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406 Metabolic Engineering

of yield or productivity depends on the type of inhibition. opments in functional genomics, with new analytical tech-
In the case of competitive inhibition, an increased flux niques for measurement of the transcriptome using DNA
toward the product may result in an increase in the prod- chips, the proteome using 2D gels, and the metabolome
using different analytical techniques, will have a signifi-
uct concentration and thereby a decreased affinity of E j
for the branch-point metabolite. This may lead to a change cant impact on metabolic engineering. With the tradition
in flux distribution around the metabolite I—perhaps even of considering whole cell function in the field of metabolic
a decrease in the overall yield. With noncompetitive in- engineering, there are, however, also several lessons from
hibition the situation is quite different, since the affin- metabolic engineering for functional genomics, and in the
ity is not affected by the product concentration. How- future it is expected that these two research areas will ben-
ever, in this case an overexpression of E j may not lead efit much from each other.
to a significant increase in the in vivo activity due to the
feedback inhibition. In case of feedback inhibition it is
generally the best strategy to increase the step after the ACKNOWLEDGMENT
inhibitory metabolite as illustrated with the flux control
in the penicillin biosynthetic pathway (see Fig. 9). Alter- I dedicate this paper to Jay Bailey, who has served as a constant inspira-
natively, one can introduce feedback-insensitive enzymes, tion for the work carried out in my research group. Jay recently passed
e.g., by gene-shuffling or by recruiting a heterologous en- away and this will be a great loss to the metabolic engineering com-
zyme. Furthermore, through gene-shuffling enzymes with munity. However, I am sure that his thoughts and ideas will continue to
influence this research field in the future.
reduced or increased affinity may be constructed, and this
may enable redirection of pathway fluxes, and hereby a
common host can be used for the production of several
SEE ALSO THE FOLLOWING ARTICLES
different metabolites.
BIOMATERIALS,SYNTHESIS,FABRICATION, AND APPLI-
VIII. FUTURE DIRECTIONS CATIONS • CHROMATIN STRUCTURE AND MODIFICATION
•DNATESTING INFORENSICSCIENCE•ENZYMEMECHA-
NISMS • GENE EXPRESSION,REGULATION OF • HYBRIDO-
Metabolic engineering has come far in the last decade.
The first success stories involved introduction of a sin- MAS,GENETIC ENGINEERING OF • PROTEIN SYNTHESIS •
TISSUE ENGINEERING • TRANSLATION OF RNA TO PRO-
gle heterologous gene for protein production or disrup-
tion of a single gene for redirection of pathway fluxes. TEIN
In recent years, there have also been demonstrations of
how multiple genetic modifications can be exploited to
obtain the overall goal. These may either come around BIBLIOGRAPHY
through several rounds of the metabolic engineering cycle
(Fig. 1), or they may be the result of a careful analysis Bailey, J. E. (1991). Toward a science of metabolic engineering. Science
that immediately points to the benefit of introducing sev- 252, 1668–1674.
eral genetic modifications at the same time. The approach Christensen, B., and Nielsen, J. (1999). Metabolic network
analysis—Powerful tool in metabolic engineering. Adv. Biochem.
of suitably coordinated expression (and/or inhibition) of
Eng./Biotechnol. 66, 209–231.
several genes will be necessary to achieve more advanced Fell, D. (1997). “Understanding the Control of Metabolism,” Portland
objectives, and this calls for a systems approach. Thus, it Press, London.
is necessary to consider the complete metabolic network, Lee, S. Y., and Papoutsakis, E. T. (1999). “Metabolic Engineering,”
Marcel Dekker, New York.
or the complete set of signal transduction pathways that
Ostergaard, S., Olsson, L., and Nielsen, J. (2000). Metabolic engineering
are involved in regulation of cellular function, and it is ex-
of Saccharomyces cerevisiae. Microbiol. Mol. Biol. Rev. 64, 34–50.
actly this systems approach that distinguishes metabolic Stephanopoulos, G., Aristodou, A., and Nielsen, J. (1998). “Metabolic
engineering from applied molecular biology. The devel- Engineering,” Academic Press, San Diego, CA.