Benno, I have to take you up on this. You wrote
> It seems to me that the central statement of the metabolic
> control analysis theory, that control is shared between steps, is
> moderately falsifiable. If a large number of pathways were analyzed
> and all would have a single step with control coefficient 1.0 this
> would falsify the theory. What if roughly half of all pathways would
> have a single rate controlling step? It seems to me that the best is
> to take Hans Westerhoff's definition: MCA is indeed a tool and the
> theory it is based upon is the MCA theory. As long as it works
> something about it is right.
You are replacing one hypothesis (dogma?), namely, each pathway must
have a rate-limiting step, with another, namely, control must be shared
between steps (in fact, you imply the stronger statement of "no step can be
rate-limiting"). Yes, I know that you said "is shared" but your argument implies
"must be shared". MCA only says "there is nothing inherent in a reaction
network that requires one step to be rate-limiting; in general the control of flux
can be shared amongst the steps in the system"; if and how control is shared
must be calculated. So, there is nothing in MCA which says that a large
number of pathways cannot each have a single rate-controlling step. On the
other hand, finding such a large number also proves nothing (Yea, Popper).
In this regard MCA certainly is not a theory. The competing "theories" would
be 1. There must be a rate-limiting step versus 2. There cannot be rate-limiting
step; control must be shared. As it has done so successfully before, MCA is
the tool with which it can be shown that the truth lies in between.
I think we must be very careful to avoid creating a new dogma, i.e. MCA
shows that flux-control must be shared so that a rate-limiting step cannot exist.
Remember that the results of MCA competely depend on the definition of the
system. In principle I can define each step in the metabolic network as a
pathway and then (if there is no channelling or other complicating
phenomena, Douglas :-) the flux-response coefficient of each enzyme will be
one on its own flux. I can even regard each elementary step in each reaction
mechanism as a pathway so that all flux-control coefficients are one.
I regard the central statement of MCA as CE=I, or better C=E^(-1), i.e. that all
control coefficients can be expressed in terms of elasticity coefficients (and if
C refers to independent variables only, vice versa). More generally, MCA
shows that systemic (emergent?) properties such as flux and concentration
control can expressed in terms of local properties of the individual steps in the
system, measured as elasticity coefficients. In turn, each elasticity coefficient
can be understood in terms of a thermodynamic contribution and a kinetic
contribution, thereby creating the essential link to classical bio-energetics and
enzyme kinetics.
The summation theorems have played an important role in the development of
a new way of thinking about reaction networks and in our battle with the "rate-
limiting step", but they are not only what MCA is about. The connectivity
theorems are far more important in that they provide the link between control
and elasticity, provide the basis for the concept of internal responses, etc.
Jannie
Prof. Jannie Hofmeyr Tel: +27 21 808 5842
Dept. of Biochemistry Fax: +27 21 808 5863
University of Stellenbosch e-mail: jhsh at maties.sun.ac.za
Private Bag X1
Matieland 7602
South Africa
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