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Metabolic Engineering 401

and combined with transcription profiling this may give 55 billion US$. Table III lists some typical fermentation
important information about regulation at the differ- products categorized according to their synthesis route,
ent levels. Finally, powerful analytical techniques like i.e., whether they are whole cells, derived from the pri-
GC-MS and LC-MS-MS (LC: liquid chromatography) mary or secondary metabolism, are specifically synthe-
enable measurement of a large fraction of the intracel- sized (and perhaps secreted) proteins, large polymers, or
lular metabolite—often referred to as the metabolome. As genetic material. Clearly, the strategy for improving the
discussed above, the intracellular metabolite concentra- productivity depends much on whether the product is syn-
tions give unique information about the control of fluxes, thesized by the action of many enzymatic steps or whether
and therefore represent a very detailed phenotypic char- the product is derived directly from expression of a sin-
acterization. There is still, however, some significant de- gle gene. Furthermore, for high value added products like
velopments required before these methods enable high- pharmaceutical proteins, time to market is often more im-
throughput, quantitative analysis of many metabolites. portant than obtaining a high yield or high productivity,
which on the other hand are essential for optimization of
processesleadingtolow-valueaddedproductslikeethanol
VII. APPLICATIONS OF METABOLIC and many antibiotics. Despite these differences, the mind-
ENGINEERING set of metabolic engineering is still extremely valuable in
optimization of any fermentation processes, as discussed
Today metabolic engineering is applied in the optimiza- further in the following.
tion of almost all fermentation processes, and the total In recent years there have been reported on many exam-
market value of fermentation-derived products exceeds ples of metabolic engineering, and these examples can be

TABLE III List of Some Fermentation Products and Some Market Volumes
Category of product Product Typical organism
Whole cells Baker’s yeast S. cerevisiae
Lactic acid bacteria Lactic acid bacteria
Single cell protein Methanogenic bacteria
Primary metabolites Ethanol S. cerevisiae, Z. mobilis 12 billion US$
Lactic acid Lactic acid bacteria, R. oryzae 200 million US$
Citric acid A. niger 1.5 billion US$
Glutamate C. glutamicum 1 billion US$
Lysine C. glutamicum 500 million US$
Phenylalanine E. coli 200 million US$
Secondary metabolites Penicillins P. chrysogenum 4 billion US$
Cephalosporins A. chrysogenum, S. clavuligerus 11 billion US$
Statins Aspergillus 9 billion US$
Taxol Plant cells 1 billion US$
Recombinant proteins Insulin S. cerevisiae, E. coli 3 billion US$
tPA CHO cells a 1 billion US$
Erythropoitin CHO cells 3.6 billion US$
Human growth hormone E. coli 1 billion US$
Interferons E. coli 2 billion US$
Vaccines Bacteria and yeast
Monoclonal antibodies Hybridoma cells 700 million US$
Enzymes Detergent enzymes Bacillus, Aspergillus 600 million US$
Starch industry Aspergillus 200 million US$
Chymosin Aspergillus
Polymers Xanthan gum X. campestris 400 million US$
Polyhydroxybutyrates
DNA Vaccines E. coli
Gene therapy E. coli
a Chinese hamster ovary cells.