Download Chem 499 Final Exam Name

1
Chem 499
Final Exam
Spring, 2016
Beauchamp
Name: __________________________________
Topic
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Problem 1
Problem 2
Problem 3
Problem 4
Problem 5
Problem 6
Problem 7
Problem 8
Problem 9
Problem 10
Problem 11
Problem 12
Problem 13
Problem 14
Problem 15
Problem 16
Problem 17
Problem 18
Problem 19
Problem 20
Problem 21
Problem 22
Total
Total Points
Exam Points
6
6
5
5
14
14
5
13
9
8
6
11
9
10
18
8
8
12
8
10
4
6
195
Credit
Make sure you show all of your work. Draw in any lone pairs of electrons, formal charge and curved arrows to
show electron movement when required. Only write answers in the space available. Thank you for sharing this
course with me. I learned a lot and I hope you did too. Have a productive summer.
2
1. The normal pKa of the histidine in solution is about 6.0. In enzyme A it was found to be 5.1 and in
enzyme B it was found to be 7.9. What can you say about possible other amino acid residues near the
binding site to rationalize these observations? (3 pts each = 6 pts)
H
pKa = 5.1
N
N
histidine
H
H
pKa = 7.9
N
N
histidine
H
2. a. Hydrolysis of compound A occurs 108 times faster than compound B. Provide a possible
explanation. (3 pts each = 6 pts)
H2 C
CH2
O
O
CH3 H3C
O
O
P
P
O
O
O
O
compound A
compound B
b. Explain the relative reaction rates indicated.
O
O
O
O
O
Ar
O
krel. = 1.0 M-1s-1
O
Ar
O
Ar
O
krel. = 51,000 M-1s-1
O
O
O
O
O
O
O
Ar
O
O
O
O
Ar
krel. = 12,000,000 M-1s-1
O
O
O
O
Ar
3
3. Valinomycin (shown below) is an antibiotic which is able to transport ions into and out of cells.
Would you expect valinomycin is better at transporting anions, cations or both? Explain your
reasoning. Propose an explanation for how this can occur considering the polarity of all the
interacting components (blood, membranes and cytosol). Why might a microorganism make such a
compound? (5 pts)
4. Adrenaline and estrone are signaling hormones. The hormone adrenaline interacts with proteins
located on the surface of cells and does not cross the cell membrane. However, the larger steroid
estrone can cross cell membranes and interact with proteins located in the cell nucleus. Why is a
larger steroid molecule able to cross the cell membranes while a smaller molecule, such as adrenaline
cannot? (5 pts)
CH3
OH
HO
HO
NH2
adrenaline
HO
estrone
O
4
5. Briefly, discuss how epinephrine activates a cell from the time it is released into the blood stream. Make
a series of simple sketches to show this. Why might there be a need for an inhibitor of epinephrine?
(14 pts)
5
6. Discuss how vitamin C and vitamin E can work together to protect cells throughout the body from
free radical damage. “R” represents a long hydrocarbon chain. Use a hydroxyl radical (HO·) to
provide a simple mechanistic explanation for how these 2 vitamins can repeatedly quench free radicals
and eliminate the danger from the body. (14 pts)
O
O
O
HO
HO
HO
O
O
HO
vitamin C
OH
OH
HO
simplified
vitamin C
R
O
Me
H
O
R
R
simplified oxidized
vitamin C
simplified vitamin E
(R = long hydrocarbon chain)
dangerous
hydroxyl radical
6
7. a. Write a simple arrow pushing mechanism to show hydration of a ketone. (2 pts)
H
O
B
B
C
R
R
O
H
ketone
H
carbonyl hydrate
b. Show oxidation of the ketone hydrate to a carboxylic acid using either NAD+ or NADH (whichever
one works). (3 pts)
H
NADH
or
NAD+
O
C
R
R
N
R
NAD+
O
carboxylic acid
carbonyl hydrate
N
H
H
H
NADH
8. a. Physostigmine is an alkaloid found in the Calabar plant in Africa. In 1846 its main use was as a
poison, though today it is used as a medicine. It is a reversible acetylcholine inhibitor. What overall
charge would you expect on physostigmine at physiological pH (= 7.4)? If you think charge is present,
redraw the structure to show this and explain your reasons. (4 pts)
H
H3C
N
O
N
O
physostigmine
N
H
7
b. Show an arrow-pushing mechanism for acetylcholine binding and hydrolyzing at a receptor. Use B:
(base) and B+-H (acid) as needed. (3 pts)
B
(base)
O
O
H
N
H
B
(acid)
O
acetylcholine
B
(base)
O
choline
H
O
O
N
O
recycles into the
presynaptic cell
serine in receptor
HO
H
B
(acid)
O
O
acetylserine
in receptor
H
H
serine in
receptor
c. The reason physostigmine inhibits the acetylcholine receptor is because it binds to the receptor much
more strongly than acetylcholine (hydrolyzes off more slowly). Show a mechanism for physostigmine
binding to the receptor and provide an explanation for why it hydrolyzes more slowly than
acetylcholine. (6 pts)
H
H3C
N
O
O
H
?
