16 - Friday, October 16th, 2008 Biochemistry 405 Lecture #8...

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1 Friday, October 16 th, 2008 Biochemistry 405 – Lecture #8 Kane Hall 130 10:30- 11:20 am Lecturer: Wim Hol Slide Set #1
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2 Kinetics, Enzyme Inhibition and Inhibitor Design Outline I. Why and how kinetics? II. Kinetics of reactions - Meaning of velocity. - Enzyme Reaction Kinetics - Michaelis-Menten Equation. - Lineweaver-Burk plot. III. Inhibition of Enzymes. - Competitive. - Uncompetitive IV. Drug Design
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3 - To establish the speed by which a reaction is catalyzed by an enzyme or ribozyme – pure out of curiosity to understand how the enzymes and ribozymes in living organisms perform their functions in a timely fashion; - To see how catalysis is affected by factors like pH, ionic strength, temperature, etc. – out of curiosity, such as to understand how different organisms are adapted to colder and warmer environments; - To discover the substrate specificity of enzymes and ribozymes; - To figure out the mode of action of “inhibitors” – usually classified as “competitive’, “non-competitive” and “uncompetitive”; - To understand the sometimes accelerating effects of non-substrate molecules on the catalytic efficiency – in particular the so-called “allosteric effectors”; - To probe in detail the catalytic mechanism of a reaction , not only by varying the substrates but also the biocatalyst itself, by e.g. protein engineering techniques and varying precisely specific side chains. Why kinetics? Some fundamental scientific reasons
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4 - To establish the speed by which a reaction is catalyzed by an enzyme or ribozyme – to see if a reaction is useful for industrial reactors to convert compounds into more valuable compounds; - To see how catalysis is affected by factors like pH, ionic strength, temperature, etc. – to obtain robust enzymes for bioreactors ; - To discover, and modify, the substrate specificity of enzymes and ribozymes for use in bioreactors, and also as tools in biochemical and medical research; - To discover enzyme or ribozyme inhibitors in drug discovery processes , where sometimes thousands, or a few million, compounds are tested against a potential protein or RNA drug target in so-called “high-throughput screens”; -For lead optimization in drug development , i.e. optimize “leads” discovered in screens to become high affinity inhibitors with good “drug-like properties”. Why kinetics? Some practical reasons
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5 Basic Kinetic Measurements A P k 1 Step 1. Write the reaction with the k's (rate constants) indicating the process. d[A]/dt = -k 1 [A] d[P]/dt = k 1 [A] Step 2. Write how the compounds change with time: So, d[P]/dt = -d[A]/dt Velocity of the reaction is v and, v = d[P]/dt = -d[A]/dt = k 1 [A] (Units of k 1 = sec -1 ) [P] [A] [A] 0
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6 1. Use constant amount of enzyme, [E T ]. 2. Measure amount of P formed as a function of time with several initial
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This note was uploaded on 06/03/2010 for the course BIOL BIO 101 taught by Professor Drumheller during the Spring '10 term at University of Washington.

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16 - Friday, October 16th, 2008 Biochemistry 405 Lecture #8...

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