Biology Reference
In-Depth Information
inhibition in a linear pathway on an enzyme at the beginning of the pathway.
They showed that the effect of feedback inhibition was to lower the flux control
coefficient of the inhibited enzyme and to increase the flux control coefficients
of the steps consuming the feedback metabolite. This was an unpopular con-
clusion, as it contradicted the assertion that feedback-inhibited enzymes were
prime candidates for rate-limiting steps. However, the prediction has been sub-
sequently borne out because over-expression of a number of feedback-inhibited
enzymes (notably phosphofructokinase; Schaff et al., 1989; Thomas et al., 1997)
has resulted in little impact on metabolic flux. Savageau (1974) analysed the
role of feedback inhibition in branched metabolic pathways, where there can be
different configurations for the feedback loops from the end-product metabolites
on enzymes in their own branch and the common branch. The two main types
are the nested and sequential configurations (see Fig. 1), which he was able
to show would have distinct performance characteristics in terms of metabolite
homeostasis, cross-talk between the branches, and the range of conditions under
which they would perform appropriately. It is interesting to note that the same
sub-networks in different organisms can have different patterns of feedback
control (for example, the pathways for synthesis of aromatic amino acids), show-
ing that the regulatory interactions are more plastic than the enzymic reactions
themselves.
Hofmeyr & Cornish-Bowden (1991) also examined the properties of feedback
inhibition loops. Their approach used a combination of the algebraic relationships
of metabolic control analysis and computer simulation of hypothetical pathways.
Amongst the issues they addressed was the function of the cooperativity that
(a)
(b)
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Figure 1
Feedback inhibition patterns in branched pathways.
(a) Nested inhibition; (b) sequential inhibition. Any step shown above can be regarded as being
composed of an arbitrary number of enzyme reactions.