N
O
N
H
physostigmine
serine in receptor
9. a. The methylation of cytosine residues in DNA plays a role in the regulation of transcription and is
catalyzed by the enzyme DNA methyltransferase. Add in curved arrows to show how the reaction
proceeds. (4 pts)
Enz
Enz
O
H
H
H
S
N
N
O
R
O
H
H3C
O
H
H
R
O
N
H
H
N
R
R
cytosine
Enz
O
B
CH3
N
Enz
S
H
N
H
N
S
H
N
H
N
B
H
O
N
R
CH3
N
Enz
S
O
N
R
H
B
methylcytosine
8
b. 5-fluoro-2’-deoxycytidine is a mechanism-based inhibitor of DNA methyltransferase. Explain
why. (5 pts)
Enz
H
O
H
N
O
F
H
N
S
O
N
H
Enz
Ribose
B
5-fluoro-2'-deoxycytidine
10. Proteins can turn on or turn off through phosphorylation by a kinase enzyme. Make a sketch showing
how an enzyme might turn on and how an enzyme might turn off. (4 pts each = 8 pts)
components to work with
O
H
H
O
O
O
show turning on enzyme
show turning off enzyme
active site open
(enzyme on)
ATP
generic base
B
active site closed
(enzyme off)
O
O
other
aminoacid
other
aminoacid
serine
P
B
H
generic acid
9
11. Propose a mechanism for how thiamin (vit. B1) could decarboxylate an α-keto-acid. Supply necessary
mechanistic details (curved arrows, electron pairs, formal charge, etc.) in scheme below. (6 pts)
NH2
O
Ar
N
N
N
N
=
S
H
O
thiamin
(vitamin B1)
O
R
S
H
R
R
O
thiamin
(simplified)
generic
keto-acid
H
B
Ar
O
Ar
S
B
R
N
R
N
R
R
H
S
O
O
B
H
S
O
H
Ar
Ar
H
O
B
O
R
R
R
H
R
O
N
N
O
S
O
C
B
H
H
O
12. Show how pyridoxal phosphate, vitamin B6, can allow any of the three groups attached to serine’s
alpha carbon to become a good leaving group. Use mechanism arrows. Explain how it allows each
of these eliminations to occur so easy? What structural feature on an enzyme could orientate the
specified leaving group to be in the correct position for elimination? The example structure(s) have
been simplified (on the next page).
O
O
O
O
O
H
H
H
C
O
NH2 -2
O3 P
C
H2C
O
OH
H
O
H
serine
(-H2O)
enzyme
-2
CO2 leaving group
C
C
H2
N
H
O
O
O3P
O=CH2 leaving group
N
N
H
vitamin B6
(aldehyde)
vitamin B6
(imine)
H
H leaving group
10
H+ leaving group (2 pts)
R
B
R
H
H
HO
C
C
H2
C
N
H
C
O2C
C
C
C
R
C
C
N
N
C
HOH2C
R
R
C
N
C
O
C
C
C
R
What
how
and
why?
H
C
R
R
O
CO2 leaving group (2 pts)
R
B
C
O
C
C
C
H
R
H
O
R
C
C
N
What
how
and
why?
H
N
C
H2C
C
O2C
C
C
N
N
H
C
C
HOH2C
R
C
C
C
R
R
R
R
HO
H2C=O leaving group (2 pts)
B
R
R
H
O
C
CH2
H
O
C
C
C
O
N
N
R
H
What
how
and
why?
R
R
C
C
C
O2C
C
C
C
H
R
C
C
HOH2C
C
N
N
C
H
C
R
R
Explanation. (2 pts)
Provide a mechanism for how an amine can be released from vit B6 (imine form). (3 pts)
R
N
H
O
B
O
H
H
H
NH2
H
R
B
N
R
use these
as needed
N
R
11
13. a. What does ADME stand for? Give a one sentence explanation of each word. (3 pts)
b. What is the difference between pharmacokinetics and pharmocodynamics? (3 pts)
c. What percent of a drug is left after 6 half lives? Show your work. (3 pts)
14. a. Match the log P values with the compounds below and explain your reasoning. What is the KP
value for each compound? (log P values = -3.1, 1.0 and 3.6) (5 pts)
H
H
H
H
H
O
O
O
O
O
N
O
O
O
O
N
N
H
O
O
H
O
paroxetine
O
prednisolone
F
H
N
N
H
mitoxantrone
H
b. Provide an explanation for the observed log D plot. (5 pts)
log D
1.5
O
CH3
1.0
CH3
H3C
N
O
N
omeprazole
0.5
N
S
H
pH
0.0
O
2
CH3
-0.5
-1.0
-1.5
4
6
8
10
12
14
O
H
12
15. Cytochrom P-450 enzymes use iron in different oxidation states to change the oxidation state of many
functional groups in biochemistry. “Fe+3“ (reduced) and “Fe+4-O“ (oxidized) show simplified
representations of these enzymes that are commonly used.
