Fosmidomycin, a specific inhibitor of 1-deoxy-d-xylulose 5-phosphate reductoisomerase in the nonmevalonate pathway for terpenoid biosynthesis

Kuzuyama, Tomohisa; Shimizu, Tomohiro; Takahashi, Shunji; Seto, Haruo

doi:10.1016/s0040-4039(98)01755-9

Cited by 363 publications

(323 citation statements)

References 20 publications

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“…Fosmidomycin (Fm) is an antibiotic that specifically inhibits the conversion of deoxy-xylulose 5-phosphate into methylerythritol 4-phosphate (Kuzuyama et al, 1998a;Zeidler et al, 1998), the second step in the Und-PP de novo synthesis pathway (Kuzuyama et al, 1998b;RodriguezConcepcion & Boronat, 2002;Takahashi et al, 1998). We reasoned that in comparison to the parental strain, E. coli uppP mutants with additional defects in the Und-PP recycling pathway would exhibit higher susceptibility to Fm since de novo synthesis of Und-P and recycling of Und-PP would both be compromised.…”

Section: Fosmidomycin Hypersensitivity Suggests That Ybjg and Yeiu Armentioning

confidence: 99%

“…In the second step, MEP is synthesized by the 1-deoxy-xylulose 5-phosphate reductoisomerase encoded by the dxr gene (Takahashi et al, 1998). This reaction is specifically inhibited by the antibiotic fosmidomycin (Kuzuyama et al, 1998a;Steinbacher et al, 2003). Subsequent enzymic steps result in the formation of IPP and DMAPP, the precursors of Und-PP (Fig.…”

Section: Introductionmentioning

confidence: 99%

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An Escherichia coli undecaprenyl-pyrophosphate phosphatase implicated in undecaprenyl phosphate recycling

et al. 2007

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Section: Fosmidomycin Hypersensitivity Suggests That Ybjg and Yeiu Armentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An Escherichia coli undecaprenyl-pyrophosphate phosphatase implicated in undecaprenyl phosphate recycling

et al. 2007

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“…10 The natural antibiotic fosmidomycin ( Figure 1) is a known inhibitor of the non-mevalonate pathway in plants and bacteria. 12,13 The compound has been shown to efficiently inhibit DXRs from E. coli 14 (EcDXR) and the malaria parasite Plasmodium falciparum 11 (PfDXR), and the activities of various fosmidomycin analogues on these two enzymes seem to be well correlated. 15 Furthermore, fosmidomycin has antibacterial activity on E. coli 10,14 as well as inhibiting the growth of P. falciparum in cell culture.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and X-ray Crystallographic Studies of α-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase

et al. 2011

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The natural antibiotic fosmidomycin acts via inhibition of 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. Fosmidomycin is active on Mycobacterium tuberculosis DXR (MtDXR), but it lacks antibacterial activity probably because of poor uptake. α-Aryl substituted fosmidomycin analogues have more favorable physicochemical properties and are also more active in inhibiting malaria parasite growth. We have solved crystal structures of MtDXR in complex with 3,4-dichlorophenyl substituted fosmidomycin analogues; these show important differences compared to our previously described forsmidomycin–DXR complex. Our best inhibitor has an IC50 = 0.15 μM on MtDXR but still lacked activity in a mycobacterial growth assay (MIC > 32 μg/mL). The combined results, however, provide insights into how DXR accommodates the new inhibitors and serve as an excellent starting point for the design of other novel and more potent inhibitors, particularly against pathogens where uptake is less of a problem, such as the malaria parasite.

