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Abstract:

Chagas' disease, caused by the Trypanosoma cruzi parasite, is one of the largest public health problems in the Western hemisphere, with 16-18 million people infected, and approximately 100 million people at risk. Many efforts towards the development of targeted antiparasitic agents have recently been described. Of interest, bisphosphonates, pyrophosphate analogs in which the oxygen bridge between the two phosphorus atoms has been replaced by a carbon substituted with different side chains, are able to inhibit the growth of T. cruzi. The enzyme T. cruzi farnesyl pyrophosphate synthase (TcFPPS) involved in the mevalonate pathway, has been recently identified as the target of bisphosphonates. The protein has 362 amino acids and a molecular mass of 41.2 kDa. Several sequence motifs found in other FPPSs are present in TcFPPS. In this study we have modeled the structure of TcFPPS based on the structure of the avian FPPS. We have characterized the interaction with its substrates, isopentyl pyrophosphate and dimethylallyl pyrophosphate, and the mechanism of inhibition by the potent bisphosphonate risedronate (Ki of 0.032 ± 0.002 μM) by means of molecular dynamics techniques. We propose that homorisedronate, which has an extra methylene and a Ki of 8.17 ± 1.36 μM, does not form strong hydrogen bonds with TYR 211 and THR 208, which may be responsible for its lower activity as compared to risedronate. Moreover, we were able to reproduce the structural changes that occur upon the binding of the third Mg2+ to the active site of the protein. Taken together, our results provide a structural model for the design of novel inhibitors that may prove useful for the treatment of Chagas' disease. © 2006 Elsevier Inc. All rights reserved.

Registro:

Documento: Artículo
Título:Characterization of the farnesyl pyrophosphate synthase of Trypanosoma cruzi by homology modeling and molecular dynamics
Autor:Sigman, L.; Sánchez, V.M.; Turjanski, A.G.
Filiación:Departamento de Química Inorgánica, Analítica y Química Física, INQUIMAE, Facultad de Ciencias Exactas y Naturales, Pab. II, C1428EHA Buenos Aires, Argentina
Palabras clave:Bisphosphonates; Chagas' disease; Farnesyl pyrophosphate synthase; Homology modeling; Molecular dynamics; Carbon; Diseases; Hydrogen bonds; Molecular dynamics; Bisphosphonates; Chagas' disease; Farnesyl pyrophosphate synthase; Homology modeling; Enzymes; bisphosphonic acid derivative; dimethylallylpyrophosphate; geranyltransferase; isopentyl pyrophosphate; magnesium ion; pyrophosphoric acid derivative; risedronic acid; threonine; transferase inhibitor; tyrosine; unclassified drug; article; Chagas disease; chemical binding; chemical model; chemical structure; enzyme active site; enzyme activity; enzyme analysis; enzyme substrate; human; hydrogen bond; molecular dynamics; molecular interaction; molecular model; nonhuman; nucleotide sequence; priority journal; sequence homology; Trypanosoma cruzi; Amino Acid Sequence; Animals; Binding Sites; Geranyltranstransferase; Models, Molecular; Molecular Sequence Data; Molecular Structure; Sequence Homology, Amino Acid; Structural Homology, Protein; Structure-Activity Relationship; Trypanosoma cruzi; Aves; Trypanosoma cruzi
Año:2006
Volumen:25
Número:3
Página de inicio:345
Página de fin:352
DOI: http://dx.doi.org/10.1016/j.jmgm.2006.02.001
Título revista:Journal of Molecular Graphics and Modelling
Título revista abreviado:J. Mol. Graph. Model.
ISSN:10933263
CODEN:JMGMF
CAS:dimethylallylpyrophosphate, 358-72-5; geranyltransferase, 37277-79-5, 50812-36-7; magnesium ion, 22537-22-0; risedronic acid, 105462-24-6, 122458-82-6; threonine, 36676-50-3, 72-19-5; tyrosine, 16870-43-2, 55520-40-6, 60-18-4; Geranyltranstransferase, EC 2.5.1.10
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_10933263_v25_n3_p345_Sigman

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Citas:

---------- APA ----------
Sigman, L., Sánchez, V.M. & Turjanski, A.G. (2006) . Characterization of the farnesyl pyrophosphate synthase of Trypanosoma cruzi by homology modeling and molecular dynamics. Journal of Molecular Graphics and Modelling, 25(3), 345-352.
http://dx.doi.org/10.1016/j.jmgm.2006.02.001
---------- CHICAGO ----------
Sigman, L., Sánchez, V.M., Turjanski, A.G. "Characterization of the farnesyl pyrophosphate synthase of Trypanosoma cruzi by homology modeling and molecular dynamics" . Journal of Molecular Graphics and Modelling 25, no. 3 (2006) : 345-352.
http://dx.doi.org/10.1016/j.jmgm.2006.02.001
---------- MLA ----------
Sigman, L., Sánchez, V.M., Turjanski, A.G. "Characterization of the farnesyl pyrophosphate synthase of Trypanosoma cruzi by homology modeling and molecular dynamics" . Journal of Molecular Graphics and Modelling, vol. 25, no. 3, 2006, pp. 345-352.
http://dx.doi.org/10.1016/j.jmgm.2006.02.001
---------- VANCOUVER ----------
Sigman, L., Sánchez, V.M., Turjanski, A.G. Characterization of the farnesyl pyrophosphate synthase of Trypanosoma cruzi by homology modeling and molecular dynamics. J. Mol. Graph. Model. 2006;25(3):345-352.
http://dx.doi.org/10.1016/j.jmgm.2006.02.001