Acetate-shikimate biosynthesis

Flavonoids are essentially universal plant pigments and exist in at least nine different structure classes, frequently with attached sugar units. They are derived from a mixed acetate-shikimate biosynthesis. 4-Coumaroyl CoA reacts with a triketide unit to... 

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. 

Coumarins and isocoumarins appear to be of varied origins. Simple coumarins, such as umbelliferone, are formed by the shikimic acid pathway in which hydroxylation of p-hydroxycinnamic acid occurs. Other coumarins, for example alternariol (690), are derived from a polyketide unit, as are a number of chromanones, chromones, pyranones and isocoumarins (B-78MI22400). The biosynthesis of 5-hydroxy-2-methylchromone has been shown to involve the chromanone (60JCS654). However, isocoumarins are also derived from the mixed acetate-shikimate route, through initial cyclization of the polyketide and subsequent lactonization. 

The ansa-chain of the ansamycins streptovaricins (4), rifamycins (263), geldanamycin (4), and herbimycin (32) has been shown to be polyketide in origin, being made up of propionate and acetate units with the 0-methyl groups coming from methionine. The remaining aromatic C N portion of the ansamacroHdes is derived from 3-amino-5-hydroxybenzoic acid (264—266) which is formed via shikimate precursors. Based on the precursors of the rifamycins and streptovaricins isolated from mutant bacteria strains, a detailed scheme for the biosynthesis of most of the ansamacroHdes has been proposed (95,263). 

FIGURE 16.3 Overview of the biosynthesis of (I) chalcones and (II) 6 -deoxychalcones. The sequential condensation of three molecules of malonyl-CoA (acetate pathway) and p-coumaroyl-CoA (shikimate pathway) is catalyzed by the enzyme chalcone synthase.The production of 6 -deoxychalcones is thought to involve an additional reduction step at the tri- or tetraketide level, catalyzed by polyketide reductase.The origin of the A-ring carbons derived from the acetate pathway is indicated in bold. CoA, coenzyme A. 

Shihunine.—Preliminary results139 indicated that the orchid alkaloid shihunine (153) was derived from (152), an important intermediate in naphthoquinone biosynthesis.140 Further details are now available in a full paper.141 The intact incorporation of (152) is affirmed by the observation that (152), labelled with 13C at C-l, was an efficient and specific precursor for (153). [l-14C]Acetate was examined as a shihunine precursor and was found only to label C-5. This is consistent with the expected formation of (152) from shikimic acid (144) and a-ketoglutarate (151),140 the latter gaining acetate label in its carboxy-groups through the tricarboxylic acid cycle. 

As described above, administration experiment with C-labelled acetates revealed that both the mulberry chalcone and 2-arylbenzofuran skeletons originate frcmi cinnamoylpolyketide. In order to confirm the biosynthesis of the cinnamoyl moiety derived from shikimate via aromatic amino acid, phenylalanine or tyrosine, further experiments administering phenylalanine and tyrosine to the M. alba cell cultures were carried out [59]. In the administration experiment with L-[3- 3c]phenylalanine to the cell cultures, a high C-enrichment (about 33 %) from the amino acid was observed at the... 

Phenylalanine and tyrosine acts as precursor for opium alkaloid biosynthesis. Tryptophan is a significant source of Vinca alkaloids. Alkaloids are derived from anthranilic acid, which is an intermediate in biosynthesis of tryptophan. Some alkaloids are derived from acetate, terpene or shikimic acid. Shikimic acid is a significant metabolite as most of the aromatic constituents are derived from shikimic acid pathway. 

Previous researchers have suggested [6,8] that benzophenones are biosynthesized by condensation of metabolites from the shikimate pathway, forming the A-ring, and the acetate-malonate pathway, creating the B-ring. This produces the basic 13-carbon benzophenone skeleton, Fig. (1). Support for this biosynthetic pathway includes the isolation of benzophenone synthase from Centaurium erythraea [9] and research by Atkinson etal. [10] who examined benzophenones as intermediates in the synthesis of xanthones. (Xanthone biosynthesis is reviewed by... 

It remains unclear whether the basic 13-carbon benzophenone is constructed (from the shikimate and acetate pathways) and then prenylated and cyclized or the B-ring is derived from phloroglucinol and later the 7-membered carbon substructure (A-ring) is added. Given the structural diversity of benzophenones, their biosynthesis is suggestive of multiple pathways. Further research is needed to fully understand the biosynthesis of benzophenones. 

One of the most fascinating problems in natural product biosynthesis during the last decade was the origin of the C9-10 unit found in Ipecacuanha, indole, and Cinchona alkaloids. In the initial phases of the work it was proved by tracer studies that this unit did not arise from phenylalanine (45), tyrosine (45), shikimic acid (49), malonate (45), acetate (45,50,51), formate (45), or methionine (52). The role of glycine has also been investigated (53). 

In its biosynthesis the 2-pyrrolecarbonyl unit originates from proline, the spiroketal from acetate/propa-noate, and the substituted benzene ring from shikimic acid. 

The biosynthesis of the hop resins occurs by similar routes. Experiments with radioactively labelled substrates have established that the phloroglucinol nucleus is formed from three molecules of acetic acid and not from sugars or shikimate. The acyl side-chains are formed from amino acids or intermediates in their biosynthesis. Thus, in humulone and lupulone they arise from leucine, in the co-analogues from valine, and in the ad-analogues from isoleucine. The amino acids themselves undergo transamination and decarboxylation to give... 

Use of Mutants in Biosynthetic Studies Formation of Chorismic Acid Derivatives of Chorismic Acid Biosynthesis of Tryptophan Indole 3-Acetic Acid Avenalumins from Oats DIMBOA and Related Compounds Biosynthesis of Phenylalanine and Tyrosine Compounds Derived from Shikimic Pathway Intermediates... 

A wide range of aromatic products in the plant kingdom originate from intermediates of the shikimic acid pathway. These include amino acids and ubiquinone among important primary metabolites and also many other compounds (in contrast fo fungi which possess many acetate-derived products), such as lignins, alkaloids, and phenolic acids. Flavonoids (and stilbenes) also arise in part by this route but additionally utilize acetate in the course of their biosynthesis, which will therefore be described in this chapter. 

From a biosynthetic point of view, flavonoids derive from both the shikimate and the acetate pathways. A detailed discussion on the biosynthesis of these compounds is beyond the scope of this work however, a simplified representation of the biosynthetic pathway can be seen in Scheme 68.2. 

---