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“…DOXP reductoisomerase (DXR) then catalyzes the intramolecular rearrangement and reduction of DOXP to MEP. The activity of this enzyme is specifically inhibited by fosmidomycin (Kuzuyama et al 1998). Several subsequent reaction steps are necessary for the conversion of MEP to IPP and DMAPP (Fig.…”

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Effect of fosmidomycin on metabolic and transcript profiles of the methylerythritol phosphate pathway in Plasmodium falciparum

Cassera

Merino

Peres

et al. 2007

Mem. Inst. Oswaldo Cruz

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Key words: Plasmodium falciparum -malaria -fosmidomycin -isoprenoid biosynthesis -real time polymerase chain reaction Malaria is a leading cause of morbidity and mortality in the tropical regions, with 300 to 500 million clinical cases and 1.5 to 2.7 million deaths per year (Snow et al. 2005). With the availability of the complete genome sequence from Plasmodium falciparum, increasing attention has focused on transcript profiling and proteomic analyses of the parasite stages responsible for severe disease and pathogenesis in humans (Florens et al. 2002, Bozdech et al. 2003, Le Roch et al. 2003, Nirmalan et al. 2004, Llinas et al. 2006.Two different biosynthetic routes are used to produce isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) for isoprenoid biosynthesis including ubiquinones, dolichols and the prenylation of proteins (Sacchettini & Poulter 1997, Sinensky 2000, Barkovich & Liao 2001. In mammals, plants (cytoplasm), fungi, some bacteria and several protozoa, the isoprenic units are derived from the classical mevalonate pathway (Goldstein & Brown 1990). In plastids of plants, several algae, eubacteria, cyanobacteria and apicomplexa (apicoplast), the 2C-methyl-D-erythritol-4-phosphate (MEP) pathway produces IPP and DMAPP (Rohmer 1999). The MEP pathway starts with the condensation of pyruvate and glyceraldehyde-3-phosphate (GAP), which yields 1-deoxy-D-xylulose-5-phosphate (DOXP) catalyzed by DOXP synthase (DXS); for reviews see references (Lichtenthaler 1999, Rohmer 1999, Eisenreich et al. 2004, Rodriguez-Concepcion 2004. DOXP reductoisomerase (DXR) then catalyzes the intramolecular rearrangement and reduction of DOXP to MEP. The activity of this enzyme is specifically inhibited by fosmidomycin (Kuzuyama et al. 1998). Several subsequent reaction steps are necessary for the conversion of MEP to IPP and DMAPP (Fig. 1).Discovery of the MEP pathway for isoprenoid biosynthesis in P. falciparum revealed several antimalarial drug targets (Jomaa et al. 1999). Jomaa and co-workers demonstrated that fosmidomycin and its derivate FR900098, are able to inhibit the growth of P. falciparum in culture and to cure mice infected with the related malaria parasite, P. vinckei (Jomaa et al. 1999). Recent field trials in humans have also demonstrated the effectiveness of fosmidomycin in the treatment of human malarial infections, but it has to be administered for more than four days when used alone (Missinou et al. 2002, Borrmann et al. 2005. Recently, biochemical and mass spectrometric analyses revealed that the MEP pathway is functionally active in all intraerythrocytic stages of P. falciparum (Cassera et al. 2004).In this study we characterized the effect of fosmidomycin on the metabolic levels of each intermediate of the MEP pathway as well as dolichol and ubiquino- nes in ring, trophozoite and schizont stages of P. falciparum parasites and correlated these to the steadystate MEP enzyme transcript levels under drug pressure. MATERIALS AND METHODSExperimental design -Three characteristic developmental sta...

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Fosmidomycin, a specific inhibitor of 1-deoxy-d-xylulose 5-phosphate reductoisomerase in the nonmevalonate pathway for terpenoid biosynthesis

Cited by 363 publications

References 20 publications

An Escherichia coli undecaprenyl-pyrophosphate phosphatase implicated in undecaprenyl phosphate recycling

An Escherichia coli undecaprenyl-pyrophosphate phosphatase implicated in undecaprenyl phosphate recycling

Design, Synthesis, and X-ray Crystallographic Studies of α-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase

Effect of fosmidomycin on metabolic and transcript profiles of the methylerythritol phosphate pathway in Plasmodium falciparum

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