1-Deoxyxylulose 5-phosphate, biosynthesis

Rodriguez-Concepcion, M. and Boronat, A., Elncidation of the methylerythritol phosphate pathway for isoprenoid biosynthesis in hacteria and plastids a metabolic milestone achieved throngh genomics. Plant Physiol. 130, 1079, 2002. Rodriguez-Concepcion, M., Early steps in isoprenoid biosynthesis multilevel regulation of the supply of common precursors in plant cells, Phytochem. Rev. 5, 1, 2006. Eisenreich, W., Rohdich, F., and Bacher, A., Deoxyxylulose phosphate pathway to terpenoids, Trends Plant Sci. 6, 78, 2001. 

Rohdich, F., Zepeck, F., Adam, P. et al. (2003) The deoxyxylulose phosphate pathway of isoprenoid biosynthesis studies on the mechanisms of the reactions catalyzed by IspG and IspH protein. Proceedings of the National Academy of Sciences of the United States of America, 100, 1586-1591. 

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 the 1970s the biosynthesis of cannabinoids was investigated with radiolabeling experiments. 14C-labeled mevalonate and malonate were shown to be incorporated into tetrahydrocannabinolic acid and cannabichromenic acid at very low rates (< 0.02%). Until 1990 the precursors of all terpenoids, isopentenyl diphosphate and dimethyl-allyl diphosphate were believed to be biosynthesized via the mevalonate pathway. Subsequent studies, however, proved that many plant terpenoids are biosynthesized via the recently discovered deoxyxylulose phosphate pathway (Eisenreich et al., 1998 Rohmer, 1999). It was shown that the Cio-terpenoid moiety of cannabinoids is biosynthesized entirely or predominantly (>98%) via this pathway (Fellermeister et al., 2001). The phenolic moiety is generated by a polyketide-type reaction sequence. 

Eisenreich, W., Schwarz, M., Cartayrade, A., Arigoni, D., Zenk, M.H., and Bacher, A. (1998). The deoxyxylulose phosphate pathway of terpenoid biosynthesis in plants and microorganisms. Chem Biol 5 R221-R233. 

The MEP pathway is the only pathway involved in the biosynthesis of essential isoprenoids in pathogenic bacteria and in parasites, and it is absent in animals and in humans. Therefore, any enzyme of this pathway is a potential target for a novel type of antimicrobial drugs (16, 17). This concept has been validated by the mode of action of fosmidomycin, a natural antibiotic that inhibits the second step of the MEP pathway catalyzed by the deoxyxylulose phosphate reducto-isomerase (DXR). 

Stable isotope-labelled intermediates playing an important role in the study of the mevalonate as well as the deoxyxylulose phosphate pathway of isoprenoid biosynthesis have been prepared. C- and " C-labelled 4-diphosphacytidyl-2C-methyl-D-erythrytol (52) and 2C-methyl-D-erythrytol-4-phosphate (53) have been obtained in milimol quantity and in high yield by sequences of one-pot reactions using C-labelled pyruvate, or dihydroxyacetone phosphate... 

Among the H-NMR data of isoprenoids practically exclusively those of monoterpe-nes are of interest in the present context. As already outlined before, these compounds are normally synthesised in plants via the deoxyxylulose-phosphate pathway and show therefore H-pattems in agreement with their common biosynthesis and its modulations [111], e.g. in the case of R(-)-linalool, distinct deuterium depletions at position C-2 and C-9, corresponding to (D/H)j and (D/H) in the NMR nomenclature but individual shifts from a common mean value, depending on the botanical origin [230] (see Fig. 6.22 and Tables 6.12 and 6.13). 

Matthew PD, Wurtzel RT (2000) Metabolic engineering of carotenoid accumulation in Escherichia coli by modulation of the isoprenoid precursor pool with expression of deoxyxylulose phosphate synthase. ApplMicrobioIBiotechnol 53 396 Marker M, Bramley PM (1999) Expression of prokaryotic l-deoxy-D-xylulose-5-phosphatases in Escherichia coli increases carotenoid and ubiquinone biosynthesis. FEBS Lett 448 115... 

Diterpenes are a heterogeneous class of natural compounds based on 20 carbon atoms. They are widely distributed in nature, both in terrestrial and marine organisms, and originate by condensation of four isoprene units derived from mevalonate or deoxyxylulose phosphate [1] pathways, wherein the latter pathway was recently discovered taking place in the biosynthesis of diterpene compounds in plants [2]. As for other classes of natural compounds diterpenes have shown an importance as biomarker of certain species, thus contributing to their chemotaxonomy classification [3]. For example, macrocyclic diterpenes and their cyclization products have been isolated only from Euphorbiae plants of which they could be considered as biomarker [4]. Although thousands of diterpene compounds have been described in nature from terrestrial and marine organisms, only few of them became clinically effective [5]. Active compounds isolated from plants are used directly in therapy or... 

Mechanism of step 5 in pyridoxal phosphate biosynthesis, the thiamin-dependent aldol reaction of D-glyceraldehyde 3-phosphate with pyruvate to give i-deoxyxylulose 5phosphate. 

In the biosynthesis of the thia2ole, cysteine is the common sulfur donor. In yeasts, the C-2 and N may be suppHed by glycine, and the remaining carbons byD-ribulose-5-phosphate [108321-99-9] (50). In anaerobic bacteria, the C-2 andN maybe recmited from tyrosine and the carbons from D-l-deoxyxylulose [16709-34-5] (51), whereas in aerobic bacteria the C-2 and N maybe derived from glycine, as in yeasts 7 (74—76,83—86) (see Fig. 9). 

