Cell Metabolism - Bioprocess Engineering: Kinetics, Biosystems, Sustainability and Reactor Design - page 499

10.5.2. Metabolic Pathway Control
In Chapter 8, we learned how enzyme activity could be modulated by inhibitors or acti-
vators. Here, we discuss how the activities of a group of enzymes (a pathway) can be
controlled. The cell will attempt to make the most efficient use of its resources; the fermen-
tation specialist tries to disrupt the cell's control strategy so as to cause the cell to overpro-
duce the product of commercial interest. An understanding of how cells control their
pathways is therefore vital to the development of many bioprocesses.
First, consider the very simple case of a linear pathway making a product, P 1 . Most often
the first reaction in the pathway is inhibited by accumulation of the product ( feedback inhibi-
tion or end-product inhibition). The enzyme for the entry of substrate into the pathway would
be an allosteric enzyme (as described in Chapter 8), where the binding of the end product in
a secondary site distorts the enzyme so as to render the primary active site ineffective. Thus,
if the cell has a sufficient supply of P 1 (perhaps through an addition to the growth medium), it
will deactivate the pathway so that the substrates normally used to make P 1 can be utilized
elsewhere.
This simple concept can be extended to more complicated pathways with many branch
points (see Fig. 10.15 ). Assuming that P 1 and P 2 are both essential metabolites, the cell
may use one of several strategies to ensure adequate levels of P 1 and P 2 with efficient utili-
zation of substrates.
One strategy is the use of isofunctional enzymes (isozymes). Two separate enzymes are
made to carry out the same conversion, while each is sensitive to inhibition by a different
end product. Thus, if P 1 is added in excess in the growth medium, it inhibits one of the

(a) Isozymes

(b) Concerted feedback

P 1

P 1

E 4

M 4 E 4

M 4

E 2

M 2

M 1 M 3

M 1

M 2 M 3

E 3

E 3

E 2

/

E 2

E 5

E 5

M 5

M 5

P 2

P 2

(c) Sequential feedback

(d) Cumulative feedback

P 1

P 1

E 4

M 4

E 4 M 4

M 1 M 2 M 3

M 1 M 2

M 3

E 3

E 2

E 2 E 3

E 5

E 5

M 5

M 5

P 2

P 2

FIGURE 10.15 Examples of feedback control of branched pathways. P 1 and P 2 are the desired end products. M 1 ,
M 2 ,

,M j are intermediates, and E j is the enzyme involved in converting metabolite M j 1 to M j possible paths of
inhibition are shown by dashed lines.

.