Biosynthesis of phenolic metabolites and ldopa

Plant phenolics are synthesized using several different routes. This constitutes a heterogeneous group from a metabolic point of view. Two basic pathways are the shikimic acid pathway and the acetate-malonate (polyketide) pathway. The shikimic acid pathway represents the principal mode of accumulation of plant stress related phenolic compounds. The acetate-malonate pathway is also an important source of phenolic secondary products for biosynthesis of flavonoids and isoflavonoids that have many human disease protective chemoprevention properties.

The shikimic acid pathway requires substrates such as erythrose-4-phosphate (E4P) from the pentose phosphate pathway (PPP) and phosphoenol pyruvate (PEP) from glycolysis (Figure 9.1). The oxidative pentose phosphate pathway in plants is thought of as comprising two stages (50). The first is an essential irreversible conversion of glucose 6 phosphate (G6P) to ribulose-5-phosphate (Ril5P) by the enzymes glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconolactonase, and 6-phospho gluconolactonate dehydrogenase (6 PGDH). This oxidative stage provides reductant in the form of NADPH for a wide range of anabolic pathways including the synthesis of fatty acids, the reduction of nitrite, and synthesis of glutamate (51,52). The second stage is the irreversible series of interconversions between phosphorylated carbon sugars. The function of this stage of the pathway is to provide a carbon skeleton for the shikimate pathway via erythrose-4-phos-phate (E4P), nucleotide synthesis utilizing ribose-5-phosphate, as well as recycling of sugar phosphate intermediates for use in the glycolytic pathway (53).

The shikimate pathway is often referred to as the common aromatic biosynthetic pathway, even though in nature it does not synthesize all aromatic compounds by this route (54). The shikimic acid pathway converts the simple carbohydrate precursors to aromatic amino acids phenylalanine, tyrosine, and tryptophan. The flux from this pathway is critical for both auxin and phenylpropanoid synthesis (23,30). Auxins are plant hormones that regulate plant development (2). Up to 60% of the dry weight in some plant tissue consists of metabolites derived from the shikimate pathway. Activity of the distinct isoenzyme of 3-deoxy arabinose heptulosonate-7-phosphate (DAHP) synthase in the shikimate pathway is dependent on metabolite flux from E4P. This enzyme has been shown to be subject to feedback inhibition by L-phenylalanine, L-tyrosine, and L-tryptophan (54,55). Therefore, this enzyme controls the carbon flow into the shikimate pathway.

The most abundant class of secondary phenolic compounds in plants is derived from phenylalanine via the elimination of an ammonia molecule to form cinnamic acid. This reaction is catalyzed by phenylalanine ammonia lyase (PAL). This is the branch point between the primary (shikimate pathway) and the secondary (phenylpropanoid pathway) (6). Studies with several different species of plants have shown that the activity of PAL is increased by environmental factors such as low nutrient levels, light (through the effect of phytochrome), and fungal infection (11). Fungal invasion triggers the transcription of messenger RNA (mRNA) in the plant, which then stimulates the synthesis of phenolic compounds (6). Many phenylpropanoid compounds are induced in response to wounding or in response to microbial pathogens, insect pests, or herbivores. Anthocyanins increase in response to high visible light levels and it is thought that they attenuate the amount of light reaching the photosynthetic cells (6).

The product of PAL, frans-cinnamic acid, is converted to para-coumaric acid by the addition of a hydroxyl group on the aromatic ring in para position. Subsequent reactions lead to the addition of more hydroxyl groups and other substituents. These are simple phenolic compounds called phenylpropanoids because they contain a benzene ring and a three carbon side chain. Phenylpropanoids are building blocks for more complex phenolic compounds (1,3).

As previously discussed, phenolic compounds have wide ranges of functions. The synthesized phenolics can be either antioxidant in nature or they may function in lignification of the plant cells. Depending on the requirements, the type of the phenolics synthesized and their complexity vary from species to species in different environmental niches. Flavonoids, tannins, caffeic acids, curcumin, gallic acids, eugenol, rosmarinic acid, and many more have antioxidant properties (56,57). These ranges of phenolics provide plants with defense mechanisms and act as scavengers of free radicals as described earlier. Other functions of phenolics include their ability to provide structural stability to the plants by lignins and lignans. These are complex phenolics are formed from the polymerization of simple phenols (58). Figure 9.2 illustrates the origins of varied phenolic compounds from simple phenols.

Lignin is a polymer of aromatic subunits usually derived from phenylalanine. It serves as a matrix around the polysaccharide components of some plant cell walls, providing additional rigidity and compressive strength, as well as rendering the walls hydrophobic for water impermeability (59,60). The final enzymatic steps of lignin biosynthesis, the production of mesomeric phenoxy radicals from cinnamoyl alcohol, is catalyzed by peroxidase and must occur outside the cell to allow these short lived radicals to polymerize in situ (61). Phenol polymerization is catalyzed by the peroxidase enzyme (62) and a specific enzyme, Guaiacol peroxidase (GPX), is suggested to be important in the metabolic interconversion of phenolic antioxidants. The same phenylpropanoid pathway also supports the synthesis of l-DOPA, which is a simple phenolic compound found in many seeded legumes such as fava beans and velvet beans with relevance for Parkinson's therapy (37,63-66). This pathway

Isoflavonoids Condensed tannins

Isoflavonoids Condensed tannins

Phenolic Biosynthetic Pathway
Figure 9.2 General phenolic flux through the phenylpropanoid pathway from the shikimic pathway.

provides the precursor chorismate, which oxidizes to L-phenylalanine, before going through a hydroxylation step to form L-tyrosine and than l-DOPA (Figure 9.1).

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