxygen bridge between the two phosphorus atoms has been replaced by a carbon substituted with different side chains, are able to inhibit the FPPS enzyme. Moreover, nitrogen-containing bisphosphonates have been proposed as carbocation transition state analogues of FPPS. On the basis of structural and kinetic data, different catalytic mechanisms have been proposed for FPPS. By analyzing different reaction coordinates we propose that the reaction occurs in one step through a carbocationic transition state and the subsequent transfer of a hydrogen atom from IPP to the pyrophosphate moiety of DMAPP. Moreover, we have analyzed the role of the active site amino acids on the activation barrier and the reaction mechanism. The structure of the active site is well conserved in the isoprenyl diphosphate synthase family; thus, our results are relevant for the understanding of this important class of enzymes and for the design of more potent and specific inhibitors for the treatment of parasitic diseases. © 2006 American Chemical Society.

Registro:

Documento: Artículo
Título:Investigation of the catalytic mechanism of farnesyl pyrophosphate synthase by computer simulation
Autor:Sanchez, V.M.; Crespo, A.; Gutkind, J.S.; Turjanski, A.G.
Filiación:Departamento de Quimica Inorganici, Analitica y Quimica Fisica/INQUIMAE, Facultad de Ciencias Exactas y Naturales, Ciudad Universitaria, Pab. II, P. 3t, C1428EHA Buenos Aires, Argentina
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, United States
Palabras clave:Amino acids; Catalysis; Computer simulation; Metabolism; Phosphates; Reaction kinetics; Substitution reactions; Activation barrier; Carbocation transition; Farnesyl pyrophosphate synthase; Metabolic pathways; Enzymes
Año:2006
Volumen:110
Número:36
Página de inicio:18052
Página de fin:18057
DOI: http://dx.doi.org/10.1021/jp063099q
Título revista:Journal of Physical Chemistry B
Título revista abreviado:J Phys Chem B
ISSN:15206106
CODEN:JPCBF
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_15206106_v110_n36_p18052_Sanchez

Referencias:

  • Glomset, J.A., Gelb, M.H., Farnsworth, C.C., Prenyl proteins in eukaryotic cells: A new type of membrane anchor (1990) Trends Biochem. Sci., 15 (4), pp. 139-142
  • Ashby, M.N., Edwards, P.A., Identification and regulation of a rat liver cDNA encoding farnesyl pyrophosphate synthetase (1989) J. Biol. Chem., 264 (1), pp. 635-640
  • Urbina, J.A., Moreno, B., Vierkotter, S., Oldfield, E., Payares, G., Sanoja, C., Bailey, B.N., Docampo, R., Trypanosoma cruzi contains major pyrophosphate stores, and its growth in vitro and in vivo is blocked by pyrophosphate analogues (1999) J. Biol. Chem., 274 (47), pp. 33609-33615
  • Dunford, J.E., Thompson, K., Coxon, F.P., Luckman, S.P., Hahn, F.M., Poulter, C.D., Ebetino, F.H., Rogers, M.J., Structure - Activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates (2001) J. Phamacol. Exp. Ther., 296 (2), pp. 235-242
  • Sanders, J.M., Song, Y., Chan, J.M., Zhang, Y., Jennings, S., Kosztowski, T., Odeh, S., Oldfield, E., Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption (2005) J. Med. Chem., 48 (8), pp. 2957-2963
  • Ling, Y., Sahota, G., Odeh, S., Chan, J.M., Araujo, F.G., Moreno, S.N., Oldfield, E., Bisphosphonate inhibitors of Toxoplasma gondi growth: In vitro, QSAR, and in vivo investigations (2005) J. Med. Chem., 48 (9), pp. 3130-3140
  • Cheng, F., Oldfield, E., Inhibition of isoprene biosynthesis pathway enzymes by phosphonates, bisphosphonates, and diphosphates (2004) J. Med. Chem., 47 (21), pp. 5149-5158
  • Hosfield, D.J., Zhang, Y., Dougan, D.R., Broun, A., Tari, L.W., Swanson, R.V., Finn, J., Structural basis for bisphosphonate-mediated inhibition of isoprenoid biosynthesis (2004) J. Biol. Chem., 279 (10), pp. 8526-8529
