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404 Metabolic Engineering

FIGURE 11 Pathways for the production of 7-ADCA and 7-ACA directly by fermentation. In this process the acyl-
transferase converts isopenicillin N to adipoyl-6-APA, and when the expandase of S. clavuligerus is expressed in
P. chrysogenum, this compound is directly converted to adipoyl-7-ADCA. When P. chrysogenum is transformed with
the expandase/hydroxylase and the acyltransferase of Acremonium chrysogenum, adipoyl-6-APA is converted first to
adipoyl-7-ADACA, which is further converted to adipoyl-7-ACA.

Glucose repression. Many industrial fermentations are e.g., in beer fermentation, whereas in other

carried out on sugar mixtures, e.g., molasses that fermentations it is optimal to have disperse cellular
contain sucrose, glucose, fructose, and raffinose, and structures, e.g., in fermentations with filamentous
the presence of glucose represses the utilization of the microorganisms.
other sugars. This causes lag phases leading to
prolonged fermentation times. Another problem may F. Elimination of By-Product Formation
be encountered in the field of enzyme production,
Many fermentation processes have been optimized such
where glucose repression of the expression promoter
that the desired product is predominantly formed. How-
results in reduced expression of the gene encoding the
ever, due to the complexity of cellular metabolism it is
product. Disrupting DNA-binding proteins that
inevitable that by-products are formed. This may be un-
mediates glucose repression in different
desirable for at least three reasons:
microorganisms has solved problems with glucose
repression.
High sensitivity to low oxygen concentrations. Many
The by-product(s) may be toxic to humans or animals.
microbial cells are sensitive to low oxygen The by-product(s) may cause problems in the
concentration, which may result in reduced product subsequent separation process.
formation—or even irreversible loss of product Formation of the by-product(s) results in a loss of
formation—or onset of fermentative metabolism. This carbon, and the overall yield of product on the raw
problem can partly be overcome by expression material is therefore below the theoretical maximum.
bacterial hemoglobin, which has demonstrated to have
a positive influence in many different fermentation The first reason is clearly problematic if humans or an-
processes. imals may be exposed to the product, either directly or
Modulation of macroscopic structures. In some indirectly. Typically, one chooses a cellular system that

fermentations it is desirable to improve flocculation, do not produce toxins when products are made for human