Chapter10 - Chapter 10 Enzyme regulation Aspartate...

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Aspartate transcarbamoylase Hemoglobin Isozymes Covalent modification Activation by proteolysis: proenzymes Chapter 10: Enzyme regulation
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A case study of aspartate transcarbamoylase and allosteric inhibition -catalyzes the first committed step in pyrimidine biosynthesis Feedback inhibition: How does this work?
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PMB reacts with free cysteine side chains -in ATCase this dissociates the enzyme into two different subunits We start our investigation of ATCase here:
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PMB treatment of ATCase reveals two subunits -gradient ultracentrifugation “r” is a dimer (17 kd each), “c” is a trimer (34 kd each)
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The structure of ATCase 2c 3 + 3r 2 = c 6 r 6 (PMB displaces Zn 2+ )
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Where is the active site? -use a bisubstrate analog aspartate carbamoyl phosphate
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PALA bound to ATCase -it binds with contacts on two c chains
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PALA bound to ATCase results in a structural rearrangement 15 10 PALA converts ATCase from the T to the R state.
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ATCase structural rearrangement affects substrate affinity Higher Km (lower affinity) lower Km (higher affinity) “Cooperativity”
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This is great, but what happened to CTP feedback inhibition? -CTP binds the T state, reduces the transition to the R state
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ATP increases ATCase activity by binding the R state. Some Terms: Allosteric affecter (both ATP and CTP) Allosteric activator (i.e. ATP) Allosteric inhibitor (i.e. CTP) Homotropic effects (substrate induced allostery) Heterotropic effects (allostery induced by a non-substrate molecule) (pyrimidine) (purine)
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Remember our allosteric mechanism: the MWC model (Monod-Wyman-Changeux)
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Chapter10 - Chapter 10 Enzyme regulation Aspartate...

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