Hi there, danielhduffysr:
While not answers to your question per-se, you might find the
following of interest, nonetheless. From a website titled "Metabolic
Control Analysis", Copyright 1995 by Pedro Mendes, pjm@ncgr.org
http://gepasi.dbs.aber.ac.uk/metab/mca_cc.htm
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In the past many authors referred to some enzymes as rate-limiting (or
bottlenecks, or even pace-makers). These enzymes were mostly after a
branch point and catalyse essentially irreversible reactions (with
very high equilibrium constants). The thought was that these enzymes
operated at a lower velocity than the others (downstream) in the
pathway and so they "controlled" the pathway; if one wanted to
increase the throughput of the pathway it would be enough to increase
the amount of that enzyme. Applying the MCA reasoning, such
rate-limiting enzymes must have a flux-control coefficient equal to 1,
and consequently (see equation 3) all other enzymes have flux-control
coefficients of 0. While this is theoretically not impossible, it is
very improbable and most experimental studies of enzyme
over-expression by cloning have revealed that large increases of
enzyme concentrations are not accompanied by equivalent increases in
pathway flux. Furthermore, while one is increasing the amount of the
hypothetical rate-limiting enzyme, its control over the pathway flux
would decrease until it eventually approached 0 (as is illustrated in
figure 1. The moral is that one must be extremely careful to use the
expression "rate-limiting" as enzymes are almost never such.
A more reallistic picture of the way that a pathway flux is controlled
by its enzymes emanates from the flux-control summation theorem
(equation 3). The magnitude of the flux-control coefficients can be
seen as a percentage of control exerted by the individual step over
the flux of interest. Control is shared between all enzymes in
different proportions.
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Also of interest, this is from a site titled "Fundamentals of Enzyme
Kinetics",
By: Athel Cornish-Bowden
http://bip.cnrs-mrs.fr/bip10/mcap.htm
Q: Much of modern biotechnology is based on the premise that
identifying the enzymes that catalyse the rate-limiting steps in
pathways leading to desirable products, cloning these enzymes and then
overexpressing them in suitable organisms will allow greatly increased
yields of the desirable products. What implications does the analysis
of this chapter have for such a strategy?
A: A method based on overexpressing rate-limiting enzymes can only
work if rate-limiting enzymes exist and remain rate-limiting when
their activities are increased. Metabolic control analysis suggests
not only that rate-limiting enzymes do not exist, but also that the
fux control coeffcients of any enzyme will tend to decrease when its
activity in the system is increased. Thus the strategy outlined cannot
work. For more discussion of this point, see Cornish-Bowden (1995b),
and for a practical example, see Niederberger et al. (1992).
Hope this helps.
Google search terms:
rate-limiting metabolic enzymes
rate-limiting factors human metabolism |
