Exam 1 2006 BLANK - Biochemistry 441 2nd Hour Exam March 3,...

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Biochemistry 441 2nd Hour Exam March 3, 2006 Name____________________________________ 1. A. Individuals with familial hypercholesterolemia synthesize cholesterol rapidly even though the concentration of cholesterol in their blood is abnormally high. Most people with this condition are found to have genetic defects in their LDL receptors. Why does regulation of cholesterol biosynthesis fail in this situation? (5 points) Cholesterol travels in the blood mainly in low-density lipoproteins (LDL), which must bind to LDL receptors in order to be taken up by cells in peripheral tissues. The control systems for cholesterol biosynthesis sense the intracellular cholesterol concentration, not the concentration in the blood. For example, expression of the gene for HMG-CoA reductase is triggered when cholesterol dissociates from a protein that binds to the sterol regulatory element in the ER membrane. If a defect in the LDL receptor prevents cholesterol uptake, the intracellular cholesterol concentration will remain low and HMG-CoA reductase, the controlling enzyme for cholesterol synthesis, will be expressed at high levels. Synthesis of the LDL receptor also will remain activated for the same reason, and protolysis of HMG-CoA reductase will remain switched off. B. You find a strain of mice with hereditary hypercholesterolemia who have normal LDL receptors and normal amounts of HMG-CoA reductase in their tissues. On ion-exchange chromatography, which can resolve proteins with different net charges, HMG-CoA reductase purified from these mice migrates in a single band whereas the enzyme from normal mice separates into two bands. Suggest an explanation for these observations based on what you know about the control of cholesterol biosynthesis. (5 points) HMG-CoA reductase also is regulated by phosphorylation. Phosphorylation inactivates the enzyme; dephosphorylation activates it. Phosphorylation changes the charge of the protein, so the two bands seen with HMG-CoA reductase from normal mice could be the phosphorylated and unphosphorylated forms. A mutation that prevented phosphorylation (e.g., substitution of a different amino acid for the residue that normally gets phosphorylated, substitution of a residue that
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Exam 1 2006 BLANK - Biochemistry 441 2nd Hour Exam March 3,...

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