  • Szajnman, S.H., Ravaschino, E.L., Docampo, R., Rodriguez, J.B., Synthesis and biological evaluation of 1-amino-1,1-bisphosphonates derived from fatty acids against Trypanosoma cruzi targeting farnesyl pyrophosphate synthase (2005) Bioorg. Med. Chem. Lett., 15, pp. 4685-4690
  • Van Beek, E.R., Cohen, L.H., Leroy, I.M., Ebetino, F.H., Lowik, C.W., Papapoulos, S.E., Differentiating the mechanisms of antiresorptive action of nitrogen containing bisphosphonates (2003) Bone, 33 (5), pp. 805-811
  • Van Beek, E.R., Lowik, C.W., Papapoulos, S.E., Bisphosphonates suppress bone resorption by a direct effect on early osteoclast precursors without affecting the osteoclastogenic capacity of osteogenic cells: The role of protein geranylgeranylation in the action of nitrogen-containing bisphosphonates on osteoclast precursors (2002) Bone, 30 (1), pp. 64-70
  • Cinque, G.M., Szajnman, S.H., Zhong, L., Docampo, R., Schyartzapel, A.J., Rodriguez, J.B., Gros, E.G., Structure-activity relationship of new growth inhibitors of Trypanosoma cruzi (1998) J. Med. Chem., 4 (1-9), pp. 1540-1554
  • Garzoni, L.R., Waghabi, M.C., Baptista, M.M., De Castro, S.L., Meirelles, M.N., Britto, C.C., Docampo, R., Urbina, J.A., Antiparasitic activity of risedronate in a murine model of acute Chagas' disease (2004) Int. J. Antimicrob. Agents, 23 (3), pp. 286-290
  • Garzoni, L.R., Caldera, A., Meirelles, M.N., De Castro, S.L., Docampo, R., Meints, G.A., Oldfield, E., Urbina, J.A., Selective in vitro effects of the farnesyl pyrophosphate synthase inhibitor risedronate on Trypanosoma cruzi (2004) Int. J. Antimicrob. Agents, 23 (3), pp. 273-285
  • Montalvetti, A., Bailey, B.N., Martin, M.B., Severin, G.W., Oldfield, E., Docampo, R., Bisphosphonates are potent inhibitors of Trypanosoma cruzi farnesyl pyrophosphate synthase (2001) J. Biol. Chem., 276 (36), pp. 33930-33937
  • Szajnman, S.H., Montalvetti, A., Wang, Y., Docampo, R., Rodriguez, J.B., Bisphosphonates derived from fatty acids are potent inhibitors of Trypanosoma cruzi farnesyl pyrophosphate synthase (2003) Bioorg. Med. Chem. Lett., 13 (19), pp. 3231-3235
  • Urbina, J.A., Docampo, R., Specific chemotherapy of Chagas disease: Controversies and advances (2003) Trends Parasitol., 19 (11), pp. 495-501
  • Miles, M.A., Feliciangeli, M.D., De Arias, A.R., American trypanosomiasis (Chagas' disease) and the role of molecular epidemiology in guiding control strategies (2003) Br. Med. J., 326 (7404), pp. 1444-1448
  • Tarshis, L.C., Yan, M., Poulter, C.D., Sacchettini, J.C., Crystal structure of recombinant farnesyl diphosphate synthase at 2.6-A resolution (1994) Biochemistry, 33 (36), pp. 10871-10877
  • Tarshis, L.C., Proteau, P.J., Kellogg, B.A., Sacchettini, J.C., Poulter, C.D., Regulation of product chain length by isoprenyl diphosphate synthases (1996) Proc. Natl. Acad. Sci. U.S.A., 93 (26), pp. 15018-15023
  • Kavanagh, K.L., Guo, K., Dunford, J.E., Wu, X., Knapp, S., Ebetino, F.H., Rogers, M.J., Oppermann, U., The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs (2006) Proc. Natl. Acad. Sci. U.S.A., 103 (20), pp. 7829-7834
  • Phan, R.M., Poulter, C.D., Synthesis of (S)-isoprenoid thiodiphosphates as substrates and inhibitors (2001) J. Org. Chem., 66 (20), pp. 6705-6710
  • Sigman, L., Sanchez, V.M., Turjanski, A.G., Characterization of the farnesyl pyrophosphate synthase of Trypanosoma cruzi by homology modeling and molecular dynamics J. Mol. Modell., , in press
  • Gabelli, S.B., McLellan, J.S., Montalvetti, A., Oldfield, E., Docampo, R., Amzel, L.M., Structure and mechanism of the farnesyl diphosphate synthase from Trypanosoma cruzi: Implications for drug design (2006) Proteins, 62 (1), pp. 80-88
