Since Blackman [1] proposed the concept of the 'rate-limiting
step' in 1905, it has dominated the approach to understanding
the control of metabolic pathways. For example, it was endorsed
in Krebs' concept of 'pacemaker' enzymes [2], which he saw as
the target sites for hormone and drug action on metabolism.
Even though the theory of Metabolic Control Analysis [3,4] has
since shown that control can be distributed over many steps in a
pathway, and that the degree of control of any given step can be
quantified by its flux control coefficient, qualitative explanations
of how a pathway can be controlled have not been greatly
affected. Indeed, although Metabolic Control Analysis has been
increasingly adopted in metabolic biochemistry, and experiments
have confirmed both that control is generally distributed [5] and
that genuinely rate-limiting enzymes are rare, it has also
legitimized the concept that an enzyme that responds to some
external controlling factor can be an agent of metabolic control
provided the enzyme has a finite flux control coefficient. However,
we shall cite arguments that such mechanisms cannot be responsible
for large changes in metabolic flux. On the other hand,
recent theoretical developments arising from Metabolic Control
Analysis do allow us to characterize how large changes in
metabolic flux could be implemented; they can only be achieved
with minimal disturbance ofmetabolite concentrations and fluxes
in other pathways by co-ordinated changes in the activities of
many of the enzymes in the pathway, and this can be shown to
be a common mechanism of control.
Related experimental and theoretical evidence also contradicts
the view that regulatory enzymes exhibiting allosteric properties
are effective agents for control of metabolic flux. Our conclusion
is that their more significant role is in homoeostasis. In consequence,
different approaches are needed to both the study and
explanation of metabolic control.