Pathways methyl-erythritol-phosphate

IPP and its DMAPP structural isomer are produced from glycolytic products by the methyl erythritol phosphate (MEP) pathway (Figure 5.3.1, Pathway 1). These isoprene units are condensed in a stepwise fashion to form the precursor to all carotenoids, geranylgeranyl di-phosphate (GGPP). GGPP is not solely metabolized to make carotenoids, but is a precursor for many other primary and secondary metab-... 

One of the more exciting and recent advances in the field of plant biochemistry has been the discovery of the mevalonate-independent pathway for the biosynthesis of isoprenoids (Fig. 10.4). This new pathway, referred to a the methyl-erythritol-phosphate or MEP pathway for the first intermediate committed solely to the biosynthesis of isoprenoids, was first discovered in prokaryotes capable of accumulating hopenes, the equivalent of eukaryotic sterols. 6,17 The MEP pathway has since been confirmed in plants and, not surprisingly, has been localized to chloroplasts.18 Operation of the MEP pathway is intimately related to the reactions of CO2 fixation and photosynthesis, as evidenced by the two immediate precursors pyruvate and phosphoglyceraldehyde for this pathway. Two important features of this pathway are that mevalonate is not an intermediate in the plastidic synthesis of isopentenyl (IPP) and dimethylallyl diphosphate, (DMAPP), and this pathway... 

Figure 10.7 All terpenes are derived from allylic diphosphates which are polymers of repeating isopentyl units (IPP) put together by the action of prenyltransferases. In plants, IPP can be derived from the mevalonate biosynthetic pathway (a cytoplasmic pathway) or the methyl erythritol phosphate pathway (a plastidic pathway). Monoterpenes are then derived from the CIO precursor geranyl diphosphate (GPP), sesquiterpenes from the C15 precursor famesyl diphosphate (FPP), and diterpenes from the C20 precursor geranylgeranyl diphosphate (GGPP) by the action of terpene synthases or cyclases, which divert carbon into the specific branch pathways.

Singh, N., Cheve, G., Avery, M. A., McCurdy, C. R. Targeting the methyl erythritol phosphate (MEP) pathway for novel antimalarial, antibacterial and herbicidal drug discovery inhibition of 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) enzyme. Curr. Pharm. Des. 2007, 13, 1161-1177. 

Figure 2.5 Biosynthetic pathway to IPP and DMAPP via the mevalonate pathway (a) and the methyl-erythritol phosphate (MEP) pathway (h).

Scheme 102.3 reports the mevalonate-independent pathway, also named as deoxyxylulose (DXP) or methyl erythritol phosphate pathway. It starts from pyruvic acid and o-glyceraldehyde to form 1 -deoxy-o-xylulose 5P (DXP) reduced to 2 C-methyl-D-erythritol 4P which by phosphorylation affords a cyclic intermediate 2 C-methyl-D-erythritol 2,4-cyclophosphate. This compound by elimination reaction followed by tautomerization gives IPP and DMAPP, the latter possibly formed either independently or by isomerization. 

Biosynthetically, majority of terpenoids are formed via the mevalonic acid, but they may also be formed through methyl-erythritol-4-phosphate (MEP) pathway. The C5 isoprene unit which can be linked together head to tail to form linear chains or cyclized to form rings is considered the building blocks of terpenes. Rather the C5 units exist as isopentenyl pyrophosphate or its isomer dimethylallyl pyrophosphate by enzymatic conversion and phosphorylation from mevalonic acid. The IPP may be considered as the precursor of hemiterpenes. In the biosynthesis of mono- and higher terpenes/terpenoids, the starting molecule is DMAPP, which... 

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],... 

Figure 9.4 Monoterpene biosynthesis in peppermint oil gland secretory cells. The enzymes involved in this pathway are (1) 1-deoxy-D-xylulose 5-phosphate synthase, (2) 2-C-methyl-D-erythritol 4-phosphate reductoisomerase, (3) 2-C-methyl-D-erythritol 4-phosphate cytidyltransferase, (4) 4-(cytidine 5 -diphospho)-2-C-methyl-D-erythritol kinase, (5) 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase, (6) isopentenyl diphosphate isomerase, (7) geranyl diphosphate synthase, (8)...

It had been suggested that the second step of the mevalonate-independent pathway involved an intramolecular rearrangement and subsequent reduction of DXP to yield 2-C-methyl-D-erythritol 4-phosphate (Fig. 9.6A).29-3 Seto and co-workers reported the isolation, by using a mutant complementation approach, and characterization of such a reductoisomerase gene from E. coli)2 Based on likely... 

TAKAHASHI, S., KUZUYAMA, T WATANABE H., SETO, H., A 1-deoxy-D-xylulose 5-phosphate reductoisomerase catalyzing the formation of 2-C-methyl-D-erythritol 4-phosphate in an alternative nonmevalonate pathway, Proc. Natl. Acad. Sci. USA, 1998, 95, 9879-9884. 

KUZUYAMA, T., TAKAGI, M., KANEDA, K., WATANABE, H., DAIRI, T., SETO, H., Formation of 4-(cytidine 5 -diphospho)-2-C-methyl-D-erythritol from 2-C-methyl-D-erythritol 4-phosphate by 2-C-methyl-D-erythritol 4-phosphate cytidyltransferase, a new enzyme in the nonmevalonate pathway, Tetrahedron Lett., 2000, 41, 703-706. 

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]. 

Fig. 2 Two possible biosynthetic pathways to pyrethrolone. The [l-13C]D-glucose-derived 13C labels that occur in the mevalonic acid and 2-C-methyl-D-erythritol 4-phosphate (13) pathways are colored in red and green, respectively. The phosphate moiety is indicated as P ...

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... 

