Solution Set 5_2011

Solution Set 5_2011 - Bioc100B Winter 2011 Rubin Solution...

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Bioc100B Winter 2011 Rubin Solution Set #5 Due Tuesday, February 15 th 4:00 P.M. 1) Recall that the active site of HIV protease contains two aspartic acids. The pKa values for these acids are tuned in the protein such that one is in the deprotonated state. a) Propose a mechanism for acid/base catalyzed hydrolysis of a peptide bond by this important enzyme. Use the following picture as the beginning (ES complex) state and draw the tetrahedral intermediate and product states. Be sure to indicate movement of electrons with arrows and all formal charges.
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Bioc100B Winter 2011 Rubin b) The serine protease mechanism (e.g. chymotrypsin, etc.) is often characterized as covalent catalysis. Would you characterize the acid protease mechanism as covalent catalysis? What is the key difference between this mechanism and the serine protease mechanism? The acid protease mechanism is not considered covalent catalysis because there is no covalent intermediate formed between the enzyme and the substrate. In serine proteases, the nucleophilic serine attacks the substrate and forms an acyl intermediate that is then eliminated by water. In the mechanism above, the water and carbonyl are activated by acid/base chemistry so the water directly hydrolyzes the substrate. 2) Leupeptin is a common protease inhibitor. Here is its structure:
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Bioc100B Winter 2011 Rubin Use the structure of trypsin bound to leupeptin (PDB ID: 1JRT) to answer the following: a) Explain the mechanism of leupeptin inhibition. Leupeptin is a peptide mimic that contains a C-terminal aldehyde instead of a carboxylic acid. The aldehyde carbonyl can still be attacked by the catalytic serine but there is nothing to eliminate from the resulting hemiacetal. While the hemiacetal can be readily
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Solution Set 5_2011 - Bioc100B Winter 2011 Rubin Solution...

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