O
O2
+3
Fe
Fe
cytochrom P-450 oxidation states
+4
oxidizes organic molecules
a. Flavins, in their oxidized form can accept up to two electrons and two protons (1 electron at a time
or 2 electrons at a time). Show how these transformation might occur by adding in simple 1 electron
arrows and proton transfers. Include mechanism arrows. (4 pts)
Flox
Flox
Flox
Flox
R
N
N
H-Flox
R
O
N
1 e_
N
O
NH
H
B
R
H
N
N
NH
N
R
H-Fl-H red
H-Flox
H-Flox
N
add
electron
NH
add
proton
O
O
N
O
R
O
add
electron
H-Fl-H red
1 e_
H-Flox
R
H
N
N
O
R
H
add
proton
N
N
B
N
NH
N
H
O
NH
H
O
O
b. Show an appropriate flavin in any necessary steps below (write simplistically as “Fl” in an
acceptable oxidation state as shown above). Also draw any mechanism arrows, acids (B-H+), bases
(B:), water molecules (H2O), etc as needed. (4 pts)
oxidizing iron
O
H-Fl-H, red
+3
Fe
O
O
O
+2
Fe
Fe
O
O
H-Flox
+3
Fe+3
H
H
O
Fe
+4
O
B
H
B
H
O
O
O
Fe+3
Fe+3
H
13
c. Write a simplistic mechanism for 2 electron reduction of the given Flavin using the appropriate
reagent, NAD+ or NADH, and any other necessary compounds. (2 pts)
oxidized flavin
R
reduced flavin
R
H
N
N
N
O
N
O
NH
NH
N
N
O
H
O
d. Show how the oxidized form of iron (cytochrom P-450s) could cause the indicated transformations
below (write mechanisms) and provide an explanation for why this is useful to an organism.
reaction 1 (2 pts)
O
R
R
C
H
Fe
R
R
+4
C
R
OH
R
reaction 2 (2 pts)
O
O
S
R
R
Fe
+4
S
R
R
reaction 3 (2 pts)
O
Fe
+4
O
reaction 4 (additional hydration step for the epoxides) (2 pts)
H
OH
B
B
O
O
H
H
OH
14
16. Porphobilinogen synthase is a zinc-dependent enzyme (contains two zinc ions) that catalyzes the
condensation of two molecules of 5-aminolevulinic acid to give porphobilinogen, a compound used to
make porphyrin rings that complex metals, such as iron in cytochrom P-450. Supply necessary
mechanistic details (curved arrows, electron pairs, correct formal charge, etc.) in the scheme below.
(8 pts)
lysine
O2 C
N
H
O 2C
O2C
H
O2C
lysine
lysine
H
B
N
B
+2
N
H
O
H
N
H
H
Zn
Zn
Zn
N
B
N
O
O
lysine
HN
H
B
H
H
N
NH2
B
O
O2C
NH2
O
Zn
H3C
Zn+2
lysine
O2C
N
H
O 2C
H
lysine
O2C
N
O2C
H
B
H
N
lysine
N
H
N
B
N
O
H
H
N
B
B
B
H
H
B
NH2
CO2
O2C
O2C
H
N
H
N
H
B
NH2
NH2
H
lysine
B
H
B
NH2
NH2
O2C
O2C
CO2
Zn
15
17. Eflornithine (α-difluoromethylonithine) is used for treating African sleeping sickness. A possible
mechanism for inactivating a key enzyme in the microorganism is shown below. Add in the necessary
mechanistic details (curved arrows, formal charge, important lone pairs) to show how this might
occur. (8 pts)
lysine
F
O
H
lysine
H
H
lysine
F
CH
O2C
N
C
B
B
F
H
O2C
N
H
Eflornithine
CH
C
H
H
R
simplified
vitamin B6
lysine
F
lysine
B
N
R
R
F
F
CH
NH2
O
C
O
F
N
H
H
N
B
NH2
CH
N
H
N
C
H
C
N
N
R
R
N
H
C
N
R
N
H
C
C
N
R
N
NH2
F
CH
H
lysine
H
N
B
N
H
C
NH2
N
H
NH2
CH
O
F
C
NH2
N
NH2
F
H
F
N
NH2
16
18. Indicate what kind of DNA drug is shown below and how it interferes with DNA function. Supply
necessary mechanism details.