Gerber E, Hemmerlin A, Hartmann M, Heintz D, Hartmann MA, Mutterer J, Rodriguez-Concepcion M, Boronat A, Van Dorsselaer A, Rohmer M, CroweU DN, Bach TJ (2009) The plastidial 2-C-methyl-D-erythritol 4-phosphate pathway provides the isoprenyl moiety for protein geranylgeranylation in tobacco BY-2 ceUs. Plant Cell 21 285-300... 

C-methyl-D-erythritol 2,4-cyclodiphosphate synthase catalyses the conversion of 4-diphospho-cytidyl-2-C-methyl-D-erythritol 2-phosphate to 2-C-methyl-D-erythritol 2,4-cyclodiphosphate (MECDP) (Equation (7)). This reaction is part of the isoprenoid biosynthesis pathway in many plants and bacteria. The structure of the E. coli enzyme bound to Mn, cytosine monophosphate, and 2-C-methyl-D-erythritol 2,4-cyclodiphosphate has been determined. The enzyme in the crystal and probably in solution is trimeric, three monomers are packed in a circular assembly with three-fold symmetry. The active site is at the interface of two adjacent monomers all the ligands bound to the Mn + come from one monomer and a MECDP molecule. The structure of this active site is shown in Figure 29 ... 

Terpenes, biogenetically, arise from two simple five-carbon moieties. Isoprenyl-diphosphate (IPP) and dimethylallyldiphosphate (DMAPP) serve as universal precursors for the biosynthesis of terpenes. They are biosynthesised from three acetylcoenzyme A moieties through mevalonic acid (MVA) via the so-called mevalonate pathway. About 10 years ago, the existence of a second pathway leading to IPP and DMAPP was discovered involving l-deoxy-D-xylulose-5-phos-phate (DXP) and 2C-methyl-D-erythritol-4-phosphate (MEP). This so-called non-mevalonate or deoxyxylulose phosphate pathway starts off with the condensation of glyceraldehyde phosphate and pyruvate affording DXP. Through a series of reactions as shown in Fig. 4.1, IPP and DMAPP are formed, respectively [3,7, 42, 43]. 

S ATP + 4-(cytidine 5 -diphospho)-2-C-methyl-D-erythritol <1> (<1> involved in terpenoid biosynthesis via deoxyxylulose phosphate pathway... 

In addition, three glycosides of 2-C-methyl-D-erythritol 1-O-jS-D-glucopyranoside, 3-0-/2-D-glucopyranoside and 4-O-jd-D-glucopyranoside, were identified from cumin fruit (Kitaj ima etal, 2003). Though the phosphate of 2-C-methyl-D-erythritol was known to be one of the first precursors of isoprenoids in the non-mevalonate pathway, and was considered to be a common constituent in Umbelliferous plants, its glycosides were found for the first time. 

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.

Figure 5.4 Outline of the newly discovered glyceraldehyde phosphate/pyruvate pathway for the formation of C5 isoprenoid units. None of the intermediates after 2-C-methyl-D-erythritol 4-phosphate is known. P indicates a phosphate moiety. TPP, thiamine pyrophosphate NADP, nicotinamide adenine dinucleotide phosphate.

The mevalonate pathway starts with a sequence of two Claisen condensations that afford (6 )-3-hydroxy-3-methyl-glutaryl-CoA (84) from three acetyl-CoA moieties. The pathway affords IPP that can be converted into DMAPP by isomerization. The first committed intermediate of the nonmevalonate pathway is 2C-methyl-D-erythritol 4-phosphate (90) obtained from 1-deoxy-D-xylulose 5-phosphate (43), which is a compound also involved in the biosynthesis of vitamins Bi (46, cf. Fig. 4) and Be (39, cf. Fig. 5), by rearrangement and subsequent reduction. Three enzyme-catalyzed steps are required to convert the compound into the cognate cyclic diphosphate 91 that is then converted reductively into a mixture of IPP and DMAPP by the consecutive action of two iron/sulfur proteins. 

Several coenzymes are involved in the biosynthesis of their own precursors. Thus, thiamine is the cofactor of the enzyme that converts 1-deoxy-D-xylulose 5-phosphate (43) (the precursor of thiamine pyrophosphate, pyridoxal 5 -phosphate and of iso-prenoids via the nomnevalonate pathway) into 2 C-methyl-D-erythritol 4-phosphate (90, Fig. 11). Similarly, two enzymes required for the biosynthesis of GTP, which is the precursor of tetrahydrofolate, require tetrahydrofolate derivatives as cofactors (Fig. 3). When a given coenzyme is involved in its own biosynthesis, we are faced with a hen and egg problem, namely how the biosynthesis could have evolved in the absence of the cmcially required final product. The answers to that question must remain speculative. The final product may have been formed via an alternative biosynthetic pathway that has been abandoned in later phases of evolution or that may persist in certain organisms but remains to be discovered. Alternatively, the coenzyme under study may have been accessible by a prebiotic sequence of spontaneous reactions. An interesting example in this respect is the biosynthesis of flavin coenzymes, in which several reaction steps can proceed without enzyme catalysis despite their mechanistic complexity. 

The universal precursors to terpenoids, the C5-compounds dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP), originate from two pathways in plants (Fig. 1). The mevalonate (MEV) pathway is well described in many eukaryotic organisms. This pathway is present in the cy-tosol/endoplasmic reticulum of plants. More recently, another pathway has been described, the 2C-methyl-D-erythritol-4-phosphate (MEP) pathway, which is found in the plastids of plants (19). The localization of the different pathways and the plastid-directing transit peptides found in hemi-TPS, mono-TPS, and di-TPS, but not in sesqui-TPS, result in the production of terpenoids from at least two different precursors pools. 

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