Guy Brown wrote:
>What effects will totally inhibiting the activity of a particular enzyme
>have on the
>steady-state fluxes of a system? Can we say anything interesting or
>useful about this?
>
There's at least 3 possibilities, 2 of which pose problems for making a
prediction of the consequences before the event.
1. The organism responds by induction of another enzyme that takes over the
role. e.g. there is no doubt that the glycolytic pathway is used in
potatoes, but deleting pyruvate kinase gives virtually no observable
phenotype. It seems that a PEP phophatase takes over the role, and the loss
of ATP production is not significant. This is presumably a specific
adaptation in plants, because loss of pyruvate kinase is not generally so
benign.
2. There are other routes through the network that can reach the required
end-points. This can be analysed in advance (e.g. with the elementary modes
analysis that we have developed with Stefan Schuster & Claus Hilgetag), and
we can estimate how fluxes would have to change in the network for it to
cope. As Jannie pointed out in his reply, there would be 'blind-ended'
pathway fragments that would reach equilibrium. Nevertheless, this case
could be tractable, perhaps along the lines Guy suggested.
3. Steady state breaks down and intermediates start to accumulate. Which
intermediates could be extrapolated from a finite change analysis for the
metabolite concentrations. It's not uncommon for some metabolites to rise
to tens or hundreds of mM. In this case, previously untested effects come
into play e.g. other enzymes that have a very low affinity for the
metabolite now strat to metabolise it in significant amounts (and are
partially inhibited as a result) to form novel metabolic products; or the
intermediate leaks across cell membranes and a new steady state is
established at higher intermediate concentrations. These types of effect
are one of the reasons why the detailed symptoms of metabolic diseases are
not necessarily easily predictable from knowing the identity of the affected
enzyme.
David Fell
=========================================================
David Fell,
School of Biological & Molecular Sciences,
Oxford Brookes University,
Oxford OX3 0BP, Tel. +44 (0)1865 483247
UK FAX +44 (0)1865 484017
daf at bms.brookes.ac.uk
See my book at: http://www.portlandpress.co.uk/books/isbn/185578047X.htm
