The universal terpenoid precursors isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) are synthesized either via
the classical mevalonate (MVA) pathway or the novel nonmevalonate pathway. In the MVA pathway, IPP is synthesized from three molecules of acetyl-CoA via
the intermediate MVA. It has long been assumed that the MVA pathway is commonly used for isoprenoid biosynthesis in all organisms. Recently, however, the existence of a second mevalonate-independent pathway for the biosynthesis of IPP and DMAPP has been detected in eubacteria, higher plants, algae, cyanobacteria and diatoms (Rohmer, 1999
; Lichtenthaler, 2000
). This novel nonmevalonate pathway also occurs in the apicoplast of the human malaria parasite Plasmodium falciparum
(Jomaa et al.
). Since the nonmevalonate pathway is not found in animals, it is an ideal target for the development of herbicides and antibacterial drugs.
The second enzyme of the nonmevalonate pathway, 1-deoxy-d
-xylulose 5-phosphate reductoisomerase (DXR; EC 126.96.36.1997), catalyzes the NADPH and divalent cation (Mg2+
) dependent transformation of 1-deoxy-d
-xylulose 5-phosphate (DXP) into 2-C
-erythritol 4-phosphate (MEP). In 1999, Jomaa and coworkers reported that DXR from P. falciparum
(PfDXR) was inhibited by fosmidomycin and its derivative FR-900098 and that mice infected with P. vinckei
, a relative of the human malaria parasite, could be cured using these drugs (Jomaa et al.
). These data established PfDXR as a promising antimalarial target; indeed, clinical phase II studies using fosmidomycin in combination with clindamycin in Gabon and Thailand proved that PfDXR is an effective target for the chemotherapy of malaria (Borrmann et al.
To date, several crystal structures of DXR from Escherichia coli
(Reuter et al.
; Yajima et al.
; Steinbacher et al.
; MacSweeney et al.
), from Zymomonas mobilis
(Ricagno et al.
) and from Mycobacterium tuberculosis
(Henriksson et al.
) have been reported. However, the crystal structure of PfDXR has not yet been reported. Here, we report the crystallization of PfDXR in the presence of NADPH. The structural study of PfDXR should be useful for the development of novel PfDXR inhibitors.