Metabolic engineering for microbial production of shikimic acid.
Shikimic acid is a high valued compound used as a key starting material for the synthesis of the neuramidase inhibitor GS4104, which was developed under the name Tamiflu for treatment of antiviral infections. An excellent alternative to the isolation of shikimic acid from fruits of the Illicium plant is the fermentative production by metabolic engineered microorganisms. Fermentative production of shikimic acid was most successfully carried out by rational designed Escherichia coli strains by blocking the aromatic amino acid pathway after the production of shikimic acid. An alternative is to produce shikimic acid as a result of dephosphorylation of shikimate-3-phosphate. Engineering the uptake of carbon, the regulatory circuits, central metabolism and the common aromatic pathway including shikimic acid import that have all been targeted to effect higher productivities and lower by-product formation are discussed.
Krämer
Marco
M
DSM Biotech GmbH, Karl-Heinz-Beckurts-Strasse 13, D-52428 Jülich, Germany. marco.kraemer@dsm.com
Bongaerts
Johannes
J
Bovenberg
Roel
R
Kremer
Susanne
S
Müller
Ulrike
U
Orf
Sonja
S
Wubbolts
Marcel
M
Raeven
Leon
L
D018929:Cell Culture Techniques / Q000379:methods*; D004926:Escherichia coli / Q000235:genetics* / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology; D005818:Genetic Engineering / Q000379:methods*; D005947:Glucose / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012765:Shikimic Acid / Q000302:isolation & purification / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D009097:Multienzyme Complexes; D011994:Recombinant Proteins; D012765:Shikimic Acid; D017853:Phosphotransferases (Alcohol Group Acceptor); C022642:shikimate kinase; D005947:Glucose