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thymidine kinase

Giovanni Maga maga at vetbio.unizh.ch
Tue Nov 7 05:51:16 EST 1995

In article <47bphf$10uc at usenetw1.news.prodigy.com>, FYDS16A at prodigy.com
(Michael Ostrander) wrote:

> To correct a common misunderstanding, ACV does NOT inhibit the HSV 
> thymidine kinase (TK). ACV is an alternative substrate for the enzyme and 
> undergoes preferential phosphorylation by viral TK but not by cellular TK.
>   The resulting ACV monophosphate is then phosphorylated to the 
> triphosphate. The ACV triphosphate is itself an alternative substrate for 
> DNA polymerases resulting in incorporation into viral DNA and termination 
> of DNA elongation.
> Mike 

This is correct from the point of view of the mechanism of action, but ACV
is commonly referred as a substrate inhibitor of viral TK, in order to
distinguish it from non-substrate inhibitors like the N2-phenylguanines.
This definition comes from the fact that ACV competes with the viral TK
for its natural substrate thymidine (thus acting as a competitive
inhibitor when assayed in the presence of labelled thymidine). The
definition of competitive inhibitor in its general formulation does not
distinguish between substrate and non substrate inhibitors (i.e. between
false substrates and alternative substrates), being simply derived from
the effect of the inhibitor on the Km of the enzyme for the natural
substrate, thus every alternative substrate can be viewed (correctly) as a
competitive inhibitor. 
The antiviral effect is (as you coorectly pointed out) mediated by ACVTP
that acts as an alternative substrate for the HSV pol. It is also
incorporated by the cellular pols, even if to a lesser extent. The same
problem, however, is faced by other antiherpetic drugs such as BVdU or
IdU, that are activated as well by the viral TK (albeit with different
efficiencies), but also by the cellular TK, resulting in cytotoxic

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