SHIKIMIC ACID

PATHWAY
 Shikimic acid

 Commonly known as its anionic form shikimate, is a cyclohexene, a cyclitol and a

cyclohexanecarboxylic acid.
 It is an important biochemical metabolite in plants and microorganisms.
 Its name comes from the Japanese flower shikimi the Japanese star anise, Illicium
anisatum), from which it was first isolated in 1885 by Johan Fredrik Eykman.
 The elucidation of its structure was made nearly 50 years later.
 Shikimic acid is also the glycoside part of some hydrolysable tannins.
 The shikimate pathway is a seven step metabolic route used by bacteria, fungi, algae,
parasites, and plants for the biosynthesis of aromatic amino acids (phenylalanine,
tyrosine, and tryptophan).
 This pathway is not found in animals; therefore, phenylalanine and tryptophan
represent essential amino acids that must be obtained from the animal's diet
 Animals can synthesize tyrosine from phenylalanine, and therefore
is not an essential amino acid except for individuals unable to
hydroxylate phenylalanine to tyrosine).
KEY FEATURES
• The shikimate pathway is the only known pathway for biosynthesis of chorismate and the aromatic
amino acids Phe, Tyr and Trp.
• The shikimate pathway is a bridge between central metabolism and specialised metabolism.
• The shikimate pathway occurs in various groups of microorganisms, plants and parasites, whereas it
does not occur in animals.
• The pathway enzymes are being targeted for antimicrobial drug and herbicide design.
• Shikimic acid is an essential metabolite that may balance the metabolic status of the pathway.
• Chorismate is a branch point metabolite for aromatic amino acids and phenolic compounds.
• This is an ancient eukaryotic pathway which has been subject to diverse evolutionary processes.
• Several enzymes from these pathways are allosterically regulated by their end products: Phe, Tyr or
Trp.
• The shikimate pathway and aromatic amino acids, and the specialised metabolites derived from
them, simultaneously respond to rhythmic changes.
MAJOR ENZYMES
1. Synthase: Joints two molecules together w/o hydrolyzing a pyrophosphate
bond.
2. Dehydratase: Removes water to create a double bond
3. Dehydrogenase: Removes hydrogen atom from its substrate
4. Kinase: Transfer a phosphate group from a high-energy phosphate compound
such as ATP to its substrate.
5. Isomerase is an enzyme that catalyzes the structural rearrangement of isomers.
6. Mutase: catalyzes the shifting of a functional group from one position to
another within the same molecule.
7. Transferase: catalyzes the transfer of a functional group (methyl or
phosphate)from one molecule to another
 SHIKIMIC ACID PATHWAY

The first reaction is the condensation of phosphoenolpyruvate (PEP) with erythrose-4-phosphate which
yields a C7 compound, 3-deoxy-D-arabinoheptulosonate 7-phosphate (DAHP).
The enzyme involved DAHP synthase, NAD+ .
 SHIKIMIC ACID PATHWAY
H+ COOH
HO
O C COOH
CH2
H
H2C H
OH
O OH
H O HO H OH

The second step is the cyclization of DAHP to 3-dehydroquinate is a complex reaction which involves an
intramolecular aldol condensation subsequent to elimination of the phosphate group.
The enzyme involved is 3-dehydroquinate synthase.
SHIKIMIC ACID PATHWAY
H+
HO COOH
COOH
H

O OH
O OH
OH
OH

The dehydration of 3-dehydroquinate is catalyzed by an enzyme which forms a transient Schiff base between a lysine
residue and carbonyl group of 3-dehydroquinate and induces a sterospecific cis elimination of water molecule .
The enzyme involved is 3-dehydroquinate dehydratase.
 SHIKIMIC ACID PATHWAY

Following the reaction of 3-dehydroshikimate, there is a reduction of 3-dehydroshikimate to shikimate.

The enzyme involved is shikimate oxydoreductase, NADP+.
 SHIKIMIC ACID PATHWAY

In this step of the shikimate pathway, shikimate kinase catalyzes the specific phosphorylation of the 3-hydroxyl group of D-
shikimate to yield shikimate 3-phosphate using ATP as a co-subtrate
The enzyme involved is shikimate kinase, ATP.
SHIKIMIC ACID PATHWAY

Following phosphorylation, condensation with another molecule of PEP yields an enol ether, 5-Enolpyruvylshikimate 3-
Phosphate (EPSP).
The enzyme involved is EPSP synthase, PEP.
 SHIKIMIC ACID PATHWAY

This leads, via an unusual trans 1,4- elimination of phosphate from EPSP to chorismate.
The enzyme involved is chorismate synthase.
 SHIKIMIC ACID PATHWAY
Chorismic acid holds a key position in metabolism and has
multiple fates:
 Claisen type pericyclic rearrangement to prephenate. This
pathway leads, via phenylpyruvate, to phenylalanine and
tyrosine.
 This rearrangement is catalyzed by an enzyme chorismate
mutase, which transfers the side chain derived from PEP
to the carbocycle, and thereby generates the skeleton of
phenylpropanes.
 The enzyme is thought to control the conformation by
favoring a chair transition state with pseudoaxial
substituents.
 SHIKIMIC ACID PATHWAY

Chorismate mutase catalyzes the Claisen rearrangement of chorismate ion to prephenate ion

 SHIKIMIC ACID PATHWAY

This step is catalysed by chorismate mutase-prephenatedehydratase enzyme

 SHIKIMIC ACID PATHWAY

This step is catalysed by phenylpyruvate aminotransferase.

 SHIKIMIC ACID PATHWAY
Chorismic acid holds a key position in metabolism and has
multiple fates:
 Claisen type pericyclic rearrangement to prephenate. This
pathway leads, via phenylpyruvate, to phenylalanine and
tyrosine.
 This rearrangement is catalyzed by an enzyme chorismate
mutase, which transfers the side chain derived from PEP
to the carbocycle, and thereby generates the skeleton of
phenylpropanes.
 The enzyme is thought to control the conformation by
favoring a chair transition state with pseudoaxial
substituents.
 SHIKIMIC ACID PATHWAY

This step is catalysed by prephenate deshydrogenase enzyme, NAD+

 SHIKIMIC ACID PATHWAY

This step is catalysed by phenylpyruvate aminotransferase.

 SHIKIMIC ACID PATHWAY
Chorismic acid holds a key position in metabolism and has
multiple fates:
 Amination and anthranilate (2 aminobenzoate) formation.
 Anthranilate is the required intermediate of the
biosynthesis of tryptophan, which is the starting point of
the formation of all indole alkaloids. It is also the (direct
precursor of all most quinolone alkaloids and of antibiotics
in microorganisms.
 Uses:

• In the pharmaceutical industry, shikimic acid from the Chinese star anise (Illicium verum) is used as a base material
for production of oseltamivir (Tamiflu).

Target for drugs

 Shikimate can be used to synthesize (6S)-6-Fluoroshikimic acid, an antibiotic which inhibits the aromatic
biosynthetic pathway.
 Glyphosate, the active ingredient in the herbicide Roundup, kills plants by interfering with the shikimate pathway
in plants. More specifically, glyphosate inhibits the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS).
"Roundup Ready" genetically modified crops overcome that inhibition.