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Perfect enzymes (WAS: Phosphofructokinase controls...)

Petr Kuzmic pkuzmic at biokin.com
Fri Jun 9 09:37:00 EST 2000



Athel Cornish-Bowden wrote:

> [...] Is it really true that people
> who apply transition-state theory to enzymes assume equilibrium binding
> (who? when? where?), because I don't get much sense of this when I read
> Alan Fersht, for example.

I think Guy *might* have referred to the fundamentals of the Transition
State Theory.  I don't have my Eyring papers handy, or his textbook, but
if I remember correctly the Transition State Theory includes a term
called

	   /
	  =
	 /
	K

or "capital K, double dagger" which is defined as a *thermodynamic
equilibrium constant*.  So, for example, a Transition State Theory
applied to a bimolecular reaction involves a term corresponding to the
*thermodynamic equilibrium constant* for the transition state [AB]**.  
At the same time, the transition state itself is presumed to have *zero
lifetime*.  

In other words, the Transition State Theory is wonderfully
self-contradictory in its very essence (it contains an *equilibrium*
constant for something that has zero lifetime).  The fact that TST has
been successfully applied to so many phenomena in chemistry, physics,
and biology is a testimony to the power of Eyring's intellect.  However,
it should be applied and /interpreted/ very carefully and with proper
respect to the contradictions it contains.  I always thought of TST as
an "abstract"  or "mathematical" theory, rather then trying to interpret
it "literally" as some people involved in the study of enzymes.

Along the lines of Guy's comment: It is quite likely that certain
writers applying the Transition State Theory to enzyme catalysis and
inhibition ("enzyme active site is somehow magically complementary to
the structure of the Transition State"; "rationally designed de-novo
inhibitors should mimic the structure of the Transition State") were
unaware of all features of the original TS theory.  This is especially
true for the Rational Drug Design movement in the 1980s, when people
tried to manufacture pharmaceutically effective inhibitors as purported
analogs of the elusive "transition state structure".  I think it is
important that this was once perceived as one of the leading
methodologies in a multi-billion dollar industry.

	-- Petr

_____________________________________________________________________
Petr Kuzmic, Ph.D. * BioKin, Ltd. * Consulting & Software Development
http://www.biokin.com * (608) 256-4790 * (608) 256-1269 FAX






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