Beruflich Dokumente
Kultur Dokumente
Biotechnology Advances
journal homepage: www.elsevier.com/locate/biotechadv
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
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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strains
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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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1425
1426
1426
1427
1427
1428
1429
1429
1430
1430
1426
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.
1427
Table 2
Modied E. coli strains with 3-dehydroshikimic acid yield and titer (Li et al., 1999).
Number Strain
Modication
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)
0.23
66
PTS/glf+/tktA over
expression
Over expression of tktA
0.27
71
0.18
52
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
DHS titer
(g/L)
36.4
41.7
53.0
DHS yield
(mol/mol)
0.22
0.32
0.36
1428
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,
Fig. 4. Shikimic acid synthesis of Koreeda and Ciufolini (1982) as summarized by Ambhaikar (2005).
1429
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
1430
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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