Shikimic Acid Pathway

Shikimic acid pathway

Shikimic acid (1) is the precursor to many natural products that contain an aromatic benzene
ring as part of their structure.

There are two other important intermediates in the synthesis of these natural products, and they
are chorismic acid (2) and prephenic acid (3).

Shikimic acid (1) Chorismic acid (2) Periphenic acid (3)

2
Shikimic acid pathway

Chorismic acid is biosynthesized from shikimic acid. Prephenic acid is derived from chorismic

acid by a rearrangement (these two compounds 2 and 3 have the same empirical formulae).

3
Biosynthesis of Shikimic acid

Shikimic is produced by the

reaction of erythro-4-
phosphate and
phosphoenol pyruvic acid.
Both are product of glucose
metabolism. Erythro-4-
phosphate is
biosynthesized in pentose
phosphate cycle while,
phosphoeneol pyruvic acid
is a product of glycolysis.

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Biosynthesis of Shikimic acid

1. Phosphoenolpyruvate and erythrose-4-phosphate react to form 3-deoxy-D-arabinoheptulosonate-7-

phosphate (DAHP), in a reaction catalyzed by the enzyme DAHP synthase.

2. DAHP is then transformed to 3-dehydroquinate (DHQ), in a reaction catalyzed by DHQ synthase. Although

this reaction requires nicotinamide adenine dinucleotide (NAD) as a cofactor, the enzyme mechanism

regenerates it, resulting in the net use of no NAD.

3. DHQ is converted to dehydroshikimic acid which is converted to shikimic acid by using NADPH.

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Biosynthesis of Shikimic acid

6
Biosynthesis of Chorismic acid

1. The first enzyme involved in this pathway is shikimate kinase, an enzyme that catalyzes
the ATP-dependent phosphorylation of shikimate to form shikimate 3-phosphate.

2. Shikimate 3-phosphate is then coupled with phosphoenol pyruvate to give 5-

enolpyruvylshikimate-3-phosphate via the enzyme 5-enolpyruvylshikimate-3-phosphate
(EPSP) synthase.

3. Then 5-enolpyruvylshikimate-3-phosphate is transformed into chorismate by

a chorismate synthase.

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Biosynthesis of Chorismic acid

8
Biosynthesis of Prephenic acid

Prephenic acid is then synthesized by a Claisen rearrangement of chorismate by Chorismate

mutase

Chorismic acid Prephenic acid

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Amino acids produced from Shikimic acid pathway

Different amino acids are known to be biosynthesized using shikimic acid pathway including anthranilic acid,
tyrosine, tryptophan and phenylalanine

Anthranilic acid 4 Tryptophan 5 Phenylalanine 6 Tyrosine 7

Chorismic acid is the precursor of amino acid Anthranilic acid 4 Tryptophan (5)

Prephenic acid is the precursor to amino acid phenylalanine 6 and tyrosine 7

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Biosynthesis of Anthranilic acid and tryptophan

Chorismic acid (2) reacts with ammonia and forms an intermediate (8) with the removal of a proton. This intermediate is

converted into anthranilic acid (4) with the elimination of enol tautomer of pyruvic acid (9). The biosynthesized anthranilic acid

(4) is converted to tryptophan (5) after several steps.

(8) (4)
(2)

(9)
(5) 11
Transamination

Before considering the biosynthesis of phenylalanine 6 and tyrosine 7 from prephenic acid 3, there is a need to
know about a common biological reaction called Transmission. Transmission is controlled by enzymes termed
transaminases, and the overall reaction shown with the side chains of the substrate and the product molecules
represented by the circles and squares. The substrates for this reaction are an amino acid and α-keto acid. The
amino acid substrate is converted into the α-keto acid product and α-keto acid is converted to amino acid. Thus,
transmission is an exchange of an amino group to a ketone group and vise versa.

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The mechanism of the transamination

The amino group of an amino acid reacts with the aldehyde group of the transaminase enzyme

co-factor, pyridoxal phosphate 10 to give an imine 11. Tautomerization of this imine gives the

new imine 12 which is then hydrolyzed giving the α-keto acid and pyridoxamine phosphate

13. Since transamination can proceed in either direction, pyridoxamine phosphate and an α-

keto acid would produce an amino acid and thus regenerate the pyridoxal phosphate 10.

