The Shikimate Pathway: Biosynthesis of Phenolic Products from Shikimic Acid

Abstract

Like other amino acids, the aromatic amino acids phenylalanine, tyrosine, and tryptophan are vitally important for protein synthesis in all organisms. However, while animals can synthesize tyrosine via oxidation of phenylalanine, they can synthesize neither phenylalanine itself nor tryptophan and so these essential amino acids must be obtained in the diet, usually from plant material. Though many other investigators made significant contributions in this area over the years, it was Bernhard Davis in the early 1950s whose use of mutant stains of Escherichia coli led to a full understanding of the so-called shikimic acid pathway that is used by plants and also by some microorganisms for the biosynthesis of these essential amino acids. The pathway is almost completely devoted to their synthesis for protein production in bacteria, while in plants the pathway extends their use to the construction of a wide array of secondary metabolites, many of which are valuable medicinal agents. These secondary metabolites range from simple and familiar compounds such as vanillin (vanilla flavor and fragrance) and eugenol (oil of clove, a useful dental anesthetic) to more complex structures such as pinoresinol, a common plant biochemical, and podophyllotoxin, a powerful cancer chemotherapy agent. Earlier in Chapter 3, we encountered two important intermediates, erythrose-4-phosphate and phosphoenolpyruvate (PEP), each of which was derived from a different pathway utilized in carbohydrate metabolism. Erythrose-4-P was an intermediate in one of the steps of the pentose phosphate pathway while hydrolysis of PEP to pyruvic acid was the final step in glycolysis. These two simple intermediates provide the seven carbon atoms required for construction of shikimic acid itself. The two are linked to one another via a sequence of enzyme-mediated aldol-type reactions, the first being a bimolecular reaction and the second an intramolecular variant that ultimately leads to a cyclic precursor of shikimic acid known as 3-dehydroquinic acid as shown in Fig. 6.3. Subsequent dehydration of 3-dehydroquinic acid leads to 3-dehydroshikimic acid which then leads directly to shikimic acid via NADPH reduction.