  • Martin, M.B., Arnold, W., Heath III, H.T., Urbina, J.A., Oldfield, E., Nitrogen-containing bisphosphonates as carbocation transition state analogues for isoprenoid biosynthesis (1999) Biochem. Biophys. Res. Commun., 265 (3), pp. 754-758
  • Cornforth, J.W., Olefin alkylation in biosynthesis (1968) Angew. Chem., Int. Ed Engl., 7 (12), pp. 903-911
  • Rilling, H.G., Bloch, K., On the mechanism of squalene biogenesis from mevalonic acid (1959) J. Biol. Chem., 234 (6), pp. 1424-1432
  • Mulholland, A.J., Grant, G.H., Richards, W.G., Computer modelling of enzyme catalysed reaction mechanisms (1993) Protein Eng., 6 (2), pp. 133-147
  • Friesner, R.A., Guallar, V., Ab initio quantum chemical and mixed quantum mechanics/molecular mechanics (QM/MM) methods for studying enzymatic catalysis (2005) Anna. Rev. Phys. Chem., 56, pp. 389-427
  • Marti, M.A., Crespo, A., Capece, L., Boechi, L., Bikiel, D.E., Scherlis, D.A., Estrin, D.A., Dioxygen affinity in heme proteins investigated by computer simulation (2006) J. Inorg. Biochem., 100, pp. 761-770
  • Fernandez, M.L., Marti, M.A., Crespo, A., Estrin, D.A., Proximal effects in the modulation of nitric oxide synthase reactivity: A QM-MM study (2005) J. Biol. Inorg. Chem., 10 (6), pp. 595-604
  • Crespo, A., Marti, M.A., Kalko, S.G., Morreale, A., Orozco, M., Gelpi, J.L., Luque, F.J., Estrin, D.A., Theoretical study of the truncated hemoglobin HbN: Exploring the molecular basis of the NO detoxification mechanism (2005) J. Am. Chem. Soc., 127 (12), pp. 4433-4444
  • Marti, M.A., Scherlis, D.A., Doctorovich, F.A., Ordejon, P., Estrin, D.A., Modulation of the NO Irans effect in heme proteins: Implications for the activation of soluble guanylate cyclase (2003) J. Biol. Inorg. Chem., 8 (6), pp. 595-600
  • Zhang, Y., Kua, J., McCammon, J.A., Role of the catalytic triad and oxyanion hole in acetylcholinesterase catalysis: An ab initio QM/MM study (2002) J. Am. Chem. Soc., 124 (35), pp. 10572-10577
  • Puig, E., Garcia-Viloca, M., Gonzalez-Lafont, A., Lluch, J.M., On the ionization state of the substrate in the active site of glutamate racemase. A QM/MM study about the importance of being zwitterionic (2006) J. Phys. Chem. A, 110 (2), pp. 717-725
  • Garcia-Viloca, M., Gonzalez-Lafont, A., Lluch, J.M., A QM/MM study of the racemization of vinylglycolate catalyzed by mandelate racemase enzyme (2001) J. Am. Chem. Soc., 123 (4), pp. 709-721
  • Dinner, A.R., Blackburn, G.M., Karplus, M., Uracil-DNA glycosylase acts by substrate autocatalysis (2001) Nature, 413 (6857), pp. 752-755
  • Berman, H.M., Battistuz, T., Bhat, T.N., Bluhm, W.F., Bourne, P.E., Burkhardt, K., Feng, Z., Zardecki, C., The protein data bank (2002) Acta Ciystallogr., Sect D, 58 (1-6 PART), pp. 899-907
  • Jorgensen, W.L., Chandrasekhar, J., Madura, J.D., Impey, R.W., Klein, M.L., Comparison of simple potential functions for simulating liquid water (1983) J. Chem. Phys., 79 (2), pp. 926-935
  • Kale, L., Skeel, R., Bhandarkar, M., Brunner, R., Gursoy, A., Krawetz, N., Phillips, J., Schulten, K., NAMD2: Greater scalability for parallel molecular dynamics (1999) J. Comput. Phys., 151 (1), pp. 283-312
  • Wang, J.M., Cieplak, P., Kollman, P.A., How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules? (2000) J. Comput. Chem., 21 (12), pp. 1049-1074
  • (2002) Amber, 7. , University of California: San Francisco, CA
  • Breneman, C.M., Wiberg, K.B., Determining atom-centered monopoles from molecular electrostatic potentials-the need for high sampling density in formamide conformational- analysis (1990) J. Comput. Chem., 11 (3), pp. 361-373
  • (1998) Gaussian 98, Rev. A7, , Oaussian, Inc.: Pittsburgh, PA
