The shikimic pathway, also known as the shikimate pathway, is a metabolic pathway commonly seen in plants, bacteria, and fungi. Shikimate is the anionic form, a cyclohexane, cyclohexanecarboxylic acid, and a cyclitol. Shikimic acid is an intermediate from the carbohydrates which is used in the biosynthesis of Phenylpropane derivatives.
The shikimic acid pathway in pharmacognosy is essential for the biosynthesis of various aromatic compounds, including the amino acids phenylalanine, tyrosine, and tryptophan, as well as other important secondary metabolites like flavonoids, lignin, and some vitamins. Shikimic acid is named after Illicium anisatum, a toxic Japanese shikimi flower from which it was first isolated.
Shikimic Pathway
The pathway begins with the precursor molecule called phosphoenolpyruvate (PEP) and erythrose-4-phosphate (E4P). They produce chorismate through a series of enzymatic reactions.
Chorismate forms the starting point for the synthesis of various aromatic compounds.
The shikimic pathway consists of seven enzymatic steps, each catalyzed by a specific enzyme.
The shikimic acid pathway starts with the precursors, Erythrose 4-phosphate and Phosphoenolpyruvate, forming 3-deoxy-D-arabino-heptulosonic acid-7-phosphate (DAHP), a reaction catalysed by phospho-2-oxo-3-deoxyheptonate aldolase.
The enzyme, 3-dehydroquinate synthase, catalyses cyclization of DAHP to 3-dehydroquinic acid, and requires cobalt (II) and nicotinamide adenine dinucleotide (NAD) as cofactors.
The dehydroquinic acid, on reduction, gives quinic acid.
On dehydration, 3-dehydroquinic acid forms 3-dehydroshikimic acid, which forms shikimic acid, followed by reduction. The enzymes catalysing the dehydration of dehydroquinic acid are of two kinds.
Form 1, associated with shikimate dehydrogenase, is independent of shikimate concentration, while form 2 is specifically activated by shikimate. It has been suggested that the two forms provide a control in the utilization of dehydroquinic acid that produces either shikimic acid or protocatechuic acid.
After phosphorylation, catalysed by shikimate kinase, shikimic acid adds on enol pyruvate to form 3-enolpyruvylshikimic acid-5-phosphate. This reaction is catalysed by enolpyruvylshikimate phosphate synthase.
3-Enolpyruvylshikimic acid-5-phosphate is converted into chorismic acid by chorismate synthase. The formation of chorismic acid is an important branch point in the shikimic acid pathway as this compound can undergo three different types of conversion.
In the presence of glutamine, chorismic acid is converted to anthranilic acid, whereas chorismate mutase catalyses the formation of prephenic acid. In another way, chorismic acid is converted into p-aminobenzoic acid.
Anthranilic acid is first converted into phosphoribosyl anthranilic acid and then to carboxyphenylaminodeoxyribulose-5-phosphate. These reactions are catalysed by anthranilate phosphoribosyl transferase and phosphoribosyl anthranilate isomerase, respectively.
Ring closure to form indolyl-3-glycerol phosphate is catalysed by indolyl-glycerol phosphate synthase.
The enzyme catalysing the final reaction, that is, tryptophan synthase, consists of two components; component A catalyses the dissociation of indolylglycerol phosphate to indole and glyceraldehyde-3-phosphate, whereas component B catalyses the direct condensation of indole with serine to form tryptophan.
Tyrosine and phenylalanine are biosynthesized from prephenic acid, in independent pathways, and act as precursors for the biosynthesis of phenylpropanoids. The phenylpropanoids are then used to produce flavonoids, coumarins, lignin, and tannins.
In the formation of tyrosine, prephenic acid is first aromatized to -hydroxyphenylpyruvic acid, a reaction catalysed by prephenate dehydrogenase. Transamination, catalysed by tyrosine aminotransferase, then gives tyrosine.
The biosynthesis of phenylalanine starts with the aromatization of prephenic acid to form phenylpyruvic acid. This reaction is catalysed by prephenate dehydratase. It undergoes a transamination reaction catalysed by phenylalanine aminotransferase to form phenylalanine.
Pic Credit: Bhowmick et al.
Moreover, the pathway produces important secondary metabolites like flavonoids, which have antioxidant properties, and lignin, which provides structural support to plants.
Importance of Shikimic Acid Pathway in Pharmacognosy
Shikimic acid is the starting material for the biosynthesis of various phenolics.
The end products of the shikimic pathway, such as phenylalanine, tyrosine, and tryptophan, are essential amino acids that form building blocks for protein synthesis.
Phenylalanine and tyrosine are precursors for the biosynthesis of phenylpropanoids that are used to produce the flavonoids, coumarins, tannins, and lignin.
Gallic acid, formed from 3-dehydroshikimate by shikimate dehydrogenase, produces 3,5-didehydroshikimate.
Shikimic acid is a precursor for indole, indole derivatives, tryptophan, and tryptophan derivatives such as dimethyltryptamine. many alkaloids and other aromatic metabolites
The shikimic pathway is involved in the production of the antiviral drug oseltamivir (Tamiflu), which is used to treat influenza infections.
Conclusion
Overall, the shikimic pathway is a crucial metabolic pathway that plays a crucial role in the synthesis of aromatic compounds in plants, bacteria, and fungi. Its importance extends beyond basic metabolism and has significant implications in various fields, including medicine, agriculture, and biotechnology.
Bhowmick, Rupa & Sinha, Noopur & Sarkar, Ram Rup. (2017). An in-silico perspective towards target ability of available drugs in infectious disease treatment: a possible strategy.. Journal of Bioinformatics and Genomics. 2. 10.18454/jbg.2017.2.4.1.