Shikimic acid biosynthetic intermediates

Phenylpropanoids have an aromatic ring with a three-carbon substituent. Caffeic acid (308) and eugenol (309) are known examples of this class of compounds. Phenylpropanoids are formed via the shikimic acid biosynthetic pathway via phenylalanine or tyrosine with cinnamic acid as an important intermediate. Phenylpropanoids are a diverse group of secondary plant compounds and include the flavonoids (plant-derived dyes), lignin, coumarins, and many small phenolic molecules. They are known to act as feeding deterrents, contributing bitter or astringent properties to plants such as lemons and tea. 

Danishefsky and Hirama have published a neat total synthesis of the disodium salt of prephenic acid (24), a central intermediate in the shikimic acid biosynthetic pathway.The key step involves a Diels-Alder reaction between the diene (22) and the unsaturated lactone (23). A crucial feature of this synthesis is the simultaneous protection of both the C-lO-carboxy and C-8-keto functions as a methoxy-lactone, allowing umasking in a single step by alkaline hydrolysis. 

Deoxy-araWno-heptulosonic acid 7-phosphate (10) is a metabolic intermediate before shikimic acid in the biosynthetic pathway to aromatic amino-acids in bacteria and plants. While (10) is formed enzymically from erythrose 4-phosphate (11) and phosphoenol pyruvate, a one-step chemical synthesis from (11) and oxalacetate has now been published.36 The synthesis takes place at room temperature and neutral pH... 

Aryl side chain containing L-a-amino acids, such as phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp), are derived through the shikimate pathway. The enzymatic transformation of phosphoenolpyr-uvate (PEP) and erythro-4-phosphate, through a series of reactions, yields shikimate (Scheme 2). Although shikimate is an important biosynthetic intermediate for a number of secondary metabolites, this chapter only describes the conversion of shikimate to amino acids containing aryl side chains. In the second part of the biosynthesis, shikimate is converted into chorismate by the addition of PEP to the hydroxyl group at the C5 position. Chorismate is then transformed into prephenate by the enzyme chorismate mutase (Scheme 3). 

In Scheme 1.2 one possible retrosynthetic analysis of the unnatural enantiomer of shikimic acid, a major biosynthetic precursor of aromatic a-amino acids, is sketched. Because cis dihydroxylations can be performed with high diastereoselectiv-ity and yield, this step might be placed at the end of a synthesis, what leads to a cyclohexadienoic acid derivative as an intermediate. Chemoselective dihydroxylation of this compound should be possible, because the double bond to be oxidized is less strongly deactivated than the double bond directly bound to the (electron-withdrawing) carboxyl group. 

Figure 7 Biosynthesis of aromatic amino acids and products derived from phenylalanine or from intermediates of the shikimate pathway. Biosynthetically equivalent positions are indicated by colored bars. The atoms indicated by the blue bars are equivalent to atoms from phosphoenol pyruvate precursor followed by the loss of one carbon atom by decarboxylation.

Coumarins are lactones with the basic structure of 1,2-benzopyrone. Biosynthetically, they are mainly originated from shikimic acid padiway, with the intermediate of cinnamic acid. By the addition of a furan ring, the furanocoumarins are resulted, which are represented by psoralen (linear) and angelicin (angular) [10]. 

The building blocks for secondary metabolites are derived from primary metabolism. In fact, the biosynthesis of secondary metabolites is derived from the fundamental processes of photosynthesis, glycolysis, and the Krebs cycle to afford biosynthetic intermediates, which, ultimately, results in the formation of secondary metabolites also known as natural products. The most important building blocks employed in the biosynthesis of secondary metabolites are those derived from the intermediates acetyl-coenzyme A (acetyl-CoA), shikimic acid, mevalonic acid, and l-deoxyxylulose-5-phosphate (Figure 1.1). 

Most steps of the shikimic acid pathway have been studied by means of mutants, isotopically labeled precursors, and studies of the specific enzymes from cell-free systems. The use of mutants for examination of various steps of the shikimic acid pathway has been of great value for the study of the enzymes and intermediates involved. Use of mutants permits interruption of the pathway at a stage that normally would not be seen. Mutants that involve one step of die pathway are especially useful. In some situations, intermediates are accumulated in large quantities, facilitating analysis of the sequence of steps in the pathways. Sometimes, however, the accumulation of intermediates exerts control over earlier stages of the biosynthetic process and inhibits the activity or represses formation of enzymes at a previous point in the pathway. In these circumstances, the biosynthetic intermediate before the break in the pathway often will be unable to serve as a precursor. Mutants of this tjqie normally do not survive unless provided with an outside source of an intermediate or product that occurs after the point at which the pathway is blocked. 

Extensive studies support the hypothesis that these phenazine precursors are derived from the shikimic acid pathway, as outlined in Scheme 1, with chorismic acid (51) as the most probable branch point intermediate. Shikimic acid (50) is converted to chorismic acid (51) in known transformations that are part of the common aromatic amino acid biosynthetic pathway. The transformation from chorismic acid (51) to the phenazine precursors has been discussed and investigated through intensive biochemical studies so far, no intermediates have been identified and little is known about the genetic origin and details of the phenazine biosynthesis. ... 

Phenazines compounds based on the phenazine ring system (Table). All known naturally occurring P. are produced only by bacteria, which excrete them into the growth medium. Both six-membered carbon rings of P. are biosynthesized in the shikimate pathway of aromatic biosynthesis, via chorismic acid (not from anthranilate, as reported earlier). The earliest identified biosynthetic intermediate after chorismate is phenazine 1,6-dicarboxylate, which has been isolated from Pseudomonas phenazinium and from non-... 

