Final Exam for The Chemical Basis of Metabolism. Biosynthesis of Cholesterol

 

The purpose of this Problem Set is to convince you that you can deal logically with sophisticated chemistry that you have not encountered before. Although cholesterol is discussed in the current version of CBM,  please do not refer to that chapter in writing your answers. You have all the principles you need to work out the pathway logically.  The answers will be posted next week.

 

 

The stereochemistry of cholesterol is important.

The angular methyl groups, which point towards you, are said to be oriented β. This is signified by a solid bond. The α orientation, which points away from you, is indicated by a dashed bond. C 20 is R.

According to the “Isoprene Rule”, isoprene units condense “head” to “tail”. Predict the product of the reaction:

 

 

Given:

A. Cholesterol is formed from two identical, acyclic sesquiterpenes.

B. In two separate experiments, acetate labeled in either the methyl or the carboxyl group was fed to rats. The animals were sacrificed and cholesterol was isolate from their livers. Degradation of the cholesterol gave the following labeling pattern (m= methyl, c= carboxyl):

 

C. Both malonyl-CoA and mevalonic acid 5-diphosphate are important intermediates in cholesterol biosynthesis.

D. The equilibrium constant, Keq for cleavage of acetoacetyl-CoA by CoA is 1.7 x 105 at 25º C (R = 1.987 cal/mol/degree K).

Predict the pathway for biosynthesis of cholesterol.

 

Remember, this course is about thinking logically. Use the facts you are given and build on them step by step.

1. What can you conclude from the cholesterol labeling pattern?

2. Squalene is a key intermediate in cholestereol biosynthesis. Show how can it be converted to an intermediate that contains the cholesterol ring system?

3. Show how the product you predicted from cyclization and rearrangement of squalene is converted to cholesterol

4. Show how acetate is converted to isopentenyl-5-pyrophosphate (“active isoprene”).

5. How can isopentenyl pyrophosphate be used to form the sesquiterpene, farnesyl pyrophosphate?

6. Show how farnesyl diphosphate molecules are joined to form squalene. Write a balanced equation for the process and suggest a mechanism.

 

 

 

 

 

 

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