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Biotechnology Advances 30 (2012) 14251431

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Biotechnology Advances
journal homepage: www.elsevier.com/locate/biotechadv

Research review paper

Production of shikimic acid


Saptarshi Ghosh a, Yusuf Chisti b, Uttam C. Banerjee a,
a
b

Department of Pharmaceutical Technology (Biotechnology), National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar-160 062, Punjab, India
School of Engineering, Massey University, Private Bag 11 222, Palmerston North, New Zealand

a r t i c l e

i n f o

Available online 14 March 2012


Keywords:
Shikimic acid
Oseltamivir
Quinic acid

a b s t r a c t
Shikimic acid is a key intermediate for the synthesis of the antiviral drug oseltamivir (Tamiu). Shikimic
acid can be produced via chemical synthesis, microbial fermentation and extraction from certain plants. An
alternative production route is via biotransformation of the more readily available quinic acid. Much of the
current supply of shikimic acid is sourced from the seeds of Chinese star anise (Illicium verum). Supply
from star anise seeds has experienced difculties and is susceptible to vagaries of weather. Star anise tree
takes around six-years from planting to bear fruit, but remains productive for long. Extraction and purication from seeds are expensive. Production via fermentation is increasing. Other production methods are
too expensive, or insufciently developed. In the future, production in recombinant microorganisms via fermentation may become established as the preferred route. Methods for producing shikimic acid are
reviewed.
2012 Elsevier Inc. All rights reserved.

Contents
1.
2.

Introduction . . . . . . . . . . . . . . . . . . .
Production methods . . . . . . . . . . . . . . .
2.1.
Extraction from plants . . . . . . . . . . .
2.2.
Fermentation processes . . . . . . . . . .
2.2.1.
The shikimic acid pathway . . . .
2.2.2.
Use of recombinant and engineered
2.3.
Chemical synthesis . . . . . . . . . . . .
2.4.
Microbial biotransformation . . . . . . . .
3.
Concluding remarks . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction
This review is focussed on the methods of producing shikimic acid
(3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid), a chemical
building block for the antiviral drug oseltamivir (Tamiu). Shikimic
acid is named after the Japanese shikimi (Illicium anisatum) ower
Abbreviations: DAHP, 3-Deoxy-D-arabino-heptulosonate-7-phosphate; DHQ,
3-Dehydroquinate or 3-dehydroquinic acid; DHS, 3-Dehydroshikimate or 3dehyroshikimic acid; DQD, 3-Dehydroquinate dehydrogenase; EPSP, 5-Enolpyruvylshikimate-3-phosphate; E4P, Erythrose-4-phosphate; GDH, Glucose dehydrogenase; NADP,
Nicotinamide adenine dinucleotide phosphate; NADPH, Reduced form of nicotinamide adenine dinucleotide phosphate; PEP, Phosphoenolpyruvate; QDH, Quinic acid dehydrogenase; SKDH, Shikimic acid dehydrogenase.
Corresponding author. Tel.: + 91 172 2214682 87; fax: + 91 172 2214692.
E-mail address: ucbanerjee@niper.ac.in (U.C. Banerjee).
0734-9750/$ see front matter 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.biotechadv.2012.03.001

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from which it was rst isolated. Shikimic acid is an intermediate of


the shikimic acid pathway (Herrmann and Weaver, 1999) that is involved in the synthesis of aromatic metabolites in plants and microorganisms (Ganem, 1978; Herrmann, 1995; Pittard, 1996; Wilson et
al., 1998). Metabolically essential products of the shikimic acid pathway include the three aromatic amino acids L-phenylalanine,
L-tryptophan and L-tyrosine. Shikimic acid pathway is not normally
associated with animals, but genes for coding some of the enzymes
of the pathway have been found in certain animals (Starcevic et al.,
2008). Properties and toxicology of shikimic acid have been discussed
elsewhere (Stavric and Stoltz, 1976). An insufciency of shikimic acid
has in the past affected the supply of oseltamivir (Farina and Brown,
2006).
As a highly functionalised, six-carbon ring with three chiral carbons and a carboxylic acid functional group, shikimic acid (Fig. 1) is