Sprenger, G.A. et al.. Identification of a thiamin-dependent synthase in Escherichia coli required for the formation of the 1-deoxy-D-xylulose 5-phosphate precursor to isoprenoids, thiamin, and pyridoxol, Proc. Natl. Acad Sci. USA 94, 12857, 1997. Lange, B.M. et al., A family of transketolases that directs isoprenoid biosynthesis via a mevalonate-independent pathway, Proc. Natl. Acad Sci. USA 95, 2100, 1998. Lois, L.M. et al., Cloning and characterization of a gene from Escherichia coli encoding a transketolase-like enzyme that catalyzes the synthesis of D-1- deoxyxylulose 5-phosphate, a common precursor for isoprenoid, thiamin, and pyridoxol biosynthesis, Proc. Natl. Acad. Sci. USA 95, 2105, 1998. 

McCASKILL, D., CROTEAU, R., Isopentenyl diphosphate is the terminal product of the deoxyxylulose 5-phosphate pathway for terpenoid biosynthesis in plants, Tetrahedron Lett., 1999,40,653-656. 

Schoenwaelder MEA (2002) Physode distribution and the effect of thallus sunburn in Flormosira banksii (Fucales, Phaeophyceae). Bot Mar 45 262-266 Schoenwaelder MEA, Clayton MN (2000) Physode formation in embryos of Phyllospora comosa and Flormosira banksii (Phaeophyceae). Phycologia 39 1-9 Schwender J, Gemunden C, Lichtenthaler HK (2001) Chlorophyta exclusively use the 1-deoxyxylulose 5-phosphate/2-C-methylerythritol 4-phosphate pathway for the biosynthesis of isoprenoids. Planta 212 416 123... 

Alkaloid biosynthesis needs the substrate. Substrates are derivatives of the secondary metabolism building blocks the acetyl coenzyme A (acetyl-CoA), shikimic acid, mevalonic acid and 1-deoxyxylulose 5-phosphate (Figure 21). The synthesis of alkaloids starts from the acetate, shikimate, mevalonate and deoxyxylulose pathways. The acetyl coenzyme A pathway (acetate pathway) is the source of some alkaloids and their precursors (e.g., piperidine alkaloids or anthraniUc acid as aromatized CoA ester (antraniloyl-CoA)). Shikimic acid is a product of the glycolytic and pentose phosphate pathways, a construction facilitated by parts of phosphoenolpyruvate and erythrose 4-phosphate (Figure 21). The shikimic acid pathway is the source of such alkaloids as quinazoline, quinoline and acridine. 

Figure 22-2 The glyceraldehyde 3-phosphate pyruvate alternative pathway of isoprenoid biosynthesis. The intermediate 1-deoxyxylulose 5-phosphate may enter terpenes, vitamin B6, and thiamin. Isopentenyl diphosphate is shown as the final product, but the intermediate steps are uncertain. See Lange et al 2 ...

Until 1993, all terpenes were considered to be derived from the classical acetate/mevalonate pathway involving the condensation of three units of acetyl CoA to 3-hydroxy-3-methylglutaryl CoA, reduction of this intermediate to mevalonic acid and the conversion of the latter to the essential, biological isoprenoid unit, isopentenyl diphosphate (IPP) [17,18,15]. Recently, a totally different IPP biosynthesis was found to operate in certain eubacteria, green algae and higher plants. In this new pathway glyceradehyde-3-phosphate (GAP) and pyruvate are precursurs of isopentenyl diphosphate, but not acetyl-CoA and mevalonate [19,20]. So, an isoprene unit is derived from isopentenyl diphosphate, and can be formed via two alternative pathways, the mevalonate pathway (in eukaryotes) and the deoxyxylulose pathway in prokaryotes and plant plastids [16,19]. 

LM Lois, N Campos, SR Putra, K Danielsen, M Rohmer, A Boronat. Cloning and characterization of a gene from Escherichia coli encoding a transketolase-like enzyme that catalyzes the synthesis of D-l-deoxyxylulose 5-phosphate, a common precursor for isoprenoid, thiamin, and pyridoxol biosynthesis. Proc Natl Acad Sci (USA) 95 2105-2110, 1998. 

Fig. 3. Biosynthesis of TIAs in C. roseus. Solid arrows indicate single enzymatic conversions, whereas dashed arrows indicate multiple enzymatic conversions. AS Anthranilate synthase, DXS D-l-deoxyxylulose 5-phosphate synthase G10H geraniol 10-hydroxylase CPR cytochrome P450 reductase TDC tryptophan decarboxylase STR strictosidine synthase SGD strictosidine /1-D-glucosidase D4H desacetoxyvindoline 4-hydroxylase DAT acetyl-CoA 4-O-deacetylvindoline 4-O-acetyl transferase. Genes regulated by ORCA3 are underlined. Reprinted with permission from [91]. Copyright (2000) American Association for the Advancement of Science...

The natural precursors of any flavourings of this group are isopentenylpyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). In the classic pathway these are synthesised from three molecules acetyl/malonyl-CoA via mevalonic acid (MA). Recently a second pathway of the isoprenoid biosynthesis has been detected, in which IPP and DMAPP are synthesised from pyruvate and glyceraldehyde 3-phosphate via deoxyxylulose (DOX) 5-phosphate [322-324],... 

---