Bacteria, fungi, and plants share a common pathway for the biosynthesis of aromatic amino acids with shikimic acid as a common intermediate and therefore named after it—the shikimate pathway. Availability of shikimic acid has proven to provide growth requirements to tryptophan, tyrosine, and phenylalanine triple auxotrophic bacterial strains. Chorismate is also the last common precursor in the aromatic amino acid biosynthetic pathway, but the pathway is not named after it, as it failed to provide growth requirements to the triple auxotrophs. The aromatic biosynthetic pathway starts with two molecules of phosphoenol pyruvate and one molecule of erythrose 4-phosphate and reach the common precursor, chorismate through shikimate. From chorismate, the pathway branches to form phenylalanine and tyrosine in one and tryptophan in another. Tryptophan biosynthesis proceeds from chorismate in five steps in all organisms. Phenylalanine and tyrosine can be produced by either or both of the two biosynthetic routes. So phenylalanine can be synthesized from arogenate or phenylpyruvate whereas tyrosine can be synthesized from arogenate or 4-hydroxy phenylpyruvate. 

The precursors of flavonoid biosynthesis include shikimic acid, phenylalanine, cinnamic acid, and p-coumaric acid. Shikimic acid acts as an intermediate in the biosynthesis of aromatic acid. The basic pathways to the core isoflavonoid skeletons have been established both enzymatically and genetically [16]. The synthesis of isoflavones can be broadly divided into three main synthetic pathways the formylation of deoxybenzoins, the oxidative rearrangement of chalcones and flavanones, and the arylation of a preformed chromanone ring. In leguminous plants, the major isoflavonoids are produced via two branches of the isoflavonoid biosynthetic pathway, and the different branches share a majority of common reactions [1]. Unlike the common flavonoid compotmds, which have a 2-phenyl-benzopyrone core structure, isoflavones, such as daidzein and genistein, are 3-phenyl-benzopyrone compounds. Biochemically, the synthesis of isoflavones is an offshoot of the flavonoids biosynthesis pathway. Several attempts have aimed to increase... 

A compound of unsuspected importance was isolated in 1885 from the fruit of Illicium religiosum. To this compound was given the name shikimic acid, a name derived from shikimi-no-ki which is the Japanese name for the plant. Shikimic acid (5.7), it transpired from the very elegant studies of much later investigators, is a key intermediate in the biosynthesis of the aromatic amino acids, L-phenylalanine, L-tyrosine and L-tryptophan, in plants and micro-organisms (animals cannot carry out de novo synthesis using this pathway). These three aromatic amino acids are individually important precursors for numerous secondary metabolites, and so to some extent are earlier biosynthetic intermediates related to shikimic acid, as the ensuing discussion in this chapter and in Chapters 6 and 7 will show. 

The radioactivities associated with the vanous fragments in the degradation of iodinin are shown in the annexed scheme (Figure 3.13), and from a consideration of these results, Podojil and Gerber proposed that the phenazine nucleus was elaborated from two molecules of (—)-shikimic acid coming together as shown (Figure 3.13) to yield (79) as the hypothetical key biosynthetic intermediate to all phenazines. Further details of the condensation mechanism have yet to be elucidated. 

The identified intermediates in the aromatic biosynthetic pathway are ven in Fig. 12. Shikimic acid (3d>4a,5a-trihydroxy-A - -cyclohexene-1-carboxylic acid) was the first one to be isolated and identified, as already mentioned (iSOS). It was found to be the only compound that satisfied the total requirement for growth of the bacterial mutants exhibiting a quintuple aromatic requirement. The amount of shikimic acid producing... 

The individual members of the shikimic acid pathway discussed above are examples of obligatory intermediates. The shikimic acid pathway is certainly the main route to the synthesis of the aromatic amino acids. Any doubts that might have existed have been removed by experiments with bacterial mutants. If, as a result of a mutation, the biosynthetic pathway is blocked beyond a certain substance and aromatic amino acids are then no longer formed, the substance affected must be an obligatory intermediate along the route to the synthesis of these amino acids. 

Nature utilizes the shikimate pathway for the biosynthesis of amino acids with aryl side chains. These nonprotein amino acids are often synthesized through intermediates found in the shikimate pathway. In many cases, L-a-amino acids are functionalized at different sites to yield nonprotein amino acids. These modifications include oxidation, hydroxylation, halogenation, methylation, and thiolation. In addition to these modifications, nature also utilizes modified biosynthetic pathways to produce compounds that are structurally more complex. When analyzing the structures of these nonprotein amino acids, one can generally identify the structural similarities to one of the L-a-amino acids with aromatic side chains. 

The biosynthesis of gallic acid (3.47) has been under investigation for more than 50 years. Different biosynthetic routes have been proposed, as depicted in Figure 3-6 (/) direct biosynthesis from an intermediate of the shikimate pathway, (2) biosynthesis via phenylalanine (3.27), cinnamic acid (3.29), />coumaric acid (3.30), caffeic acid (3.32), and 3,4, 5-trihydroxycinnamic acid (3.44), or (3) biosynthesis via caffeic acid (3.32) and protocatechuic acid (3.45). The possibility that different pathways co-existed in different species or even within one species was also considered. 

Chorismic acid 360 is known to be a key intermediate in the shikimate biosynthetic pathway that bacteria and lower plants use to convert carbohydrates into aromatic compounds. 

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