The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in bacteria, algae and higher plants†

Rohmer, Michel

doi:10.1039/a709175c

Cited by 1,067 publications

(801 citation statements)

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“…All natural isoprenoids are derived from two basic five-carbon molecules, isopentenyl diphosphate (IPP) and its allylic isomer dimethylallyl diphosphate (DMAPP) [1,3]. In higher plants, the isoprenoid building units are formed from two pathways that operate in different subcellular compartments [4][5][6]. One is the mevalonate (MVA) pathway, which is localized in the cytosol [7].…”

Section: Introductionmentioning

confidence: 99%

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Disruption of the 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) gene results in albino, dwarf and defects in trichome initiation and stomata closure in Arabidopsis

Xing

Miao

et al. 2010

Cell Res

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1-Deoxy-d-xylulose-5-phosphate reductoisomerase (DXR) is an important enzyme involved in the 2-C-methyl-d-erythritol-4-phosphate (MEP) pathway which provides the basic five-carbon units for isoprenoid biosynthesis. To investigate the role of the MEP pathway in plant development and metabolism, we carried out detailed analyses on a dxr mutant (GK_215C01) and two DXR transgenic co-suppression lines, OX-DXR-L2 and OX-DXR-L7. We found that the dxr mutant was albino and dwarf. It never bolted, had significantly reduced number of trichomes and most of the stomata could not close normally in the leaves. The two co-suppression lines produced more yellow inflorescences and albino sepals with no trichomes. The transcription levels of genes involved in trichome initiation were found to be strongly affected, including GLABRA1, TRANSPARENT TESTA GLABROUS 1, TRIPTYCHON and SPINDLY, expression of which is regulated by gibberellic acids (GAs). Exogenous application of GA 3 could partially rescue the dwarf phenotype and the trichome initiation of dxr, whereas exogenous application of abscisic acid (ABA) could rescue the stomata closure defect, suggesting that lower levels of both GA and ABA contribute to the phenotype in the dxr mutants. We further found that genes involved in the biosynthetic pathways of GA and ABA were coordinately regulated. These results indicate that disruption of the plastidial MEP pathway leads to biosynthetic deficiency of photosynthetic pigments, GAs and ABA, and thus the developmental abnormalities, and that the flux from the cytoplasmic mevalonate pathway is not sufficient to rescue the deficiency caused by the blockage of the plastidial MEP pathway. These results reveal a critical role for the MEP biosynthetic pathway in controlling the biosynthesis of isoprenoids.

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Section: Introductionmentioning

confidence: 99%

“…The MVA pathway has been extensively studied since its discovery in the 1950s, and has been reviewed in detail [1,3]. Different from the MVA pathway, the MEP pathway was first identified in bacteria about 15 years ago and later in plants [6,10]. Currently, all the enzymes involved in the MEP pathway have been identified.…”

Section: Introductionmentioning

confidence: 99%

Disruption of the 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) gene results in albino, dwarf and defects in trichome initiation and stomata closure in Arabidopsis

Xing

Miao

et al. 2010

Cell Res

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“…E-4-P=erythrose 4-phosphate, P=phosphate residue, PEP=pho-sphoenolpyruvate, TCA=tricarboxylic acid, TPP=thiamine diphosphate. xylulose 5-phosphate by condensation of glyceraldehyde 3-phosphate and pyruvate, was found to be existing in bacteria, green algae and higher plants (Lichtenthaler, 1999;Rohmer, 1999;Eisenreich et al, 2001;Schwender et al, 2001). This raises the question about the origin of IPP, constituting ring C of the AQs in the Rubiaceae, whether it is either derived from the MVA or the MEP pathway.…”

Section: Introductionmentioning

confidence: 99%

Biosynthesis of anthraquinones in cell cultures of Cinchona ‘Robusta’ proceeds via the methylerythritol 4-phosphate pathway

et al. 2002

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“…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.…”

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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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The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in bacteria, algae and higher plants†

Cited by 1,067 publications

References 93 publications

Disruption of the 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) gene results in albino, dwarf and defects in trichome initiation and stomata closure in Arabidopsis

Disruption of the 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) gene results in albino, dwarf and defects in trichome initiation and stomata closure in Arabidopsis

Biosynthesis of anthraquinones in cell cultures of Cinchona ‘Robusta’ proceeds via the methylerythritol 4-phosphate pathway

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

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