Ferredoxin–NADP+ reductases of Apicomplexa: unique properties of protozoan plant–type enzymes

Plant-type ferredoxin-NADP+ reductases (FNRs) are a family of flavin-dependent dehydrogenases/electron transferases ubiquitous in plant plastids, cyanobacteria and some eubacteria (1). Recently, FNRs have been identified in the apicoplast of apicomplexan parasites, which includes the causative agents of malaria and toxoplasmosis. FNRs from Toxoplasma gondii (TgFNR) and Plasmodium falciparum (PfFNR) have been cloned and characterized (2, 3). Whereas TgFNR failed to yield crystals suitable for X-ray analysis, the crystal structure of PfFNR has been determined (3). Compared to FNRs from other sources, PfFNR displays a significantly lower catalytic efficiency and poorer NADH/NADPH selectivity (3). These features of PfFNR have been interpreted on the basis of the peculiar structure of its NADP(H)-binding site. Furthermore, PfFNR undergoes an unprecedented NADP-triggered, redox-dependent homodimerization process leading to enzyme inactivation, which could represent a physiologic mechanism of enzyme regulation. PfFNR has been shown to be involved in the biosynthesis of isoprenoid precursors (4), which is the site of action of known antiplasmodial compounds. On this basis, apicomplexan FNRs have been proposed as a possible new target for novel antiparasitic drugs (2). References 1. Aliverti, A., Pandini, V., Pennati, A., de Rosa, M., and Zanetti, G., Arch. Biochem. Biophys., 474, 283-291 (2008). 2. Seeber, F., Aliverti, A., and Zanetti, G., Curr. Farm. Des., 11, 3159-7312 (2005). 3. Milani, M., Balconi, E., Aliverti, A., Mastrangelo, E., Seeber, F., Bolognesi, M., and Zanetti, G., J. Mol. Biol., 367, 501-513 (2007). 4. Röhrich, R.C., et al., FEBS Lett., 579, 6433–6438 (2005)