2-C-Methyl-D-erythritol 4-phosphate MEP pathway

Terpenoids are derived from the cytosolic mevalonate pathway or from the plastidial 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway (see also Terpenoid Biosynthesis). Both pathways lead to the formation of the C5 units isopentenyl diphosphate and its allylic isomer dimethylallyl diphosphate, which are the basic terpenoid biosynthesis building blocks (Fig. 1). Although increasing evidence suggests that exchange of intermediates occurs between these compartments, the cytoplasmic mevalonate pathway is generally considered to supply the precursors for the production of sesquiterpenes and triterpenes (including sterols) and to provide precursors for protein prenylation and for ubiquinone and heme-A production in mitochondria. In the plastids, the MEP pathway supplies the precursors for the production of isoprene, monoterpenes, diterpenes (e.g., GAs), and tetraterpenes (e.g., carotenoids). 

With the possibility of the 1-deoxyxylulose 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway to the hemiterpene units, IPP and DMAPP, operating in higher plants, it will be of interest to establish whether the five-carbon unit incorporated into the quinoline nucleus is preferentially derived from mevalonic acid or 1 -deoxyxylulose. 

As artemisinin has a terpenic structure, its biosynthesis starts in the formation of isopentenyl diphosphate GPP)> as in all the natural terpenoids. In plants, IPP is synthesized either via the mevalonate pathway in the cytosol or via the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway in the plastid. The IPP derived from the mevalonate pathway is generally used in the biosynthesis of sesquiterpenes (such as artemisinin), phytosterols, and triterpenes, and the IPP derived from the non-mevalonate pathway is employed in the biosynthesis of monoterpenes, diterpenes, and tetraterpenes (Fig. 89.15). 

The importance of terpenoids to life is highlighted by the fact that two separate pathways have been found to produce the terpenoid precursor C5 units isopentenyl diphosphate (IDP) and dimethylaUyl diphosphate (DMADP). The mevalonic acid (MVA) pathway is functional in archae, animals and fungi, 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway is found in green algae, and terpenoids are produced by both pathways in bacteria and plants [2]. In plants the MVA pathway is active in the cytosol and it provides C5 units for sesquiterpene, triterpene and polyterpene biosynthesis whereas the MEP pathway occurs in plastids and produces C5 units for isoprene, monoterpenes, diterpenes and carotenoids [1]. Recent reports have indicated metabolic crosstalk between biosynthesis pathways and e.g., the homoterpene DMNT may originate from both pathways. 

Steviol glycosides are derived from the mevalonic acid pathway. The ent-kaurene skeleton of stevioside is formed via 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway [59, 60]. High activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in chloroplasts of Stevia rebaudiana has been reported [61]. Hence, the investigators anticipated mevalonic acid (MVA) as an intermediate of steviol biosynthetic route on the basis of the fact that HMG-CoA reductase is a key enzyme of the MVA route to isopentenyl-diphosphate (IPP). 

Carotenoids are synthesized from the basic C5 terpenoid precursor isopentenyl pyrophosphate (IPP) and dimethylallyl diphosphate (DMAPP). These precursors can be obtained from two distinct pathways the mevalonate pathway (MVA) and the non-MVA pathway also known as 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway [84, 85]. All eukaryotes use the MVA pathway, whereas plant plastids and most bacteria use the MEP pathway [86,87]. Some bacteria also use the MVA pathway [84]. In the MEP pathway, the first step in IPP biosynthesis is the formation of l-deoxy-D-xylulose-5-phosphate (DXP) from pyruvate and glyceraldehyde-3-phosphate catalyzed by DXP synthase (Figure 10.7). DXP is then reduced to MEP by DXP reductase. Additional MEP pathway enzymes are then used in subsequent reactions for converting MEP to IPP, which is isomer-ized to DMAPP by the enzyme IPP isomerase. The MVA pathway begins with the conversion of three molecules of acetyl-CoA to MVA through acetoacetyl-CoA... 

