On 22 Aug 2000, at 8:09, Petr Kuzmic wrote:
> Herbert M Sauro wrote:
> [...]
> > One thing his [David Garfinkel's]
> > efforts taught me was that simulation in a vacum of formal
theory is almost
> > useless, unless perhaps you're an engineer in which case
you might only be
> > interested in input and outputs. But as a scientist one needs
to understand
> > what's going on inside and for that one needs some sort of
organising
> > framework, and for me that turned out to be MCA/MCT.
> [...]
>> I am always trying to understand more about the important work
> that's been done by people belonging to the Metabolic Control
> Theory/Analysis school of thought. After having read Herbert's
> statement above, I am now wondering exactly in what sense does
> MCA contribute to a greater "understand[ing of] what's going on
> inside". I'd like to contrast what Herbert wrote with the
> following statement, taken from Athel's FAQ page:
>> "Metabolic control analysis tends to treat the kinetic
> properties of the component enzymes as a black box. Some authors
> have been very critical of this, suggesting that shedding light
> on mechanism is the only reason for studying kinetics in the
> first place. [...] Studies of biochemical kinetics have been
> dominated for nearly a century by an interest in molecular
> mechanisms, but for understanding how whole pathways behave it
> has been found useful to decrease the emphasis on mechanism.
> [...]"
>> Am I missing something? Isn't this "black box" approach
> focusing at "inputs and outputs" and not paying too much
> attention to "what's going on inside"? I believe that every step
> in Garfinkel's simulations was formulated in terms of the
> underlying *mechanism*.
It depends on your level of description. What MCA says, is that
to understand how a whole pathway behaves you don't need to
go down to the level of elementary steps of each enzyme's
mechanism. What matters are the elasticity coefficients of each
enzyme. These do, of course, depend on the enzyme kinetic
mechanism, but if we have an empiric description of the
elasticities that realistically determines their values under a
range of applicable conditions, this is sufficient for MCA of the
pathway. We don't need mechanistic detail, because this level of
detail is unnecessary to describe the pathway behaviour at a
higher level.
> Somebody has asked previously in this thread why isn't MCA/MCT
> more represented in textbooks. Could it be that people
> (including myself, I must admit) are not ready to give up the
> emphasis on "understanding" in the sense of "mechanisms" (i.e.,
> "*what* is going on inside") ?
I strongly disagree that MCA requires us to give up an emphasis
of understanding in the sense of mechanisms. It just depends at
what level you see these mechanisms. As pointed out above,
elementary steps of enzymes might not be a suitable level of
description for analysing a whole pathway. Likewise, when
analysing larger pathways, it may be suitable to aggregate whole
sequences of enzymic reactions into functional units or blocks,
as exemplified by modular or top-down MCA. Going the other
way, you may just as well to control analysis within an enzyme
mechanism, where indeed the "reactions" would be elementary
steps. MCA has been applied at all these level in theory and
experiment.
The important thing is thus to find a level of aggregation that
makes intelligent analysis of your system possible: not too
coarse (too little interactions) and not too fine (too many
components). The "mechanisms" are then defined by the
interactions between the system components at _that_ level of
description, Finding this level of aggregation, on the other hand,
is by no means trivial...
But I would certainly not venture to describe the regulation of
glycolysis at the level of quantum mechanics ;-)
Johann
--
Johann M. Rohwer
Dept. of Biochemistry, Univ. of Stellenbosch
Private Bag X1, 7602 Matieland
SOUTH AFRICA
Tel.: +27-21-8085843
Fax: +27-21-8085863
E-mail: jr at maties.sun.ac.za
WWW: http://www.sun.ac.za/biochem/
--
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