1426

S. Ghosh et al. / Biotechnology Advances 30 (2012) 14251431

extraction and purication processes are expensive. Use of recombinant bacteria for commercial production of shikimic acid is developing. Newer routes for producing oseltamivir without the use of
shikimic or quinic acids have appeared (Fukuta et al., 2006; Yeung
et al., 2006), but not been commercialized. Here we review the existing
and emerging methods for producing shikimic acid.
2. Production methods
2.1. Extraction from plants
Fig. 1. Structure of shikimic acid and oseltamivir.

a versatile enantiomerically pure precursor for making potentially


useful products. Interest in shikimic acid has been rekindled as it is
required for producing the avian u drug oseltamivir (Fig. 1). In
view of the potential impact of a u pandemic (Horimoto and
Kawaoka, 2001) and the limited usefulness of vaccines against rapidly
evolving u viruses, stockpiles of effective drugs are necessary for
managing a major outbreak. Oseltamivir is an effective treatment
for inuenza (Widmer et al., 2010), especially if administered early.
Oseltamivir is effective against both Type A and Type B inuenza
and it is used also in prophylaxis.
Oseltamivir is a viral neuraminidase inhibitor. Its synthesis from
quinic acid via shikimic acid has been described (Kim et al., 1997,
1998; Rohloff et al., 1998). Oseltamivir produced for early clinical trials
had been made from chemically synthesized shikimic acid (Federspiel
et al., 2001), but this method proved impractical for commercial production of the drug. Chemical and microbial methods for inexpensive
production of shikimic acid are being developed, but most of this
compound is currently extracted from the seeds of Chinese star
anise (Illicium verum) (Payne and Edmonds, 2005). The multistep

As an intermediate of the shikimic acid pathway, shikimic acid


is found widely in plants (Bohm, 1965; Dell and Frost, 1993;
Gurib-Fakim, 2006; Herrmann and Weaver, 1999), but generally occurs in low concentration. Seeds of Chinese star anise (Illicium verum)
are the main commercial source of shikimic acid. The botany and pharmacology of Chinese star anise have been reviewed (Wang et al., 2011).
Shikimic acid was rst isolated from owers of the highly toxic
Japanese star anise. Subsequently, it was reported in the leaves of
the sweetgum tree (Liquidambar styraciua) (Plouvier, 1961). The
seeds of the American sweetgum tree have been found to contain
up to 3.7% (w/w) shikimic acid (Enrich et al., 2008). Extraction of shikimic acid from bark and wood of the sweetgum has been reported
(Martin et al., 2010). A simple extraction method based on hot
water was used. Several varieties of pine, r and spruce are known
to produce shikimic acid. A hot water (4575 C) extraction of the
needles of Scots pine (Pinus sylvestris) yielded around 1.6% (w/w)
shikimic acid (Sui, 2008). Extraction from the needles of the pine
Pinus elliottii has been described (Xie et al., 2010). Attempts are
being made to identify other natural plant sources of shikimic acid
(Raghavendra et al., 2009).

Fig. 2. The shikimic acid or shikimate pathway.