There are two distinct pathways for biosynthesis of the IPP and DMAPP the mevalonate (MVA) pathway and the DXP pathway (Figure 12.3). The MVA pathway functions primarily in eukaryotes, while the DXP pathway is typically present in prokaryotes and the plastids of plants [90,91]. The first reaction in the DXP pathway is the condensation of pyruvate and D-glyceraldehyde-3-phosphate (G3P) to form DXP, which is catalyzed by DXP synthase encoded by the gene dxs [92]. In the second step, DXP is reduced to 2-C-methyl-D-erythritol-4-phosphate (MEP) by DXP reductoisomerase, which is encoded by the gene dxr (ispC) in E. coli. An array of other enzymes encoded by is pi), ispE, ispF, ispG, and ispH act in subsequent sequential reactions, leading to the conversion of MEP to IPP and DMAPP, which are interconverted by the enzyme encoded by idi [93-97],... 

The CPPase substrate DMAPP (15) is formed from isopentenyl pyrophosphate (IPP) (14) via the IPP isomerase reaction. It had been assumed that IPP was generated only via mevalonic acid (12) (Fig. 2), but Rohmer discovered another route, 2-C-methyl-D-erythritol 4-phosphate (13) (MEP) pathway (Fig. 2) [22, 23]. A key step in the MEP pathway is the reaction catalyzed by 1-deoxy-D-xylulose 5-phosphate synthase (DXS), which combines hydroxyethyl thiamine pyrophosphate (hydroxyethyl TPP) generated from pyruvic acid (17) and TPP with glyceral-dehyde 3-phosphate (18) to yield 1-deoxy-D-xylulose 5-phosphate (19) containing five carbons. The mevalonate pathway operates in the cytosol of plants and animals, whereas the MEP pathway is present in the plastid of plants or in eubacteria [24-27]. 

Wanke M, Skorupinska-Tudek K, Swiezewska E (2001) Isoprenoid biosynthesis via 1-deoxy-D-xylulose 5-phosphate/2-C-methyl-D-erythritol 4-phosphate (DOXP/MEP) pathway. Act... 

Figure 27 Four possible pathways for ABA biosynthesis. Open and closed circles show the 13C label from [1-13C]-d-glucose in the mevaloic acid pathway and the MEP pathway, respectively. DAP, dihydroxyacetone phosphate DXP, 1-deoxy-xylulose-5-phosphate FDP, farnesyl diphosphate GAP, glyceraldehyde-3-phosphate GGDP, geranylgeranyl diphosphate HMG-CoA, 3-hydroxy-3-methylglutaryl CoA IDP, isopentenyl diphosphate MEP, 2-C-methyl-D-erythritol-4-phosphate.

R,4S)-3,4-Dihydroxy-5-oxohexylphosphonic acid (282), an isosteric analogue of l-deoxy-D-xylulose-5-phosphate (DXP), the first C5 intermediate in the MEP pathway for isoprenoid biosynthesis has been synthesized from (+)2,3-0-benzylidene-D-threitol (283) by a seven step reaction sequence. This phosphonate (282) was next enzymatically converted into (3R,4R)-3,4,5-trihy-droxyphosphonic acid (284), an isosteric analogue of 2-C-methyl-D-erythritol-4-phosphate (Scheme 72). 

FIGURE 523 The leaf isoprene formation at subcellular compartment level based on Reference [11].This figure illustrates the role of the cytosolic mevalonate and chloroplastic deoxyxylulose-5-phosphate (DOXP) pathways in the formation of dimethylallyl diphosphate (DMAPP), the precursor of isoprene by the isoprene synthase reaction. IPP, isopentenyl diphosphate HMG-CoA, 3-hydroxy-3-methylglutaryl-coen-zyme A MEP, 2-C-methyl-D-erythritol 4-phosphate PEP, phosphoenolpyruvate. (Adapted and reprinted with kind permission from Springer Science + Business Media [16], figure 1.)... 

Fig. 117.9 An overview of the cytosolic mevalonate pathway and plastidial mevalonate-independent pathway for the biosynthesis of terpenoids (isoprenoids) in plant cells [99] (DMAPP, dimethylallyl diphosphate DXP, l-deoxy-D-xylulose-5-phosphate DXS, DXP synthase DXR, DXP reductoisomerase MEP, 2-C-methyl-D-erythritol 4-phosphate GASP, gfyc-eraldehyde-3-phosphate HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA HMGR, HMGR-CoA reductase IPP, isopentenyl diphosphate. Mevinolin and fosmidomycin are inhibitors of HMGR and DXR, respectively)...

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