1973: The Control of Flux by Kacser and Burns
http://www.ncbi.nlm.nih.gov/pubmed/7672373
Excerpt from the introduction:
"The literature on Control is distinguished by a vast quantity of detailed
information on particular systems and very little discussion on general
problems. There also appears to be confusion, or at least,
disagreement � disagreement on definitions, on concepts, on criteria and on
methodology. There are probably several reasons for this. Firstly, we are
concerned with the properties of very complex systems, complex
in the sense that there are many different types of component which interact
in a variety of ways and hence can display many modes of behaviour.
Secondly, there is no established general idea of control of
biochemical systems. There are bits of theory but no comprehensive theory.
One bit of theory is usually represented as metabolic maps. These maps give
information on the structure of the system: they tell us about
transformations, syntheses and degradations and they represent the
molecular anatomy. They tell us �what goes� but not �how much�. Another bit
of theory is called enzymology. We have many data on individual enzymes,
their kinetics, inhibition characteristics, molecular
structure and some theory of catalysis. All these give us elementary
functional information.
It is an obvious step to combine the two parts. And here we immediately come
to a stop since, as anybody who has tried this realises, we end up with a
large set of simultaneous non�linear equations for which
there is no explicit solution (Appendix A). We can, of course, use computers
to solve particular cases. In the hands of an expert such simulation can
lead to insight (e.g, see Garfinkel, 1971 ). More often it
will simply confirm that our assumptions about the system are correct. In
either case, however, it cannot yield a general theory of control.
Discussions on �control� or �regulation� usually centre on the question of
which enzymes are controlling the flux in a pathway and suggest experimental
means of identification. In the absence of a general theory
of control, the basis of such experimental identification will remain
obscure, being at best intuitively plausible. (See, however, the excellent
review by Rolleston, 1972.) The measurements which are made for
this identification include the levels of enzymes and of pools, inhibition
characteristics of enzymes and feedbacks, the levels of inhibitors or
activators, the measurement of fluxes and their changes under a
variety of conditions. The discussions suggest that �controlling enzymes�
can be identified as those which satisfy a number of different criteria (e.g
see Chance, Holmes, Higgins and Connelly, 1958; Newsholme
and Gevers, 1967, Scrutton and Utter, 1968) which are rather directly
related to the measurements. It is, however, not clear in what way diverse
criteria are related or how consistent they are with one
another. But principally, what appears to be lacking are agreed definitions
of the various aspects of control to which these criteria could be applied.
The establishment of the necessary definitions and their inter-relations
requires a rigorous theoretical approach."
Attached is a slightly altered reprint of the original paper that started
the develpoment of "Metabolic Control Analysis".
Matti