At 13:13 16/01/02 +1000, Len Pattenden wrote:
>however I have never read
>*how* MCA can be used in drug design and it kinda escapes me. Perhaps this
>is a simple thing to point out.
An example is the comparison between the action of the potential drug
5-deazaacyclotetrahydrofolate on its target, the enzyme glycinamide
ribonucleotide transformylase (of purine biosynthesis) and its impact on
the flux of de novo purine biosynthesis in a human T-cell leukaemia
line. (G K Smith et al in 'Control of Metabolic Processes ' ed A
Cornish-Bowden & M-L Cardenas, Plenum Press, 1990. Because of the low flux
control coefficient of this enzyme (0.01), the IC50 on the enzyme activity
is very much lower than the IC50 on the flux. Nevertheless, you can
eventually get substantial inhibition of the flux - though by that time the
enzyme is only 2% active and the intracellular drug level is 10 times the
concentration needed to produce an equivalent inhibition of the
enzyme. The enzyme is still being studied as a potential drug target.
I've got a Power Point slide of this data - I need to think about how to
make the graph available to the newsgroup
Athel is right that the flux control coefficient itself is not sufficient
to predict all this behaviour, though low values do correlate with
significant differences between the in vitro effect on the enzyme and the
effect on in vivo flux. The flux control coefficient of glycinamide
ribonucleotide transformylase was estimated at 0.01. My guess is that it
is still a better target than a feedback-inhibited enzyme with an
equivalent flux control coefficient.
David
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Prof David Fell, School of Biological & Molecular Sciences,
Oxford Brookes University, Oxford OX3 0BP, UK
Tel. +44 (0)1865 483247 FAX +44 (0)1865 484017
Mob: +44 (0)7786 515729 http://mudshark.brookes.ac.uk/
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