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The mechanism of the transamination

10
11

13 12

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Biosynthesis of Phenylalanin
The phenylalanine was synthesized by using prephenic acid (3) as precursor. Prephenic acid is subjected to the
removal of CO2 to form an intermediate (14). This intermediate is converted into phenylpyruvic acid (15) after
dehydration. After transamination, phenylpyruvic acid is transferred to phenylalanine (6).

3 14 15 6

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Biosynthesis of Tyrosine

3 14 16 Tyrosine 7

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Biosynthesis of Alkaloids

Alkaloids which are derived from

 Trytophan

 Phenylalanine

 Tyrosine

How decarboxylation occur?

RCOCO2H RCHO AND RCH(NH2)CO2H RCH2NH2

17
Decarboxylation of amino acid

These decarboxylation products

(aldehyde and amine) are also
important building blocks in
alkaloid biosynthesis.
The decarboxylation of amino
acids require cofactor pyridoxal
phosphate (10) which react with
an amino acid giving the
intermediate (11), which
undergoes decarboxylation
producing carbanion. Protonation
of carbanion and hydrolysis of
resulting Imine gives an amine
and 10.

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Decarboxylation of α-keto acids
This reaction requires the thiazole-containing co-factor, thiamine diphosphate (17). The nitrogen atom of the thiazole
ring in 17 is alkylated and therefore bears a positive charge. Consequently, the proton at the 2-position of the thiazole
ring is relatively acidic and on deprotonation a zwitter ion structure 18 is formed in which the negative charge is
stabilized to some extent by the adjacent positive charge.

18
17 19
Decarboxylation of α-keto acids
Nucleophilic attack by this carbanion 18 at the carbonyl carbon of the α-keto acid affords an intermediate 19, which
then undergoes decarboxylation giving compound 20. Protonation of 20 gives the alcohol 21 which fragments and
yield an aldehyde and 17.

19
20
18

H+
17 18 +

21 20
Pictet-Spengler Reaction
This reaction condenses 2-arylphenylamines with
aldehydes in the presence of an acid to construct a new
ring. First step is the condensation of amine with aldehyde
to form an imine 22. The protonated imine is electron
deficient and acr as electrophile in an intramolecular
electrophilic substitution reaction giving the 1,2,3,4-
tetrahydroisoquinoline derivatives 23.

Tryptophan 5

22
Intermediate imine

Phenylalanine 6
21
23
Alkaloids derived from Tryptophan
The tryptophan amino acid is the precursor for alkaloids having quinoline and indole skeleton.

Biosynthesis of Harmane

Tryptophan

24 25 22
Alkaloids derived from Tyrosine
The tyrosine is the precursor to an immense number of alkaloids having benzyl isoquinoline skeleton.

Biosynthesis of Morphine

Morphine biosynthesis involves various steps and different intermediate alkaloids

1. Formation of norcoclaurine
2. Formation of reticuline
3. Formation of Thebain
4. Formation of Morphine
The formation of norcoclaurine is a typical example of how alkaloids possessing a 1,2.3.4-tetrahydroisoquinoline
ring are biosynthesized. The amine and aldehyde fragments which are required for the Pictet-Spengler reaction
are derived by oxidation/decarboxylation and transamination/decarboxylation respectively of tyrosine.

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Formation of norcoclaurine
The formation of norcoclaurine 28 is a typical example of how alkaloids possessing a 1,2.3.4-tetrahydroisoquinoline ring
are biosynthesized. The amine 26 and aldehyde 27 fragments which are required for the Pictet-Spengler reaction are
derived by oxidation/decarboxylation and transamination/decarboxylation respectively of tyrosine.

26

Pictet-Spengler

28

27 24
Formation of reticuline

Alkaloids like Norcoclaurine 28 are phenolics so, can yield phenoxy radicals which can dimerize leading to
structurally more complex natural products.

25
Formation of Thebaine
Reticuline is oxidized to afford phenoxy radical. In this reaction the unpaired electron at para position of ring A
couples with the unpaired electron at the ortho position of ring B to generate the Thebaine 30 skeleton

26
30
27
Formation of Morphine
Thebaine is the precursor to morphine 31. During this transformation one methoxy group is oxidatively
removed and other is hydrolytically removed.

28
Biosynthesis of adrenaline

The phenylalanine and tyrosine amino acids are the precursor for alkaloid amines. The different examples for such

alkaloids are Ephedrine, adrenaline or epinephrine, pseudoephedrine, n-methylephedrine, norephedrine,

colchicines etc.

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