Academic literature on the topic 'Voie du méthylérythritol phosphate (la voie du MEP)'
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Dissertations / Theses on the topic "Voie du méthylérythritol phosphate (la voie du MEP)"
Bianchino, Gabriella ines. "La métalloenzyme IspH, une source pour la découverte de nouveaux agents antimicrobiens." Electronic Thesis or Diss., Strasbourg, 2024. http://www.theses.fr/2024STRAF016.
Full textOne way to tackle the arising antimicrobial resistance is to focus on underexploited series of target enzymes. In most bacteria and some parasites, the isoprenoid precursors are synthesized via the 2C-methyl-d-erythritol 4-phosphate (MEP) pathway, which is absent in humans, and it thus represents an interesting target for the development of novel anti-infectives. IspH is an oxidoreductase containing an oxygen-sensitive [4Fe-4S]2+ cluster that catalyzes the last step of the MEP pathway converting HMBPP into IPP and DMAPP. A multidisciplinary strategy has been applied for the discovery of new classes of inhibitors against IspH from Pseudomonas aeruginosa, Mycobacterium tuberculosis and Plasmodium falciparum. A method was developed to produce the IspH orthologs as holoenzymes, followed by the development of the enzymatic assay which was used for an in vitro screening campaign of different chemical libraries. The latter led to the discovery of a novel potent inhibitor targeting the three orthologs object of this study. Moreover, a prodrug approach has been exploited for an already known E. coli IspH inhibitor ((E)-4-amino-3-methylbut-2-en-1-yl diphosphate) with the goal of reaching antibacterial, antitubercular, and antimalarial activity
Meyer, Odile. "Biosynthèse des isoprénoïdes : Synthèses d'analogues du 1-désoxy-D-xylulose 5-phosphate,inhibiteurs potentiels de la voie du méthylérythritol phosphate." Université Louis Pasteur (Strasbourg) (1971-2008), 2004. https://publication-theses.unistra.fr/public/theses_doctorat/2004/MEYER_Odile_2004.pdf.
Full textIsoprenoids are natural compounds present in all living organism and can be synthesised via two different biosyntheses: the mevalonate pathway or the methylerytritol phosphate pathway (MEP). The enzymes involved in the MEP pathway are present in many microorganisms but absent in animal cells and therefore are potential targets for the design of new drugs acting on the diseases cause by pathogenic bacteria or parasites. In this purpose, the elaboration of potential inhibitors of this pathway has been considered. The deoxyxylulose 5-phosphate reducto-isomerase (DXR), one of the enzymes of the MEP pathway, has been chosen as a target. The synthesis of analogues of deoxuxylulose phosphate (DXP), the natural substrate of the DXR has been developed and their biochemical properties (substrate, inhibitor) have been determined. The first part of this work is the elaboration of a practical and efficient synthesis of DXP. This relevant synthesis allowed the preparation of deuterium labelled DXP, and its non phosphorylated analogue, DX, with a possible deuterium labelling at C-5. All these compounds were used for investigations on the MEP pathway. In a second part, phosphonate and fluorinated analogues of DXP have been synthesised via two different approaches: one from chirons and the other one from asymmetric synthesis. Compounds derived from the L-tartrate ester were used as chirons for the synthesis of the analogues of DXP. Such compounds were prepared by using biocatalysts: the aldolases, allowing an asymmetric aldolisation reaction. Due to the specific substrate of aldolases, the dihydroxyacetone phosphate (DHAP), a short and efficient synthesis of a precursor of DHAP, has been developed. The biological activity of the synthesised compounds was then determined in vitro on the DXR and in vivo on E. Coli. We found that the phosphonate analogue of DXP is substrate of DXR and that the other analogues are inhibitors
Janthawornpong, Karnjapan. "Biosynthèse des isoprénoïdes par la voie du méthylérythritol phosphate : contribution à l'étude de l'enzyme LytB, une réductase à centre Fe/S." Strasbourg, 2011. http://www.theses.fr/2011STRA6267.