S. Ghosh et al. / Biotechnology Advances 30 (2012) 14251431

Plants of the genus Illicium appear to the best source of shikimic


acid, but many Illicium species are poisonous (Lederer et al., 2006;
Yamada et al., 1968) and therefore not suitable for producing commercial shikimic acid. Japanese star anise (I. anisatum) is highly
toxic, but the Chinese star anise (I. verum) is edible. Nevertheless,
compounds found in Chinese star anise have been shown to be
toxic to infants (Ize-Ludlow et al., 2004).
Shikimic acid is highly soluble in water (180 g/L at 20 C), but not
in non-polar solvents. Therefore, a hot water extraction of the plant
tissue is used as the primary extraction step (Ohira et al., 2009; Sui,
2008; Xie et al., 2010; Ye et al., 2007). Shikimic acid content in the
plant tissue varies depending on the source of the tissue, the time of
harvest and other possible factors. Roughly 1 kg of shikimic acid can
be recovered from 30 kg of dry seed pods of Chinese star anise
(Ohira et al., 2009; Roche, 2006). Recovery is nearly complete (>95%)
within 10 min of water extraction at 70 C from seed pods ground to a
particle size of 355600 m (Ohira et al., 2009). The rate of recovery
can be further enhanced by using a higher extraction temperature.
Other extraction methods have been described, involving the use
of acids (Harring et al., 1998; Mueller, 2003), alcohols (Anderson et
al., 2001; Jaroszynska, 2003), complex formation (Miles et al., 1994;
Sadaka and Garcia, 1999) and microwave-assisted extraction
(Matallo et al., 2009). The crude water extract contains numerous
other water-soluble plant metabolites and requires extensive further
processing to yield pure shikimic acid. The recovery and purication
processes used in commercial production from Chinese star anise
are proprietary and involve multiple steps.
2.2. Fermentation processes
Microbial production of shikimic acid involves the shikimic acid (or
shikimate) pathway. Shikimic acid pathway occurs commonly in microorganisms and therefore they can be used to overproduce this compound from carbon sources such as glucose (Draths et al., 1999;
Simonart and Wiaux, 1960). Shikimic acid is a precursor for essential
amino acids and other metabolites in microorganisms. Its overproduction can be achieved for example by metabolic engineering to partly
block some of the biochemical pathways that consume shikimic acid
and by overexpression of the enzymes responsible for its synthesis. Production by fermentation using engineered microorganisms is already
supplementing the commercial supply of shikimic acid.
2.2.1. The shikimic acid pathway
The shikimic acid pathway is shown in Fig. 2. This metabolic pathway
is used to produce the aromatic amino acids that are essential to growth.
Shikimic acid is an intermediate in the pathway. This pathway has been
previously reviewed (Herrmann and Weaver, 1999).
The shikimic acid pathway begins with phosphoenolpyruvate
(PEP) and erythrose-4-phosphate (E4P) (Fig. 2). These two compounds must rst be generated from metabolism of glucose, or
other carbohydrate. PEP is produced through the glycolysis pathway
(Fig. 2) whereas the completely independent pentose phosphate

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Table 2
Modied E. coli strains with 3-dehydroshikimic acid yield and titer (Li et al., 1999).
Number Strain

Modication

DHS yield DHS titer


(mol/mol) (g/L)

aroFFBR expression controlled by


ParoF in absence of amplied tktA
aroFFBR expression controlled by
ParoF in absence of amplied tktA
aroFFBR expression controlled by
ParoF in the presence of amplied
tktA
KL3/
aroFFBR expression is controlled
pKD11.291A by ParoF in absence of amplied
tktA
KL3/
aroFFBR expression is controlled
pKL5.17A
by ParoF in presence of amplied
tktA
KL3/
aroFFBR expression under the
control of Ptac in presence of tktA
pKL4.124A

KL3/
pKL4.33B
KL3/
pKL4.66A
KL3/
pKL4.130B

2
3

0.17

20.3

0.16

38.5

0.30

69.0

0.18

41.2

0.24

58.1

0.28

66.0

pathway is used to generate E4P (Fig. 2). Thus, the shikimic acid pathway is dependent on the glycolytic pathway and the pentose phosphate pathway to provide the two starting materials it requires.
Therefore, metabolic engineering of the shikimic acid pathway alone
may be insufcient for increasing the yield of shikimic acid from the
carbon source used in a fermentation. Furthermore, because shikimic
acid is produced far downstream in the metabolic pathway relative to
the point where glucose rst enters the metabolism, channelling the
ow of carbon to production of shikimic acid can be difcult.
Once E4P and PEP have been generated through carbohydrate metabolism in other independent pathways, they are condensed in the
shikimic acid pathway through the action of the enzyme DAHP
synthase to produce DAHP. Action of three other enzymes then converts DAHP to shikimic acid. Chorismic acid is the nal product of
the SA pathway and this compound is the common precursor for
the biosynthesis of other aromatic products such as aromatic amino
acids, as it is shown in Fig. 2.
The shikimic acid pathway engineering has most commonly involved the bacterium Escherichia coli. This microorganism has three
isoforms of the DAHP synthase enzyme encoded by aroF, aroG, aroH
show feedback inhibition by the three aromatic amino acids, i.e.
L-tyrosine, L-phenylalanine and L-tryptophan respectively. The
DAHP synthase (aroG) of Bacillus subtilis is inhibited by the pathway
intermediate chorismate (Jensen and Nester, 1966a,b) (Fig. 2).
The enzyme DHQ synthase (aroB) in E. coli converts DAHP into
3-dehydroquinate (DHQ). The enzyme DHQ dehydratase (aroD) then
converts DHQ into 3-dehydroshikimate (DHS) by eliminating water.
Subsequently, NADPH-dependent shikimate dehydrogenase (aroE) reduces DHS to shikimic acid. The rate limiting enzymes of the shikimic
acid pathway of E. coli are DHQ synthase and shikimate kinase (Dell
and Frost, 1993) (Fig. 2). Shikimate kinase (aroL and aroK) is responsible
for converting shikimic acid to shikimate-3-phosphate (Fig. 2).
In E. coli, the enzymes DHQ synthase, DHQ dehydratase and
shikimate dehydrogenase (Fig. 2) are constitutively expressed
whereas the production of the DAHP synthases and one of the

