Characterization of the farnesyl pyrophosphate synthase of Trypanosoma cruzi by homology modeling and molecular dynamics

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 recentl...

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Autores principales:	Sigman, L., Sánchez, V.M., Turjanski, A.G.
Formato:	JOUR
Materias:	Bisphosphonates Chagas' disease Farnesyl pyrophosphate synthase Homology modeling Molecular dynamics Carbon Diseases Hydrogen bonds 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 Aves
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_10933263_v25_n3_p345_Sigman
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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spelling	todo:paper_10933263_v25_n3_p345_Sigman2023-10-03T16:04:59Z Characterization of the farnesyl pyrophosphate synthase of Trypanosoma cruzi by homology modeling and molecular dynamics Sigman, L. Sánchez, V.M. Turjanski, A.G. 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 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. Fil:Sigman, L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Sánchez, V.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Turjanski, A.G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_10933263_v25_n3_p345_Sigman
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	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
spellingShingle	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 Sigman, L. Sánchez, V.M. Turjanski, A.G. Characterization of the farnesyl pyrophosphate synthase of Trypanosoma cruzi by homology modeling and molecular dynamics
topic_facet	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
description	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.
format	JOUR
author	Sigman, L. Sánchez, V.M. Turjanski, A.G.
author_facet	Sigman, L. Sánchez, V.M. Turjanski, A.G.
author_sort	Sigman, L.
title	Characterization of the farnesyl pyrophosphate synthase of Trypanosoma cruzi by homology modeling and molecular dynamics
title_short	Characterization of the farnesyl pyrophosphate synthase of Trypanosoma cruzi by homology modeling and molecular dynamics
title_full	Characterization of the farnesyl pyrophosphate synthase of Trypanosoma cruzi by homology modeling and molecular dynamics
title_fullStr	Characterization of the farnesyl pyrophosphate synthase of Trypanosoma cruzi by homology modeling and molecular dynamics
title_full_unstemmed	Characterization of the farnesyl pyrophosphate synthase of Trypanosoma cruzi by homology modeling and molecular dynamics
title_sort	characterization of the farnesyl pyrophosphate synthase of trypanosoma cruzi by homology modeling and molecular dynamics
url	http://hdl.handle.net/20.500.12110/paper_10933263_v25_n3_p345_Sigman
work_keys_str_mv	AT sigmanl characterizationofthefarnesylpyrophosphatesynthaseoftrypanosomacruzibyhomologymodelingandmoleculardynamics AT sanchezvm characterizationofthefarnesylpyrophosphatesynthaseoftrypanosomacruzibyhomologymodelingandmoleculardynamics AT turjanskiag characterizationofthefarnesylpyrophosphatesynthaseoftrypanosomacruzibyhomologymodelingandmoleculardynamics
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Characterization of the farnesyl pyrophosphate synthase of Trypanosoma cruzi by homology modeling and molecular dynamics

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