I am Steve Benkovic and I hold the Eberly Chair in Chemistry at Penn State.
To begin, I'd like to update my previous lecture on Biological Catalysis.
I plan to review sufficient background material to serve as
a basis for my discussion of the recent advances that have further informed this topic.
The illustration presents the reaction cycle for DHFR,
more about that later.
A feature of enzymes is the rate accelerations,
relative to their reaction, solution,
counterpart, with their ratios being in the millions.
I wish to explore three questions.
They are, how do enzyme motions and fluctuations impact catalysis?
We know that the structures of enzymes are dynamic,
but how do these dynamic features actually impact catalysis?
Are the time scales for
protein structural changes and the enzymatic catalytic cycle similar?
We will review the time scales for protein motions in the later slide.
And the third question is,
how are electrostatics modulated in enzyme active sites in conjunction with catalysis?
Such interactions long have been implicated in catalysis,
but how are they optimized?
Remember, we still view catalysis in terms of transition state theory.
The key being selective stabilization of the transition state,
lowering the free energy barrier that,
in turn, translates into an increased reaction rate.
Our paradigm is dihydrofolate reductase, DHFR.
The reaction it catalyzes is the conversion of dihydrofolate,
shown in the box,
through the agency of NADPH,
to give you reduced tetrahydrofolate,
H4F and NADP + product.
This transformation maintains levels
of tetrahydrofolate required for biosynthesis of purines,
pyrimidines and amino acids that are key for cellular viability.
Consequently inhibitors have been found such as
methotrexate and trimethoprim for treating cancer,
bacterial infections and rheumatoid arthritis.
With this enzyme, clearly being the pharmacological target.
Our work in DHFR has been accomplished through many collaborations.
We have an excellent network of collaborators whose names are listed in this slide.
References to our joint publications can be found at the end of this lecture.