The Control Analysis of Signal Transduction - Systems Biology of Metabolic and Signaling Networks - page 38

communicate with each other through their effects on the enzyme's catalytic rate, or
where a product of a metabolic pathway interacts allosterically with an enzyme near
the beginning of the pathway. More indirectly, a metabolite may activate a protein
kinase that phosphorylates and thereby inactivates an enzyme in the pathway which
affects the concentration of a metabolite, or the metabolite may activate a whole
chain of signal transduction reactions and influences the expression of the gene
encoding one of the enzymes in the pathway that control the concentration of the
metabolite. The latter two cases are examples where signal transduction is involved.
As we mentioned above, it is the looping of the interactions that causes the whole to
differ from the sum of the parts. In our previous analyses we have called systems
engaged in such looping “democratic” control systems. Even though in principle
the DNA level encodes the other levels, the expression of the encoded information
often requires the involvement of those other levels, again causing regulatory
looping, at least in the “democratic” cases that are common to living systems
(Westerhoff et al. 1990 ; Kahn and Westerhoff 1991 ).
More, in general, processes in living organisms engage in such regulatory
looping, if not through metabolic, signal transduction, or classical gene expression
networks (Westerhoff et al. 1990 ), then through RNAs [sense, anti-sense, or micro
(Hendrickson et al. 2009 )], or through dynamic ultrastructure (Westerhoff
et al. 1990 , 2009a ; van Driel et al. 2003 ). In order to grasp the circular or spiralling
causality that ensues from the looping (Boogerd et al. 2005 ; Westerhoff
et al. 2009b ), one needs to look at the operation and integration of several simulta-
neous processes, as functions of time or all parameters involved. Since the sum of a
negative and a positive effect may be important, the experiments need to be precise
and the analysis quantitative (Westerhoff and Palsson 2004 ). It is in learning to
appreciate these concentrations of the various levels of cell functioning that systems
biology should help. In this chapter we shall focus on how metabolic control
analysis has done this for signal transduction.
3.2 Control Analysis
Biochemists have used various investigative methods for the identification of what
they referred to as rate-limiting enzymes. These enzymes were envisaged mostly to
reside at the beginning of a pathway and were supposed to catalyse essentially
irreversible reactions (i.e. reactions with very large equilibrium constants). In an
often pronounced but for linear pathways obviously erroneous concept, the rate-
limiting enzyme operated at a lower velocity than the other (downstream) enzymes
in the pathway and therefore “controlled” the pathway. If one wanted to increase
the throughput of the pathway it was supposed then to suffice to increase the amount
of that enzyme only. For many decades these ideas concerning the control of
pathways were presented, and experimental observations were interpreted so as to
fit these generalisations (Thomas and Fell 1998 ). It was not until various individuals
and groups began to criticise these concepts, began to examine where they came