Methylerythritol phosphate route

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The methylerythritol phosphate pathway , also MEP pathway or DOXP pathway , is a metabolic pathway that leads to the synthesis of dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP), two isoprenes . It occurs in the plastids of plants , various protozoa , bacteria and algae and has also been described for the unicellular parasite Plasmodium falciparum . In many more highly developed eukaryotes and some bacteria, the synthesis of this isoprene takes place in the so-calledMevalonate biosynthetic pathway instead.

The methylerithritol phosphate pathway was discovered by the research groups led by Michel Rohmer and Duilio Arigoni. In the English-language literature it is listed under non-mevalonate pathway .

biochemistry

The metabolic pathway begins with the linkage of pyruvate and glyceraldehyde-3-phosphate (G3P). This reaction is catalyzed by a deoxyxylulose phosphate synthase (DXS, EC  2.2.1.7 ) with elimination of carbon dioxide , with 1-deoxy- D - xylulose-5-phosphate (DXP) being formed. DXP is also the precursor for pyridoxal and thiamine biosynthesis .

DXP is reduced by DXP reductoisomerase (DXR, EC  1.1.1.267 ) and isomerized to 2C-methyl- D -erythritol-4-phosphate (MEP), with NADPH being oxidized to NADP + . Cytidine diphosphate (CDP) is then attached to MEP , which catalyzes a cytidine diphosphate methylerythritol synthase (CMS, EC  4.6.1.12 ). In this reaction, cytidine triphosphate (CTP) is consumed and pyrophosphate (PP i ) is split off. The resulting product, 4-diphosphocytidyl-2C-methyl- D -erythritol (CDP-ME), is converted to 4-diphosphocytidyl-2C-methyl- D- erythritol-2-P (CDP-MEP) with adenosine triphosphate (ATP) consumption phosphorylated, which catalyzes a cytidyl methyl kinase (CMK, EC 2.7.1.148 ).  

The reaction that now follows is cyclization, in which a phosphoric acid ester between C2 and C4 is formed with elimination of cytidine monophosphate (CMP). The reaction is catalyzed by methyl erythritol cyclo diphosphate synthase (MCS, EC  4.6.1.12 ), 2C-methyl- D -erythritol-2,4-cyclodiphosphate (MEcPP) is formed. The hydroxy-methyl-butenyl-diphosphate synthase (HDS, EC  1.17.7.1 ) then catalyzes the conversion to (E) -4-hydroxy-3-methylbut-2-enyl diphosphate (HMB-PP) and water, whereby two reduced ferredoxins act as reducing agents. The following enzyme catalyzes both the conversion to IPP and DMAPP in a ratio of 5: 1. The enzyme responsible for this is IPP / DMAPP synthase (IDS, EC  1.17.1.2 ), NAD (P) H is oxidized and water is split off.

Non-mevalonate pathway.svg

pharmacology

This metabolic pathway takes place in Plasmodium falciparum , the causative agent of malaria . Therefore it has also become a target for the development of pharmaceuticals against malaria. The best-known drug that has a blocking effect on the MEP pathway is fosmidomycin .

Individual evidence

  1. ↑ E. Cordoba, M. Salmi, P. León: Unraveling the regulatory mechanisms that modulate the MEP pathway in higher plants. In: Journal of experimental botany. Volume 60, number 10, 2009, pp. 2933-2943, doi : 10.1093 / jxb / erp190 . PMID 19584121 .
  2. ↑ SN Moreno, ZH Li: Anti-infectives targeting the isoprenoid pathway of Toxoplasma gondii. In: Expert Opinion on Therapeutic Targets . Volume 12, number 3, March 2008, pp. 253-263, doi : 10.1517 / 14728222.12.3.253 . PMID 18269336 .
  3. ↑ Lichtenthaler, H. (1999): The 1-Deoxy-D-xylulose-5-phosphate pathway of isoprenoid biosynthesis in plants . In: Annu Rev Plant Physiol Plant Mol Biol 50 ; 47-65; PMID 15012203 ; doi : 10.1146 / annurev.arplant.50.1.47
  4. ↑ Rohmer, M. (1999): The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in bacteria, algae and higher plants . In: Nat Prod Rep , 16 (5); 565-574; PMID 10584331 ; doi : 10.1039 / a709175c
  5. ↑ Rohdich, F. et al . (2002): Studies on the nonmevalonate terpene biosynthetic pathway: Metabolic role of IspH (LytB) protein . In: Proc Natl Acad Sci USA 99 (3); 1158-1163; PMID 11818558 ; PDF
  6. ↑ Chemistry & Biology, (1998), 5, 221-233 and Annual Review of Plant Physiology and Plant Molecular biology, (1999), 50, 47-65.
  7. ↑ Jomaa H. et al. (1999): Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs . In: Science , 285 (5433); 1573-1576; PMID 10477522 ; doi : 10.1126 / science.285.5433.1573