The dolichol pathway of N-linked glycosylation

Burda, Patricie; Aebi, Markus

doi:10.1016/s0304-4165(98)00127-5

Cited by 589 publications

(509 citation statements)

References 120 publications

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Section: Discussionmentioning

confidence: 99%

“…2I). This was expected because the main function of dolichols, as dolichyl phosphate, is their participation in glycoprotein synthesis in the endoplasmic reticulum, where the dolichol carrier is recycled (Chojnacki & Dallner 1988, Burda & Aebi 1999.In this framework, the metabolite levels of most of the intermediates of the MEP pathway showed an increase in trophozoite and a decrease in schizont stages, when ubiquinones were accumulated. Interestingly, metabolic profiles showed that DOXP and CDP-ME were highly accumulated when compared to the other intermediates, mainly in the trophozoite and schizont stages (Fig.…”

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confidence: 95%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 95%

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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“…The assembly of glycan intermediates onto isoprenoid lipid carriers is a common theme in the biogenesis of glycoproteins and cell-surface polysaccharides of prokaryotes and eukaryotes (Bugg & Brandish, 1994;Burda & Aebi, 1999;Helenius & Aebi, 2002;Helenius et al, 2002;Valvano, 2003). A 55-carbon isoprenoid, undecaprenyl phosphate (Und-P), is the lipid carrier of biosynthetic intermediates for cell wall peptidoglycan, O antigen, enterobacterial common antigen, teichoic acids and other bacterial carbohydrate polymers.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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“…DolPP-GlcNAc 2 Man 5 is delivered into the lumen of the ER by a putative flippase (Rft1p) (Hellenius et al, 2002). Within the ER, DolPP-GlcNAc 2 Man 5 is converted to DolPP-GlcNAc 2 Man 9 Glu 3 , using dolichyl phosphate mannose (DolPMan) and dolichyl phosphate glucose (DolPGlu) as sugar donors (Burda and Aebi, 1999). DolPMan is also a substrate for protein O-mannosylation, where it serves as the donor of the first mannose to be attached to hydroxyl groups of serine and threonine in the protein.…”

Section: Introductionmentioning

confidence: 99%

Dissecting the role of dolichol in cell wall assembly in the yeast mutants impaired in early glycosylation reactions

Orłowski

Machula

Janik

et al. 2007

Yeast

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Evidence is presented that temperature-sensitive Saccharomyces cerevisiae mutants, impaired in dolichol kinase (Sec59p) or dolichyl phosphate mannose synthase (Dpm1p) activity have an aberrant cell wall composition and ultrastructure. The mutants were oversensitive to Calcofluor white, an agent interacting with the cell wall chitin. In accordance with this, chemical analysis of the cell wall alkali-insoluble fraction indicated an increased amount of chitin and changes in the quantity of β1,6-and β1,3-glucan in sec59-1 and dpm1-6 mutants. In order to unravel the link between the formation of dolichyl phosphate and dolichyl phosphate mannose and the cell wall assembly, we screened a yeast genomic library for a multicopy suppressors of the thermosensitive phenotype. The RER2 and SRT1 genes, encoding cis-prenyltransferases, were isolated. In addition, the ROT1 gene, encoding protein involved in β1,6-glucan synthesis (Machi et al., 2004) and protein folding (Takeuchi et al., 2006) acted as a multicopy suppressor of the temperature-sensitive phenotype of the sec59-1 mutant. The cell wall of the mutants and of mutants bearing the multicopy suppressors was analysed for carbohydrate and mannoprotein content. We also examined the glycosylation status of the plasma membrane protein Gas1p, a β1,3-glucan elongase, and the degree of phosphorylation of the Mpk1/Slt2 protein, involved in the cell wall integrity pathway.

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The dolichol pathway of N-linked glycosylation

Cited by 589 publications

References 120 publications

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

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

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

Dissecting the role of dolichol in cell wall assembly in the yeast mutants impaired in early glycosylation reactions

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