Biocatalytic synthesis of shikimic acid

Details Biocatalytic synthesis of shikimic acid Biocatalytic synthesis of shikimic acid

1999-01-29

2003-09-02

Prouty, Rebecca E. (Department: 1652)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing oxygen-containing organic compound

C435S132000, C435S146000, C435S069100, C435S173300, C435S252300, C435S252330, C435S320100, C435S471000, C536S023200

Reexamination Certificate

active

06613552

ABSTRACT:

FIELD OF THE INVENTION
The present invention is related to the production of shikimic acid and more specifically, to methods of producing shikimic acid from bioconversion of a carbon source.
BACKGROUND OF THE INVENTION
Shikimic acid is an attractive chiral synthon with its highly functionalized; six-membered carbocyclic ring and multiple asymmetric centers. A metabolic intermediate of aromatic amino acid biosynthesis, shikimic acid has emerged as an essential chiral starting material in the synthesis of neuraminidase inhibitors effective in the treatment of influenza. Kim. C. U. et al.,
J. Am. Chem. Soc
. 119:681 (1997); Rohloff, J. C. et al.,
J. Org. Chem
. 63:4545 (1998). Chiral, as well as aromatic chemicals, can also be synthesized from shikimic acid. For example, acid catalyzed dehydration of shikimic acid affords p-hydroxybenzoic acid (Eykmann, J. F.,
Ber. Dtch. Chem. Ges
. 24:1278 (1891)). p-Hydroxybenzoic acid, which has an annual production of 7×10
6
kg, is the key precursor to parabens and a monomer used in the synthesis of liquid crystal polymers. Shikimic acid has also recently been used as the starting point for synthesis of a large combinatorial library of molecules. Tan, D. S. et al.,
J. Am. Chem. Soc
. 120:8565 (1998).
Shikimic acid is obtained via tedious multi-step isolation procedures from plants. Unfortunately, current isolation of shikimic acid from the fruit of Illicium plants (Haslem, E.,
Shikimic Acid: Metabolism and Metabolites
, Wiley & Sons, New York, pp. 40-42 (1993)) precludes its use in kilogram-level synthesis.
Therefore, it would be desirable to provide a method to produce large quantities of shikimic acid. It would also be desirable if such a method were cost-efficient, using inexpensive starting materials. It would further be desirable if the method employed non-toxic compounds and was environmentally benign.
SUMMARY OF THE INVENTION
A bioengineered synthesis scheme for production of shikimic acid from a carbon source is provided. In one embodiment, the bioconversion methods of the present invention comprise the microbe-catalyzed conversion of a carbon source to shikimic acid. As shown in the synthesis scheme of
FIG. 1
, the microbe-catalyzed conversion step of the present invention requires four enzymes which may be provided by a recombinant microbe. In a preferred embodiment, the recombinant microbe is
Escherichia coli
designed to cause reduction of 3-dehydroshikimate to shikimic acid and to inhibit any further conversion of shikimic acid along the aromatic amino acid biosynthetic pathway.
The biocatalytic synthesis method for shikimic acid provided herein, is believed to be environmentally benign, economically attractive, and utilizes abundant renewable sources as a starting material,


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