C485 Exam IV Fall ‘15
Name___________________
Legible please!
Do not use acronyms. Use structures whenever they are asked for, or appropriate. Your
explanations should be brief. Overly lengthy answers with irrelevant or erroneous
material will receive deductions. GOOD LUCK
1. (14 Pts) The compound shown below is an intermediate in the biosynthesis of
cholesterol that is derived from acetate. What is the name of this compound? Using the
numbering system shown below for acetate, number this compound so it is obvious how
it is derived from acetate. Show how you would divide this molecule into five carbon
units. Please draw and number a six carbon intermediate in this pathway.
Farnesyl pyrophosphate
HMG CoA
Mevalonic Acid
2. (10 pts) Describe the differences between agonists and antagonists. When would you
want a drug to act as an agonist? An antagonist? Is tamoxifen an agonist, or an
antagonist? Explain
Agonists: Receptor ligands that activate normal function of receptor; used to
stimulate functions in absence of normal activator.
Antagonists: Receptor ligands that block normal function via competition, do not
activate; useful to block function from occurring.
Tamoxifen is both; it is an antagonist in breast tissue, but agonist in endometrial
tissue, therefore it is a partial agonist (or a partial antagonist, depending on your
definition).
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3. (10 pts) Draw the structure of cardiolipin. Outline the biosynthesis of cardiolipin from
simple lipid precursors. (Hint- cardiolipin is synthesized via the same strategy as
phosphoinositides. If you do not remember the structure of cardiolipin, just show the
synthesis using an R group for the headgroup.)
4. (16 pts) The biosynthesis of pyrmidines utilizes two unusual enzyme-catalyzed
reactions. What are those reactions, and what is unusual about them? Explain the
strategy used by the enzyme in each case to promote catalysis. Make sure you reference
how you know what strategy the enzyme uses. (Hint- you must refer in at least one case
to a paper we discussed, and in the other, to a catalytic strategy we discussed in class.)
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The two reactions are ring closure and decarboxylation. The ring closure is
unusual because carboxylic acids are very poor electrophiles; the enzyme activates the
carbonyl with zinc as a Lewis acid.
Decarboxylation is unusual in that it usually requires phosphorylation to make for
a better leaving group. In this case, it proceeds through a vinyl anion without any
cofactors. Binding energy of the 5’ phosphate drives the reaction.
The relevant paper discussed the removal of the phosphate via chemical analogue
and measured the reaction kinetics. Without phosphite, the reaction is slow. When
phosphite is added, the reaction speeds up considerably.
5. (8 pts) Outline the pathway for the degradation of AMP. (structures please). What
condition is associated with excess amounts of the product of this degradation?
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6. (10 pts) Starting with simple sugars, amino acids and one carbon donors, draw the
biosynthetic pathway for AMP biosynthesis. You must show all reactions and include all
reactants and products. PLEASE USE STRUCTURES
7. (12 pts) The carbon backbone of ceramide and sphingosines is assembled in a carboncarbon bond forming reaction. Show the precursors for this reaction, the cofactor
required for this conversion, and a mechanism for any C-C bond forming or C-C bond
making events that take place in this conversion. You must show the entire mechanism
starting from the resting state of the cofactor and regenerating it.
See last page
8. (10 Pts) Draw the mechanism of ribonucleotide reductase. Make sure you show how
the enzyme is regenerated in the correct oxidation state.
See last page
9. (6pts) Explain the regulatory strategy used to control ribonucleotide reductase. Please
be clear about which molecule exhibits what effect. Explain the rationale for this type of
effect.
dATP reduces overall enzyme activity: Reversed by ATP
dATP/ATP selects for UDP/CDP
TTP selects for GDP
dGTP selects for ADP
The rationale for this effects is to be responsible for both energy maintenance and to keep
the ratio of purines and pyrimidines in check.
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10. (12 pts total) Draw the mechanism of thymidylate synthase. The molecule shown
below has been proposed to act as a mechanism-based inhibitor. What is a mechanismbased inhibitor? Suggest how this molecule might work.
brief mechanism here:
http://www.bing.com/images/search?q=thymidylate+synthase&view=detailv2&&id=429
537DA1485754A2B45BA4A263727BEF13FD8A5&selectedIndex=3&ccid=w9KpF4P2
&simid=608046793019887415&thid=OIP.Mc3d2a91783f67beaa3504a04bd1102e4H0&
ajaxhist=0
MBI’s are substrates that undergo part of the normal reaction to generate a reactive
species that may then become covalently attached to the enzyme, or otherwise render
catalysis impossible.
The molecule show above is difference than 5-FU (I actually gave you this in a problem
set). This molecule might work by eliminating fluoride in preference to the cysteine
whenever you form an enolate in the normal mechanism.
11. (10 pts) Tetrahydrogestrinone (structure shown below), also known as “the clear”,
was used by Barry Bonds, Marion Jones and a number of other athletes to enhance their
athletic performance. What steroid(s) does this molecule mimic? (structures and names
please) There is one very obvious difference between this molecule and its natural
congeners that gives it a property that the natural steroids lack. What is this difference
and what is the property? (Hint, identify one of the structural differences between male
and female sex hormones and this may help you.)
this molecule mimics testosterone, but it lacks a methyl group
at the ring A-B junction. This means it cannot be turned into estrogens by aromatase, and
therefore has greater potency than testosterone or dhihydrotestosterone, which can both
be turned into estrogens. This molecule does NOT mimic estrogens, which have an OH
group on ring A. You must draw the structure of testosterone for full credit.
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