  • Cornell, W.D., Cieplak, P., Bayly, C.I., Gould, I.R., Merz, K.M., Ferguson, D.M., Spellmeyer, D.C., Kollman, P.A., A 2nd generation force-field for the simulation of proteins, nucleic acids, and organic molecules (1995) J. Am. Chem. Soc., 117 (19), pp. 5179-5197
  • Berendsen, H.J.C., Postma, J.P.M., Vangunsteren, W.F., Dinola, A., Haak, J.R., Molecular-dynamics with coupling to an external bath (1984) J. Chem. Phys., 81 (8), pp. 3684-3690
  • Soler, J.M., Artacho, E., Gale, J.D., Garcia, A., Junquera, J., Ordejon, P., Sanchez-Portal, D., The SIESTA method for ab initio order-N materials simulation (2002) J. Phys.: Condens. Matter, 14 (11), pp. 2745-2779
  • Troullier, N., Martins, J.L., Efficient pseudopotentials for planewave calculations. 2. Operators for fast iterative diagonalization (1991) Phys. Rev. B, 43 (11), pp. 8861-8869
  • Troullier, N., Martins, J.L., Efficient pseudopotentials for planewave calculations (1991) Phys. Rev. B, 43 (3), pp. 1993-2006
  • Perdew, J.P., Burke, K., Ernzerhof, M., Generalized gradient approximation made simple (1996) Phys. Rev. Lett., 77 (18), pp. 3865-3868
  • Rovira, C., Schulze, B., Eichinger, M., Evanseck, J.D., Parrinello, M., Influence of the heme pocket conformation on the structure and vibrations of the Fe-CO bond in myoglobin: A QM/MM density functional study (2001) Biophys. J., 81 (1), pp. 435-445
  • Eichinger, M., Tavan, P., Hutter, J., Parrinello, M., A hybrid method for solutes in complex solvents: Density functional theory combined with empirical force fields (1999) J. Chem. Phys., 110 (21), pp. 10452-10467
  • Crespo, A., Scherlis, D.A., Marti, M.A., Ordejon, P., Roitberg, A.E., Estrin, D.A., A DFT-based QM-MM approach designed for the treatment of large molecular systems: Application to chorismate mutase (2003) J. Phys. Chem. B, 107 (49), pp. 13728-13736
  • Song, L., Poulter, C.D., Yeast farnesyl-diphosphate synthase: Sitedirected mutagenesis of residues in highly conserved prenyltransferase domains I and II (1994) Proc. Natl. Acad. Sci. U.S.A., 91 (8), pp. 3044-3048
  • Koyama, T., Tajima, M., Sano, H., Doi, T., Koike-Takeshita, A., Obata, S., Nishino, T., Ogura, K., Identification of significant residues in the substrate binding site of Bacillus stearothermophilus farnesyl diphosphate synthase (1996) Biochemistry, 35 (29), pp. 9533-9538
  • Yin, P., Cao, R., Goddard, A., Zhang, Y., Oldfield, E., Enthalpy versus entropy-driven binding of bisphosphonates to farnesyl diphosphate synthase (2006) J. Am. Chem. Soc., 128 (11), pp. 3524-3525
  • Humphrey, W., Dalke, A., Schulten, K., VMD: Visual molecular dynamics (1996) J. Mol. Graphics, 14 (1), pp. 33-38

Citas:

---------- APA ----------
Sanchez, V.M., Crespo, A., Gutkind, J.S. & Turjanski, A.G. (2006) . Investigation of the catalytic mechanism of farnesyl pyrophosphate synthase by computer simulation. Journal of Physical Chemistry B, 110(36), 18052-18057.
http://dx.doi.org/10.1021/jp063099q
---------- CHICAGO ----------
Sanchez, V.M., Crespo, A., Gutkind, J.S., Turjanski, A.G. "Investigation of the catalytic mechanism of farnesyl pyrophosphate synthase by computer simulation" . Journal of Physical Chemistry B 110, no. 36 (2006) : 18052-18057.
http://dx.doi.org/10.1021/jp063099q
---------- MLA ----------
Sanchez, V.M., Crespo, A., Gutkind, J.S., Turjanski, A.G. "Investigation of the catalytic mechanism of farnesyl pyrophosphate synthase by computer simulation" . Journal of Physical Chemistry B, vol. 110, no. 36, 2006, pp. 18052-18057.
http://dx.doi.org/10.1021/jp063099q
---------- VANCOUVER ----------
Sanchez, V.M., Crespo, A., Gutkind, J.S., Turjanski, A.G. Investigation of the catalytic mechanism of farnesyl pyrophosphate synthase by computer simulation. J Phys Chem B. 2006;110(36):18052-18057.
http://dx.doi.org/10.1021/jp063099q