Table 1
Modied E.coli strains with shikimic acid (SA) yield and titer.
Strain

Modication

SA yield
(mol/mol)

SA
titer (g/L)

SP1.1/pKD15.071B
(Chandran et al., 2003)
SP1.1pts/pSC6.090B
(Chandran et al., 2003)
SP1.1/pKD12.138
(Knop et al., 2001)
SP1.1/pKD12.112
(Draths et al., 1999)

Over expression of ppsA

0.23

66

PTS/glf+/tktA over
expression
Over expression of tktA

0.27

71

0.18

52

Insertion of aroB into the


serA locus of E.coli and
disruption of aroL and aroK

0.15

27.2

Table 3
Effect of carbon sources on the production of 3-dehydroshikimic acid by recombinant
E. coli strains (Li et al., 1999).
Strain

KL3/pKL4.124A
(tktA over expression)

KL3/pKL4.79B (tktA)

Carbon source

DHS titer
(g/L)
46.0
43.1
64.0

Carbon
source
Glucose
Xylose
Mixa

Glucose
Xylose
Mixa
a

DHS yield
(mol/mol)
0.28
0.33
0.41

Molar ratio of glucose/xylose/arabinose: 3:3:2.

DHS titer
(g/L)
36.4
41.7
53.0

DHS yield
(mol/mol)
0.22
0.32
0.36

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S. Ghosh et al. / Biotechnology Advances 30 (2012) 14251431

Fig. 3. Synthesis of shikimic acid via Diels-Alder reaction (McCrindle et al., 1960; Smissman et al., 1959). Based on Ambhaikar (2005).

shikimate kinases is transcriptionally regulated. Shikimic acid inhibits shikimate dehydrogenase (Dell and Frost, 1993).
An alternative microbial route to shikimic acid is through biotransformation of quinic acid. Certain microorganisms (Pseudomonas,
Achromobacter, Aspergillus and Neurospora crassa) can use quinic acid
(or its salt, quinate) as the sole carbon source (Case et al., 1978; Da
Silva et al., 1986; Rogoff, 1958) to produce aromatic amino acids via
the shikimic acid pathway. Quinate enters the pathway at the point
shown in Fig. 2. E. coli strains specically engineered for overproducing quinic acid from glucose have also been developed (Ran et al.,
2001).
2.2.2. Use of recombinant and engineered strains
Metabolically engineered bacteria provide an important emerging
route to production of shikimic acid via fermentation (Campbell et al.,
1993; Krmer et al., 2003). The bacterium E. coli has been the focus of
most metabolic engineering effort (Ahn et al., 2008; Escalante et al.,
2010; Johansson and Liden, 2006; Johansson et al., 2005, 2006;
Knop et al., 2001; Yi et al., 2002, 2003), but studies in other bacteria
have also been reported.
Several metabolic engineering approaches have been developed to
overproduce shikimic acid in E. coli (Ahn et al., 2008; Chandran et al.,
2003; Escalante et al., 2010; Gibson et al., 2001; Johansson et al.,
2005; Knop et al., 2001; Krmer et al., 2003). All these are based on
genetic modications to alter the central carbon metabolism and
the shikimic acid pathway (Table 1).
The shikimic acid pathway requires PEP and E4P (Fig. 2). The supply of PEP and E4P can be enhanced via metabolic engineering of the
glycolytic pathway and the pentose phosphate pathway, respectively.
Both these approaches have been demonstrated. Over expression of
transketolase (tktA) resulted in the increase of shikimic acid yield
from 0.12 to 0.18 mol/mol and titer from 38 to 52 g/L by enhancing
the concentration of E4P (Knop et al., 2001). In recombinant E. coli,

