Deoxyxylulose pathway

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. 

The active site lies in a large interior cavity. The properties of the hopene synthase are similar to those of oxidosqualene synthase, and it appears to function by a similar mechanism, which resembles that of Fig. 22-6 but does not depend upon 02. Hopene lacks polar groups, but these are provided in the hopanoids by a polyol side chain. One of these compounds, bacteiiohopanetetrol, may be one of the most abundant compounds on earth.160 165 166 Hopanoids appear to originate from mevalonate synthesized via the 1-deoxyxylulose pathway (Fig. 22-2). The polyol side chain is probably formed from ribose.166... 

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]. 

The four step synthesis of 2-C-methyl-D-erythrytol 2,4-cyclopyrophosphate (41) which is a biological intermediate in the deoxyxylulose pathway of iso-prenoid biosynthesis has been described. Bisphosphorylation of 2-C-methyl-D-erythrytol-1,3-acetate (40), followed by carbodiimide cyclization and deprotection, led to the target product in 42% overall yield (Scheme 6). ... 

A convenient synthesis of (E)-4-hydroxy-3-methyl-2-butenyl pyrophosphate (34), an intermediate in the deoxyxylulose pathway of isoprenoid biosynthesis, was accomplished by pyrophosphorylation of (E)-4-chloro-2-methyl-2-butene-l-ol (35) (Scheme 7). This route enables convenient access to isotopically... 

A second pathway for the biosynthesis of IPP and DMAPP eluded discovery until the 1990s but was then rapidly elucidated in considerable detail (deoxyxylulose pathway, Figure 8). These events have been reviewed repeatedly and will not be discussed at this point suffice it to say that retrobiosynthetic analysis has been involved to some extent in the elucidation of the nonmevalonate pathway (specific examples are given in Eisenreich et al.51). 

A far more complex situation arises in higher plants that use both the pathways in parallel.53 With hindsight, it is even obvious that the belated discovery of the deoxyxylulose pathway can be traced to a significant extent to the very occurrence of both the pathways in plants. More specifically, due to metabolite exchange between the two pathways that is the subject of this chapter, it appears likely that labeled mevalonate can contribute at least some label to most if not all plant isoprenoids hence, it was easy to jump to the conclusion — fallacious as we now know — that all plant isoprenoids are invariably biosynthesized from mevalonate. 

Whereas the isoprene units of the higher plant carotenoids that are biosynthesized within the chloroplasts are formed via the 1-deoxyxylulose pathway, the fungal carotenoids are biosynthesized from acetate via mevalonic add. The C40 carbon skeleton of the carotenoids is formed by the head-to-head coupling of two C20 geranylgeranyl diphosphate units by phytoene synthase. 

Biosynthesis H. belongs to the group of meroterpenes, i. e., isoprene units are linked with components derived from oAer key building blocks. The biosynthesis of the ring structure of the hop bitter principles H. and lupulone proceeds through the polyketide pathway. The isoprene units are formed on the deoxyxylulose pathway. 

The terpenoid precursor isopentenyl diphosphate, formerly called isopentenyl pyrophosphate and abbreviated IPP, is biosynthesized by two different pathways depending on the organism and the structure of the final product. In animals and higher plants, sesquiterpenoids and triterpenoids arise primarily from the mevalonate pathway, whereas monoterpenoids, diterpenoids, and tetraterpenoids are biosynthesized by the 1-deoxyxylulose 5-phosphate (DXP) pathway. In bacteria,... 

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. 

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. 

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. 

EISENREICH, W., ROHDICH, F., BACHER, A., Deoxyxylulose phosphate pathway to terpenoids, Trends Plant Sci., 2001,6, 78-84. 

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... 

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. 

Thiamin is synthesized in bacteria, fungi, and plants from 1-deoxyxylulose 5-phosphate (Eq. 25-21), which is also an intermediate in the nonmevalonate pathway of polyprenyl synthesis. However, thiamin diphosphate is a coenzyme for synthesis of this intermediate (p. 736), suggesting that an alternative pathway must also exist. Each of the two rings of thiamin is formed separately as the esters 4-amino-5-hydroxy-methylpyrimidine diphosphate and 4-methyl-5-((i-hydroxyethyl) thiazole monophosphate. These precursors are joined with displacement of pyrophosphate to form thiamin monophosphate.92b In eukaryotes this is hydrolyzed to thiamin, then converted to thiamin diphosphate by transfer of a diphospho group from ATP.92b c In bacteria thiamin monophosphate is converted to the diphosphate by ATP and thiamin monophosphate kinase.92b... 

The pathway also operates in some bacteria and apparently is the sole source of isoprenoid compounds for the unicellular alga Scenedesmus.28 The pathway is outlined in Fig. 22-2. Pyruvate is decarboxylated by a thiamin diphosphate-dependent enzyme,29 and the resulting enamine is condensed with D-glyceraldehyde 3-phosphate to form 1-deoxyxylulose 5-phosphate.28, i0 31a The latter undergoes an isomeroreductase rearrange-... 

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 ...

The thiazole ring is assembled on the 5-carbon backbone of 1-deoxyxylulose 5-phosphate, which is also an intermediate in the alternative biosynthetic pathway for terpenes (Fig. 22-2) and in synthesis of vitamin B6 (Fig. 25-21). In E. coli the sulfur atom of the thiazole comes from cysteine and the nitrogen from tyrosine.374 The same is true for chloroplasts,375 whereas in yeast glycine appears to donate the nitrogen.372 The thiamin biosynthetic operon of E. coli contains six genes,372a 376 one of which (ThiS) encodes a protein that serves as a sulfur carrier from cysteine into the thiazole.374 The C-terminal glycine is converted into a thiocarboxylate ... 

In addition to acetyl-CoA, shikimic acid, mevalonic acid, and deoxyxylulose phosphate, other building blocks based on amino acids are frequently employed in natural product synthesis. Peptides, proteins, alkaloids, and many antibiotics are derived from amino acids, and the origins of the most important amino acid components of these are briefly indicated in Figure 2.1. Intermediates from the glycolytic pathway and the Krebs cycle are used in constructing many of them, but the aromatic amino acids phenylalanine, tyrosine,... 

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