Full textLytB, a [4Fe-4S] ~+ protein, catalyzes the reduction of HMBPP to IPP and DMAPP in the methylerythritol phosphate pathway. Due to the oxygen sensitivity of the Fe/S cluster, the enzyme had to be reconstituted with FeCI3, Na2S, and OTT or purified in the glove box containing less than 2 ppm of oxygen. Two enzymatic assay methods were developed to determine LytB kinetic parameters. The radiometric method counts directly the amounts of products formed whereas the spectrophotometric method is based on the change in NADPH absorbance, which in combination with flavodoxin reductase (FpRl) and flavodoxin (FldA) forms the reducing system required for the reaction. The Km of LytB for HMBPP measured from the radiometric method was different from the Km published by a competitor group but was in agreement with the previous results obtained in the laboratory. Due to the limit in sensitivity of the spectrophotometer, the exact Km cannot be determined from the spectrophotometric tests. Both reconstituted and glove box purified LytB gave the same range of Km. The mechanism of LytB was investigated using two HMBPP analogues. Tests showed that these analogues were not substrates of LytB but reversible and competitive inhibitors. One of these two analogues is a slow binding inhibitor. According to the radiometric method, the Ki of both inhibitors were in the nanomolar range. Attempts were made to identify the biosynthetic route of natural rubber in Ficus elastica. The isolation protocols of the key isoprenoids, (ficaprenols, phytol, and P-sitosterol) from this plant have been developed, but the biosynthesis route of ficaprenols could not be assessed
Wolff, Murielle. "Biosynthèse des isoprénoïdes par la voie du méthylérythritol phosphate : synthèse d'intermédiaires et caractérisation de GcpE et LytB, deux enzymes à centre Fe/S." Université Louis Pasteur (Strasbourg) (1971-2008), 2004. http://www.theses.fr/2004STR13065.
Full textPonaire, Sarah. "Synthèse d'analogues de substrats ou d'inhibiteurs d'enzymes de la voie du 2-C-méthyl-D-érythritol 4-phosphate (MEP) pour la synthèse des isoprénoïdes." Strasbourg, 2010. https://publication-theses.unistra.fr/public/theses_doctorat/2010/PONAIRE_Sarah_2010_ED222.pdf.
Full textIsoprenoïds are components of the vast family of « natural compounds » present in all living organisms. They are biosynthetically obtained by two distinct pathways: the mevalonate pathway and the 2-C-methylerithritol 4-phosphate pathway; the latter is present in numerous pathogenous microorganisms and parasites. Growing microorganism resistance to antibiotics and antiparasitics forces us to identify new therapeutic targets to fight against pathogens. The great advantage of the 2-C-methylerithritol 4-phosphate pathway is that it is absent in humans thus being the ideal target to discover new antibiotics. To that end, we decided to synthesize six prodrugs derived from two phosphonic acids previously obtained in our research group. The latter, directly related to fosmidomycin were proven to be potent inhibitors of E. Coli’s DXR enzyme. The new prodrugs were tested on tobacco cell cultures, on BY-2 as well on Mycobacterium smegmatis. Results obtained on BY-2 show that our prodrugs are stronger inhibitors than fosmidomycin. Moreover, they still have an inhibitory effect on very low concentrations were fosmidomycin does not. In addition, organic synthesis of 2-C-methylerithritol 4-phosphate was studied. Though various protecting groups of the phosphate moiety were used and numerous protection / deprotection steps were tested, 2-C-methylerithritol 4-phosphate was never obtained. We then pursued our efforts on synthesizing dihydroyacetone phosphate, a small organic compound found in various metabolic pathways. The organic synthesis we propose surpasses all others by its simplicity and efficiency. Finally, we tried to synthesize L-glyceraldehyde 3-phosphate; this compound is the enantiomericaly pure substrate of DXS (deoxyxylulose phosphate synthase). Though many different synthetic schemes were tested, none of them yielded the desired product
Baatarkhuu, Zoljargal. "Metabolic labelling of bacterial isoprenoids produced by the methylerythritol phosphate pathway : a starting point towards a new inhibitor." Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAF029/document.