an increased availability of PEP has enhanced production of shikimic


acid (Chandran et al., 2003; Yi et al., 2002). The modication of the
glycolytic pathway involved over expression of PEP synthase (ppsA)
leading to increased shikimic acid titer to 66 g/L and yield on glucose
of 0.23 mol/mol (Chandran et al., 2003). Inactivation of the PTS operon
(PTS), expression of non-PTS glucose transporters like glucose facilitators (glf), glucokinase (glk) in combination with over expression of tktA
gene was reported to increase the shikimic acid titer to 71 g/L
(Chandran et al., 2003; Gibson et al., 2001). Using the engineered E.
coli strain, the shikimic acid concentration could be further raised to
84 g/L by supplementing the minimal medium with yeast extract
(Chandran et al., 2003). Shikimic acid could be produced during exponential growth on glucose to a nal concentration of 87 g/L (Chandran
et al., 2003). The nature of the carbon source affected the productivity
of shikimic acid (Ahn et al., 2008; Li et al., 1999).
In earlier studies, the shikimic acid titers from metabolically engineered E. coli strains were low partly due to simultaneous production
of quinic acid (Knop et al., 2001). Production of quinic acid during biosynthesis of shikimic acid is a consequence of the microbe-catalyzed
equilibration of the initially synthesized shikimic acid (Knop et al.,
2001). This problem appears to have been resolved in view of the aforementioned high titers.
Shikimic acid can be produced readily from DHS (Fig. 2). Therefore, some metabolic engineering studies have focussed on overproduction of DHS. Substantial overproduction of DHS in metabolically
engineered microorganisms has been achieved (Draths and Frost,
1990; Li and Frost, 1999; Li et al., 1999; Yi et al., 2002, 2003)
(Table 2). For example, E. coli constructs have produced as much as
60 g/L DHS from glucose in 60 h (Yi et al., 2003). A comparative analysis
of D-xylose, D-glucose and D-arabinose as carbon source for microbial
synthesis of DHS was also reported (Li and Frost, 1999) (Table 3). Different recombinant E. coli strains were used with various carbon sources
for DHS production.

Fig. 4. Shikimic acid synthesis of Koreeda and Ciufolini (1982) as summarized by Ambhaikar (2005).

S. Ghosh et al. / Biotechnology Advances 30 (2012) 14251431

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Fig. 5. Chemical conversion of ()-Quinic acid to ()-Shikimic acid (Dangschat and Fischer, 1938, 1950). Based on Ambhaikar (2005).

The activity of DAHP synthase (Fig. 2) controls the amount of cellular carbon directed into DHS synthesis. Transcriptional repression
and feedback inhibition of DAHP synthase by aromatic amino acids
are believed to control the activity of this enzyme. The amplied
expression of a mutant DAHP synthase, which is insensitive to
feedback inhibition by aromatic amino acids, has been used to enhance production of DHS. Metabolic engineering approaches have
been employed to produce shikimic acid in E. coli strains derived
from an evolved strain PB 12 lacking the PTS system but with ability
to grow on glucose. The double aroK -, aroL- mutant of strain PB
12.SA22 showed shikimic acid titer of 7 g/L and yield of 0.29 mol/mol
(Escalante et al., 2010).
In addition to recombinant E. coli, genetically modied or otherwise mutated Bacillus subtilis (Iomantas et al., 2002) and Citrobacter
freundii bacteria (Shirai et al., 2001) have been used to successfully
overproduce shikimic acid although the titers have not exceeded
about 20 g/L. It was reported that aroI (shikimate kinase) decient
strain of B. subtilis showed shikimic acid titer of 8.5 g/L with high
titer of DHS (9.5 g/L) as the by-product (Iomantas et al., 2002). Use
of glyphosate, an inhibitor of the enzyme EPSP synthase (Fig. 2), in
the fermentation medium to enhance accumulation of shikimic acid
by blocking its downstream consumption, has been described
(Bogosian, 2011). Metabolic engineering of microorganisms for producing shikimic acid has been reviewed by Krmer et al. (2003).
2.3. Chemical synthesis
Chemical synthesis of shikimic acid was rst achieved during the
1960s using the basic chemistry of Diels-Alder reaction (Fig. 3) to
form six membered rings (McCrindle et al., 1960; Smissman et al.,
1959), but the yield was low at 15%. Later attempts to increase
yield were not particularly successful (Grewe and Hinrichs, 1964).
In 1982, the efciency of Diels-Alder synthesis could be improved
(Fig. 4) to raise the yield to 29% (Koreeda and Ciufolini, 1982). A
more efcient synthesis further raised the yield to 55% (Koreeda et
al., 1990).
Synthesis of shikimic acid from benzene has been shown to be
possible (Birch et al., 1988). Synthesis via a palladium mediated elimination reaction was advanced by Yoshida and Ogasawara (2000).
Synthesis of ()-shikimic acid has been reported from sugars such
as D-mannose (Dangschat and Fischer, 1938, 1950; Fleet et al., 1984;
Jiang et al., 1994). Shikimic acid can be made also from ()-quinic
acid and its derivatives by chemical transformations (Box et al., 2002;
Cleophax et al., 1971, 1973; Federspiel et al., 2001; Kim et al., 1997,
1998; Rohloff et al., 1998) (Fig. 5). Other synthetic methods have

