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Unformatted text preview: ill and Increase affinity Structure leads to
“Targeted Combinatorial
Chemistry” to fill the
grooves optimally by
adenosine derivatives Surface of L. mexicana*
GAPDH with NAD bound. Hydrophobic Groove:
Fill and Increase affinity
AND selectivity Note: Leishmania mexicana GAPDH is ~77% sequence identical to Trypanosoma brucei GAPDH and all residues in the region of
interest are identical in these two pathogenic “Trypanosomatids”. So these two enzymes are used interchangeably. Inhibition of L. mexicana GAPDH by Adenosine Derivatives
Crystal structure of
L. mexicana GAPDH
with “NMDBA”
Clearly visible is the selectivity
cleft between Met39 and Val206*
(from the neighboring monomer),
with the dimethoxybenzamido
group of NMDBA inserted into it.
The surface has been color coded
according to the electrostatic
potential. Red represents negative
potential and blue positive
potential. “NMDBA”: A new inhibitor with 105fold (!) affinity gain compared
to the initial inhibitor adenosine.
(You don’t need to know the chemical formula of NMDBA) Stephen Suresh Antonysami, Michael Gelb and coworkers, Wes Van Voorhis, Fred Buckner, Christophe Verlinde Useful Problems at end of Chapter 12, 3rd Ed VVP:
1, 5, 10, 14, 19, 25
Useful Problems at end of Chapter 12, 4th Ed VVP:
1, 11, 13, 19, 27
Useful Problems at end of Chapter 8, 7th Ed Stryer:
1, 5, 6, 14, 20ac, 24 What you have to know about Enzyme Kinetics,
Equations and Plots
0. You do not need to know the derivation of any equation, but you need to know:
1. Michaelis Menten Equations
(For three cases: without inhibition, with competitive inhibition, and with
uncompetitive inhibition as discussed on the slides).
2. The definitions of Ki and α for competitive inhibition, and of Ki’
uncompetitive inhibition. and α’ for 3. The LineweaverBurk equations.
(For the same three cases as mentioned under point 1 above).
4. The definition of KM i.e. the Michaelis constant.
5. The MichaelisMenten graph and the equations mentioned on the slide
"Summary of special positions on the Michaelis Menten graph".
6. The LineweaverBurke plots for no inhibition, competitive inhibition and
uncompetitive inhibition cases – including the equations for the slope of the lines
in the case of competitive inhibition and for the point of intersection on the yaxis
in the case of uncompetitive inhibition on the LB plots....
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 Fall '08
 HOL
 Biochemistry

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