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 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 Of interest, bisphosphonates, pyrophosphate analogs in which the oxygen bridge between the two phosphorus atoms has been replaced by a carbon substituted with different side chains, are able to inhibit the growth of T. cruzi.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 (K(i) of 0.032+/-0.002 microM) by means of molecular dynamics techniques. We propose that homorisedronate, which has an extra methylene and a K(i) of 8.17+/-1.36 microM, 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.
Departamento de Química Inorgánica, Analítica y Química Física/INQUIMAE, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires/CONICET, Ciudad Universitaria, Pab. II, P. 3, C1428EHA Buenos Aires, Argentina.
Lucas
L
Sigman
Verónica Muriel
VM
Sánchez
Adrián Gustavo
AG
Turjanski
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D051228:Geranyltranstransferase / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D017386:Sequence Homology, Amino Acid; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000737:chemistry / Q000201:enzymology*
D051228:Geranyltranstransferase