been described (Kancharla et al., 2009; Snchez-Abella et al., 2006).


Chemical synthesis of shikimic acid and its analogs is further reviewed
elsewhere (Campbell et al., 1993; Jiang and Singh, 1998).
Although several routes have been described for chemical synthesis,
production of shikimic acid by these methods is too expensive to be
of commercial use. Consequently, isolation from Chinese star anise
fruit remains the principal source of commercial shikimic acid
(Raghavendra et al., 2009).
The ten step commercial route of oseltamivir (Tamiu) synthesis
uses ()-shikimic acid as the starting material (Abrecht et al., 2004).
This precursor is converted into a diethyl ketal intermediate, which is
reductively opened to give 1,2-epoxide. This epoxide is then converted into oseltamivir via a ve step reaction involving 3 potentially
toxic and explosive azide intermediates (Fig. 6). This route gives 35%
yield of oseltamivir. Future methods for making oseltamivir may
completely circumvent the need for shikimic or quinic acids (Fukuta
et al., 2006; Yeung et al., 2006).

2.4. Microbial biotransformation


Many microorganisms are able to convert quinic acid to shikimic
acid (Adachi et al., 2003, 2006). Quinic acid (or quinate) is converted
to 3-dehydroquinate (DHQ) (Fig. 2) through the action of quinate dehydrogenase. DHQ is an intermediate of the shikimic acid pathway
and is transformed to shikimic acid in a two-step process (Fig. 2).
During exponential growth of Gluconobacter oxydans, nearly all quinate supplied in the medium could be converted to DHQ (Adachi et al.,
2003). This transformation could be achieved also with dried cells of
G. oxydans (Adachi et al., 2003) and with fresh cells immobilized in
alginate beads. The intermediate DHQ could be further transformed
to DHS in a reasonable yield by both growing and immobilized
cells. Lactobacillus pastorianus is capable of converting quinic acid to a
product that was claimed to be dihydroshikimic acid (Carr et al.,
1957), but was more likely DHS.
A two-step scheme for biotransformation of quinic acid to shikimic
acid has been published (Fig. 7) (Adachi et al., 2006). The rst step of
this scheme involves an oxidative fermentation with G. oxydans to essentially quantitatively convert quinic acid in the culture medium to
DHS. The latter is subsequently converted to shikimic acid in an
NADPH-dependent reaction using the enzyme shikimic acid dehydrogenase (SKDH) (Fig. 7) puried from cells of G. oxydans. The enzymatic biotransformation medium also contained glucose and the
enzyme glucose dehydrogenase to continuously regenerate NADPH
(Fig. 7).

Fig. 6. Synthesis of oseltamivir from shikimic acid.

1430

S. Ghosh et al. / Biotechnology Advances 30 (2012) 14251431

Fig. 7. Overall reaction for shikimic acid production (based on Adachi et al., 2006).

3. Concluding remarks
Shikimic acid is a precursor for the synthesis of the important antiviral drug oseltamivir. Extraction from Chinese star anise is the main
source for shikimic acid, but fermentation processes based on the recombinant bacterium E. coli have been shown to be a viable alternative
source. Chemical synthesis of shikimic acid is possible, but apparently
not commercially viable. Chemical methods of making oseltamivir
may entirely circumvent the need for shikimic acids, but are not commercially used. Bioconversion of quinic acid to shikimic acid is another
option for production, but appears not to have been developed to the
extent of the fermentation route from glucose.
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