Biology Reference
In-Depth Information
is frequently observed in the kinetics of feedback-inhibited enzymes, and that
causes the rate of the isolated enzyme reaction to show much greater sensi-
tivity to changes in the concentration of the inhibitor. As feedback-inhibited
enzymes had in the past been regarded as candidates for rate-limiting steps,
their cooperativity was interpreted as a mechanism that improved the control
of metabolic rate. In fact, the analysis by Hofmeyr & Cornish-Bowden showed
that varying the degree of cooperativity of the inhibition of an enzyme in a
simulated system made little difference to the control of the metabolic rate,
but resulted in better homeostasis of metabolite concentrations in response to
perturbations of the system as cooperativity increased. They were also able
to show that uncompetitive inhibition is necessary to make the control pat-
tern of mammalian serine synthesis (see above) work effectively (Hofmeyr &
Cornish-Bowden, 1996).
These are merely selected examples of how the application of new modes
of analytical thinking can increase our understanding of the way metabolism
functions and can lead to predictions that are different from those derived using
axioms such as the existence of rate-limiting steps. However, they are sufficient
to illustrate a number of issues:
(1) As already stated, these methods of systems analysis contain no theory of
how the regulatory and control mechanisms of metabolism are or should
be constructed; they are frameworks for deducing the consequences of
particular configurations of enzymes and mechanisms.
(2) The analyses point at features that might be generally expected in metabolic
pathways, whilst at the same time they allow the deduction of feasible
circumstances under which such generalisations would not be true. In other
words, there is always demonstrable scope for exceptions that preclude
any of the results, such as the flux summation theorem, being presented
as invariant laws of metabolism. However, there are aspects that can be
seen to be consistent with other concepts in biology: the tendency for flux
control to be shared between enzymes so that the values of flux control
coefficients are small can be seen as a likely result of maximising the
fitness of metabolism through natural selection subject to limitations on the
amount of protein that can be committed to enzymes (Kacser & Beeby,
1984; Heinrich & Schuster, 1998; Klipp & Heinrich, 1999). The link with
the concept of dominance in genetics has been mentioned above.
(3) A fundamental weakness of teleological explanations is evident: if they
are to contribute to understanding, the system-level function fulfilled by
a component must be correctly identified. In biology, however, the func-
tions of a component at this higher level (as distinct from the activities of
