Plant-type ferredoxin-NADP+ reductases (FNRs) represent a widespread group of flavin-dependent dehydrogenases/electron transferases that catalyze the exchange of reducing equivalents between NADP(H) and ferredoxin (Fd) or flavodoxin . FNRs have been found in plant plastids, cyanobacteria and some eubacteria . FNRs structurally similar to those present in non-photosynthetic plastids, have been identified in the apicoplast of apicomplexan parasites [2,3], which includes the causative agents of malaria and toxoplasmosis. Plasmodium falciparum FNR (PfFNR) and Fd (PfFd) have been cloned and characterized. The crystal structure of both proteins has been determined [4,5]. Compared to other plastidic-type FNRs, PfFNR displays a significantly lower catalytic efficiency and lower selectivity against NADH . These functional features are probably the consequence of the lack of protein positively-charged groups stabilizing the 2’-phosphate of bound substrate. NADP(H)-binding to PfFNR occurs through an unprecedented induced-fit mechanism that involves the partial unwinding of a helix. Furthermore, PfFNR undergoes a redox-dependent homodimerization process leading to enzyme inactivation, which could represent a regulatory mechanism. The PfFNR/PfFd couple has been shown to support in vitro the activity of LytB , the last enzyme of the biosynthetic pathway of isoprenoid precursors, site of action of known antiplasmodial compounds. On this basis, PfFNR has been proposed as a possible new target for antimalarial drugs . Structure-based design of PfFNR inhibitors is in progress and has already yielded some active compounds.  Ceccarelli, E.A., Arakaki, A.K. Cortez, N., and Carrillo, N. (2004) Biochim. Biophys. Acta 1698, 155-165.  Pandini, V., Caprini, G., Thomsen, N., Aliverti, A., Seeber, F., and Zanetti, G. (2002) J. Biol. Chem. 277, 48463-48471.  Seeber, F., Aliverti, A., and Zanetti, G. (2005) Curr. Farm. Des. 11, 3159-7312.  Milani, M., Balconi, E., Aliverti, A., Mastrangelo, E., Seeber, F., Bolognesi, M., and Zanetti, G. (2007) J. Mol. Biol. 367, 501-513.  Kimata–Ariga, Y., Saitoh, T., Ikegami, T., Horii, T., and Hase, T. (2007) J. Biochem. 142, 715-720.  Röhrich, R.C., Englert, N., Troschke, K., Reichenberg, A., Hintz, M., Seeber, F., Balconi, E., Aliverti, A., Zanetti, G., Köhler, U., Pfeiffer, M., Beck, E., Jomaa, H., and Wiesner, J. (2005) FEBS Lett. 579, 6433–6438.
|Titolo:||Plasmodium falciparum ferredoxin-NADP+ reductase: unique structural and functional properties of a plant-type enzyme|
|Autori interni:||ALIVERTI, ALESSANDRO (Primo)|
PANDINI, VITTORIO ENRICO
BOLOGNESI, MARTINO (Penultimo)
ZANETTI, GIULIANA (Ultimo)
|Data di pubblicazione:||8-giu-2008|
|Parole Chiave:||Flavoprotein ; enzyme ; drug design ; drug target ; Plasmodium falciparum ; malaria|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
|Citazione:||Plasmodium falciparum ferredoxin-NADP+ reductase: unique structural and functional properties of a plant-type enzyme / A. Aliverti, M. Milani, D. Crobu, V. Pandini, R. Cerutti, M. Bolognesi, G. Zanetti. ((Intervento presentato al 16. convegno International Symposium on Flavins and Flavoproteins tenutosi a Jaca, Spain nel 2008.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|
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