Full textIsoprenoids, present in all living organisms, are synthesised according to two routes: the Mevalonate and the Methylerythritol phosphate (MEP) pathways. The MEP pathway, absent in humans, is extensively investigated as it is a target for the development of new antimicrobials. ME-N3 an azide tagged analogue of methylerythritol was synthesised and utilised for metabolic labelling studies of the MEP pathway using bioorthogonal ligation followed by LC-MS analysis. Interestingly, we found that MEP-N3, an analogue of MEP, inhibits E.coli IspD (3rd enzyme of the MEP pathway). Further inhibition kinetic studies revealed that MEP-N3 possesses the highest inhibitory activity on E.coli ispD when compared to known inhibitors. In addition, the mechanism of inhibition of E.coli ispD by MEP-N3 was found to be best described using a mixed type model. Moreover, determination of the IspD reaction mechanism has been carried out for the first time, by virtue of a bisubstrate steady state kinetic analysis
Ginis, Olivia. "Identification de facteurs de transcription régulateurs de la voie de biosynthèse des alcaloïdes indoliques monoterpéniques chez Catharanthus roseus." Thesis, Tours, 2012. http://www.theses.fr/2012TOUR4014/document.
Full textCatharanthus roseus is a tropical plant producing specifically monoterpene indole alkaloids (MIA) of high interest due to their therapeutical values. In C. roseus cells, the terpenoid branch including the methyl erythritol phosphate pathway (MEP) provides the MIA terpenoid moiety and is regarded as limited for MIA biosynthesis. This branch presents a coordinated transcriptional regulation in response to hormonal signals leading to MIA production. In this context, bioinformatic analysises and functional characterization of MEP pathway gene promoters allowed the identification of new transcription factor families involved in the MIA pathway regulation. Members of ZCT proteins, WRKY and type B RR families specifically interact with the hds promoter from the MEP pathway and regulate its activity. This work permits to gain into insight the transcriptional network controlling the MIA biosynthesis. It is possible now to consider using transcription factor that act as activators and target genes from the terpenoid branch to increase the accumulation of alkaloids of pharmaceutical interest in C. roseus by metabolic engineering approaches
Chebbi, Mouadh. "Implication de facteurs de transcription de type doigt de zinc et de la famille des WRKY dans la régulation de la voie du MEP et de la biosynthèse des alcaloïdes indoliques monoterpéniques de Catharanthus roseus." Thesis, Tours, 2015. http://www.theses.fr/2015TOUR3801/document.
Full textMonoterpene indole alkaloids (MIA) are molecules with anti-cancer properties from Catharanthus roseus. Their production cost and the important need in chemiotherapy make them major targets for the research of more efficient production strategies. The aim of this work is to identify new transcription factors (TF) that regulate MIA production. This study focuses especially on the functional characterization and the involvement in the MIA biosynthesis regulation, of proteins previously isolated in the EA2106 “Plant Biocompounds and Biotechnology” laboratory: 3 proteins that belong to the WRKY family (CrWRKYs) and 3 zinc finger proteins named ZCTs. Our experiments revealed that among them, CrWRKY22, CrWRKY32, ZCT1 and ZCT2 act as transcription factors and more specifically interact with the promoter of Crhds gene. Crhds encodes an enzyme of the methyl erythritol phosphate (MEP) pathway that is considered as limiting for MIA production. Our work allowed identifying new TFs targeting the MEP pathway those regulation through TFs is mostly unknown. Using such transcription factors in metabolic engineering could be now considered increasing MIA production by the modulation of terpenoid flux in C. roseus