Biosynthesis shikimate pathway

Quinones represent a very large and heterogeneous class of biomolecules. Three major biosynthetic pathways contribute to the formations of various quinones. The aromatic skeletons of quinones can be synthesized by the polyketide pathway and by the shikimate pathway. The isoprenoid pathways are involved in the biosynthesis of the prenyl chain and in the formation of some benzoquinones and naphthoquinones. ... 

The shikimate pathway is the major route in the biosynthesis of ubiquinone, menaquinone, phyloquinone, plastoquinone, and various colored naphthoquinones. The early steps of this process are common with the steps involved in the biosynthesis of phenols, flavonoids, and aromatic amino acids. Shikimic acid is formed in several steps from precursors of carbohydrate metabolism. The key intermediate in quinone biosynthesis via the shikimate pathway is the chorismate. In the case of ubiquinones, the chorismate is converted to para-hydoxybenzoate and then, depending on the organism, the process continues with prenylation, decarboxylation, three hydroxy-lations, and three methylation steps. - ... 

The Shikimate pathway is responsible for biosynthesis of aromatic amino acids in bacteria, fungi and plants [28], and the absence of this pathway in mammals makes it an interesting target for designing novel antibiotics, fungicides and herbicides. After the production of chorismate the pathway branches and, via specific internal pathways, the chorismate intermediate is converted to the three aromatic amino acids, in addition to a number of other aromatic compounds [29], The enzyme chorismate mutase (CM) is a key enzyme responsible for the Claisen rearrangement of chorismate to prephenate (Scheme 1-1), the first step in the branch that ultimately leads to production of tyrosine and phenylalanine. 

Ring B and the central three-carbon bridge forming the C ring (see Fig. 5.1) originate from the amino acid phenylalanine, itself a product of the shikimate pathway, a plastid-based process which generates aromatic amino acids from simple carbohydrate building blocks. Phenylalanine, and to a lesser extent tyrosine, are then fed into flavonoid biosynthesis via phenylpropanoid (C6-C3) metabolism (see Fig. 5.1). 

Schultz and coworkers (Jackson et a ., 1988) have generated an antibody which exhibits behaviour similar to the enzyme chorismate mutase. The enzyme catalyses the conversion of chorismate [49] to prephenate [50] as part of the shikimate pathway for the biosynthesis of aromatic amino acids in plants and micro-organisms (Haslam, 1974 Dixon and Webb, 1979). It is unusual for an enzyme in that it does not seem to employ acid-base chemistry, nucleophilic or electrophilic catalysis, metal ions, or redox chemistry. Rather, it binds the substrate and forces it into the appropriate conformation for reaction and stabilizes the transition state, without using distinct catalytic groups. 

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). 

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. 

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. 

Aromatic Amino Acid Biosynthesis. The shikimate pathway is the biosynthetic route to the aromatic amino acids tryptophan, tyrosine and phenylalanine as well as a large number of secondary metabolites such as flavonoids, anthocyanins, auxins and alkaloids. One enzyme in this pathway is 5-enolpyruvyl shikimate-3-phosphate synthase (EPSP synthase) (Figure 2.9). 

The shikimate pathway was identified through the study of ultraviolet light-induced mutants of E. coli, Aerobacter aerogenes, and Neurospora. In 1950, using the penicillin enrichment technique (Chapter 26), Davis obtained a series of mutants of E. coli that would not grow without the addition of aromatic substances.4 5 A number of the mutants required five compounds tyrosine, phenylalanine, tryptophan, p-aminobenzoic acid, and a trace of p-hydroxybenzoic acid. It was a surprise to find that the requirements for all five compounds could be met by the addition of shikimic acid, an aliphatic compound that was then regarded as a rare plant acid. Thus, shikimate was implicated as an intermediate in the biosynthesis of the three aromatic amino acids and of other essential aromatic substances.6 7... 

Figure 25-1 Aromatic biosynthesis by the shikimate pathway. The symbols for several of the genes coding for the required enzymes are indicated. Their locations on the E. coli chromosome map are shown in Fig. 26-4. The aminoshikimate pathway which is initiated through 4-aminoDAHP leads to rifamycin and many other nitrogen-containing products.

The shikimate pathway results in the biosynthesis of chorismate, which can subsequently serve as a recursor for the biosynthesis of the aromatic amino acids tryptophan, phenylalanine and tyrosine. The biochemistry of... 

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. 

Ghisalba O (1985) Biosynthesis of Rifamycins (Ansamycins) and Microbial Production of Shikimate Pathway Precursors, Intermediates, and Metabolites. Chimia 39 79... 

Overall, the biosynthesis of 160 is characterized by the dimerization of 168 to give the central structure of the molecule. This head-to-tail dimerization strategy is efficient, using the same substrate twice, and is a sensible route, given the existence of the shikimate pathway, which provides, in turn, a precursor to 168. An analogous dimerization route can be seen for the biosynthesis of K252c (1), described in Sect. 5, where two molecules of indole-3-pyruvic acid imine (125), derived in turn from L-tryptophan (123), are dimerized to give an intermediate that leads to chromopyrrolic acid (128). In both cases, the monomer precursors, either 168 or 125, serve as both nucleophiles and electrophiles, and are activated to react by the presence of the appropriate enzymes. 

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