A plant-type enzyme as a putative target for novel antimalarial drugs : properties of the Plasmodium falciparum ferredoxin-NADP+ reductase
Poster
Data di Pubblicazione:
2008
Citazione:
A plant-type enzyme as a putative target for novel antimalarial drugs : properties of the Plasmodium falciparum ferredoxin-NADP+ reductase / D. Crobu, M. Milani, P. Vella, V.E. Pandini, M. Bolognesi, G. Zanetti, A. Aliverti - In: 53rd National Meeting of the Italian Society of Biochemistry and Molecular Biology (SIB) and National Meeting of Chemistry of of Biological Systems Italian Chemical Society (SCI - Section CSB) : Palazzo dei Congressi di Riccione, 23rd-26th September 2008Firenze : Firenze University Press, 2008. - ISBN 978-88-8453-820-8. - pp. 15.5-15.5 (( Intervento presentato al 53. convegno National Meeting of the Italian Society of Biochemistry and Molecular Biology (SIB) and National Meeting of Chemistry of Biological Systems Italian Chemical Society (SCI - SectionCSB) tenutosi a Riccione nel 2008.
Abstract:
Apicomplexan parasites harbor a specific organelle,
named apicoplast, which is related to plant nonphotosynthetic
plastids and displays a plant-like
metabolism. The apicoplast has been shown to contain
typical vegetal proteins, such as ferredoxin–NADP+
reductase (FNR) and ferredoxin (Fd)1-2. Both proteins
from Plasmodium falciparum (PfFNR and PfFd) have
been produced in recombinant form and characterized3.
The PfFNR/PfFd couple was shown to be catalytically
active in vitro yielding reducing power to support the
activity of LytB4, the last enzyme of the biosynthetic
pathway for isoprenoid precursors, a known site of action
of antiplasmodial compounds. On this basis, PfFNR has
been proposed as a possible target for new antimalarial
drugs2.
The three-dimensional structure of PfFNR has been
determined by X-ray crystallography3. 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 positive charges stabilizing the 2’-
phosphate of the bound substrate. NADP(H) binding to
PfFNR occurs through an induced-fit mechanism never
observed in other FNRs. The conformational changes
induced by binding to the enzyme of 2’-P-AMP, a NADP+
analogue, includes the partial unwinding of an alpha-helix
localized in the NADP+-binding domain. Furthermore, the
binding of NADP+ triggers the formation of a disulfidestabilized
homodimer resulting in the inactivation of
PfFNR. This process, observed in vitro, could represent a
physiologic mechanism regulating the enzyme activity.
Structure-based design of PfFNR inhibitors is in progress
and has already yielded some active compounds, with
inhibitory constants in the range of micromolar or lower.
Tipologia IRIS:
03 - Contributo in volume
Keywords:
Malaria ; Plasmodium falciparum ; drug target ; enzyme ; flavoprotein ; inhibitor
Elenco autori:
D. Crobu, M. Milani, P. Vella, V.E. Pandini, M. Bolognesi, G. Zanetti, A. Aliverti
Link alla scheda completa:
Titolo del libro:
53rd National Meeting of the Italian Society of Biochemistry and Molecular Biology (SIB) and National Meeting of Chemistry of of Biological Systems Italian Chemical Society (SCI - Section CSB) : Palazzo dei Congressi di Riccione, 23rd-26th September 2008