disease. As such, a tron Type 2 diabetes arug metformin, which acts indirectly to inhibit gluconeogenesis in the liver. You are a research biochemist who would like to develop new drugs that act to directly inhibit gluconeogenesis. You have just gained access to a library of thousands of small molecules of unknown activity, and you would like to identify lead compounds that have specific inhibitory activity against steps in the gluconeogenesis pathway. (a) Your first approach is to reconstitute the initial set of bypass reactions that convert pyruvate into PEP in order to screen for inhibitors of enzymes specific to gluconeogenesis. Which enzymes do you need to purify, what cofactors and allosteric effectors do they require, and which reactants do you need to add to reconstitute the reactions for the first bypass? Which intermediates and products are generated? (b) What additional steps and enzymes are required in liver cells but are unnecessary in your in vitro reconstitution? (c) Your screen resulted in two lead compounds that are reversible inhibitors of each reaction. You determined that the lead compound 1 is a competitive inhibitor of the first reaction in the bypass, while lead compound 2 is a noncompetitive inhibitor of the last reaction in the bypass. Draw the curves for the velocity of each reaction as a function of substrate concentration in the presence of each inhibitor on the graphs below. Label the x-axis of each graph (no need to indicate units).
disease. As such, a tron Type 2 diabetes arug metformin, which acts indirectly to inhibit gluconeogenesis in the liver. You are a research biochemist who would like to develop new drugs that act to directly inhibit gluconeogenesis. You have just gained access to a library of thousands of small molecules of unknown activity, and you would like to identify lead compounds that have specific inhibitory activity against steps in the gluconeogenesis pathway. (a) Your first approach is to reconstitute the initial set of bypass reactions that convert pyruvate into PEP in order to screen for inhibitors of enzymes specific to gluconeogenesis. Which enzymes do you need to purify, what cofactors and allosteric effectors do they require, and which reactants do you need to add to reconstitute the reactions for the first bypass? Which intermediates and products are generated? (b) What additional steps and enzymes are required in liver cells but are unnecessary in your in vitro reconstitution? (c) Your screen resulted in two lead compounds that are reversible inhibitors of each reaction. You determined that the lead compound 1 is a competitive inhibitor of the first reaction in the bypass, while lead compound 2 is a noncompetitive inhibitor of the last reaction in the bypass. Draw the curves for the velocity of each reaction as a function of substrate concentration in the presence of each inhibitor on the graphs below. Label the x-axis of each graph (no need to indicate units).
Biochemistry
6th Edition
ISBN:9781305577206
Author:Reginald H. Garrett, Charles M. Grisham
Publisher:Reginald H. Garrett, Charles M. Grisham
Chapter24: Lipid Biosynthesis
Section: Chapter Questions
Problem 23P
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Transcribed Image Text:disease. As such, a frontline treatment for Type 2 diabetes is the drug metformin, which acts indirectly
to inhibit gluconeogenesis in the liver. You are a research biochemist who would like to develop new
drugs that act to directly inhibit gluconeogenesis. You have just gained access to a library of thousands
of small molecules of unknown activity, and you would like to identify lead compounds that have specific
inhibitory activity against steps in the gluconeogenesis pathway.
(a)
into PEP in order to screen for inhibitors of enzymes specific to gluconeogenesis. Which enzymes do
you need to purify, what cofactors and allosteric effectors do they require, and which reactants do you
need to add to reconstitute the reactions for the first bypass? Which intermediates and products are
generated?
Your first approach is to reconstitute the initial set of bypass reactions that convert pyruvate
(b)
vitro reconstitution?
What additional steps and enzymes are required in liver cells but are unnecessary in your in
(c)
You determined that the lead compound 1 is a competitive inhibitor of the first reaction in the bypass,
while lead compound 2 is a noncompetitive inhibitor of the last reaction in the bypass. Draw the curves
for the velocity of each reaction as a function of substrate concentration in the presence of each inhibitor
on the graphs below. Label the x-axis of each graph (no need to indicate units).
Your screen resulted in two lead compounds that are reversible inhibitors of each reaction.
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