a. daunorubicin (3 pts)
O
O
OH
O
O
OH
OH
N
OH
NH2
N
O
O
H
O
H
B
O
O
H
H
B
N
DNA
H
N
O
NH3
O
daunorubicin
NH3
OH
O
OH
O
O
OH
OH
DNA
O
H
O
N
N
H
N
N
b. esperamicins – show formation of the reactive species (3 pts)
duocarbycin A
Sugar
O
O
Sugar
Sugar
O
O
H
O
O
NH
B
NH
H
HO
O
H3 C
H
S
S
HO
B
O
H
S
R
H3C
B
S
S
S
R
diradical cleaves
DNA chain
O
Sugar
O
H
HO
NH
O
Sugar
O
H
HO
NH
S
HO
HO
O
B
S
S
H
Sugar
Sugar
H
O
S
Sugar
B
H
17
c. fluphenazine has a short duration of activity of 6-8 hours in the body. Fluphenazine ethanate has a
duration of about 1 month. Provide a possible explanation. (3 pts)
S
S
fluphenazine ethanate
N
N
fluphenazine
CF3
N
CF3
N
O
N
N
O
OH
e. tolmetin sodium (Tolectin) has an activity of about 1 hour in the body. The glycine conjugate as an
activity of about 9 hours. Provide a possible explanation. (3 pts)
O
O
O
N
N
H
N
O
O
Na
Tolmetin sodium
O
O
glycine conjugate of Tolmetin
18
19. Enzymes that use glutathione are an important part of the defense against toxic drugs and metabolites.
Using simplistic arrow-pushing mechanisms, show how glutathione could protect against potent
electrophiles, and how it could protect against reactive free radicals. You can write glutathione as
R-S-H. Use B: (base) and B+-H (acid) as needed.
NH3
O
H
N
O2C
N
H
CO2
glutathione (you can write this as R-S-H)
O
SH
i. Protection from electrophiles (2 pts each = 8 pts)
a.
Br
b.
O
c.
O
d. Protection from free radical
H O
19
20. In large doses Tylenol causes severe liver necrosis, resulting from over 80% depletion of glutathione
levels and depletion of P-450 capacity (so they cannot oxidize normal biological molecules and other
drugs that might be taken). This is thought to occur from oxidation of acetaminophen by cytochrome
P-450 enzymes, followed by conjugate addition of glutathione. Show simplistic mechanisms for these
processes. (10 pts)
O
H
O
N
N
NH3
O2C
H
Tylenol
(aceaminophen)
HN
O
H
N
O
O
N
H
CO2
O
Fe
O
SH
glutathione (you can write this as R-S-H)
P-450
enzyme
S
O
OH
Tylenol
(metabolites)
glutathione
20
21. An antibody was raised against a tumor cell line and was conjugated to a β-lactamase. A nitrogen
mustard was conjugated to a cephalosporin for use in ADEPT (antibody directed enzyme prodrug
therapy). Draw a mechanism for the activation of the prodrug by the ADEPT conjugate (elimination
of the “mustard drug”. (4 pts)
Cl
Cl
N
H
R
N
S
O
N
O
O
CO2H
H
B
O
O
serine
22. Propose a mechanism, using ATP, for each of the following transformations. Use B for a base and
B-H+ for an acid, if necessary. What purpose might these transformations serve in a living organism?
Hint: making a “mixed anhydride” might prove very helpful. (2 pts each = 6 pts)
O
O
R
H
O
HO
HO
O
OH
OH
foreign alcohol
in body
O
O
C
glucoronic acid
H
O
S
O
O
H3N
P
O
O
ATP
O
O
sulfate
O
glycine
simplified ATP
i. Glucoronic acid conjugation of an “ROH”.
O
O
O
C
P
O
O
HO
HO
OH
OH
glucoronic acid
R
O
ATP
O
O
O
C
O
HO
HO
foreign alcohol
in body
simplified ATP
H
O
R
H
OH
OH
H
ii. Sulfonation of an “ROH”.
O
O
O
S
O
O
P
O
ATP
O
S
O
foreign alcohol
in body
simplified ATP
O
R
O
O
O
sulfate
R
H
O
iii. Glycination of a “RCO2H”.
O
O
O
H3N
O
glycine
P
O
O
simplified ATP
ATP
O
R
H
O
foreign alcohol
in body
H3N
R
O