Organic Chemistry

Paula Yurkanis Bruice

Chapter 21

Amino Acids, Peptides, and Proteins - all with Video Answers

Educators

Chapter Questions

Problem 1

a. Explain why, when the imidazole ring of histidine is protonated, the double-bonded nitrogen is the nitrogen that accepts the proton.
b. Explain why, when the guanidino group of arginine is protonated, the double-bonded nitrogen is the nitrogen that accepts the proton.

Zubair Abdulla

Zubair Abdulla

Numerade Educator

Problem 2

a. Which isomer- $(R)$ -alanine or $(S)$ -alanine- is $\mathrm{D}$ -alanine?
b. Which isomer- $(R)$ -aspartate or $(S)$ -aspartate $-$ is D-aspartate?
c. Can a general statement be made relating $R$ and $S$ to $D$ and $L ?$

Megha Ramappan

Numerade Educator

Problem 3

Threonine has two asymmetric centers and, therefore, has four stereoisomers. Naturally occurring L-threonine is $(2 S, 3 R)$ -threonine. Which of the following stereoisomers is $L$ -threonine?

Megha Ramappan

Numerade Educator

Problem 4

Do any other amino acids in Table 21.2 have more than one asymmetric center?

Megha Ramappan

Numerade Educator

Problem 5

Alanine has $\mathrm{p} K_{\mathrm{a}}$ values of 2.34 and $9.69 .$ Therefore, alanine exists predominately as a zwitterion in an aqueous solution with $\mathrm{pH}>$ ______ and $\mathrm{pH}<$ ______.

Megha Ramappan

Numerade Educator

Problem 6

Why are the carboxylic acid groups of the amino acids more acidic ( $\mathrm{p} K_{\mathrm{a}} \sim 2$ ) than a carboxylic acid such as acetic acid $\left(\mathrm{p} K_{\mathrm{a}}=4.76\right) ?$

Megha Ramappan

Numerade Educator

Problem 7

Draw the predominant form for each of the following amino acids at physiological pH (7.4):
a. aspartate
b. histidine
c. glutamine
d. lysine
e. arginine
f. tyrosine

Megha Ramappan

Numerade Educator

Problem 8

Draw the predominant form for glutamate in a solution with the following pH:
a. 0
b. 3
c. 6
d. 11

Megha Ramappan

Numerade Educator

Problem 9

a. Why is the $\mathrm{p} K_{\mathrm{a}}$ of the glutamate side chain greater than the $\mathrm{p} K_{\mathrm{a}}$ of the aspartate side chain?
b. Why is the $p K_{a}$ of the arginine side chain greater than the $p K_{a}$ of the lysine side chain?

Megha Ramappan

Numerade Educator

Problem 10

Calculate the pI of each of the following amino acids:
a. asparagine
b. arginine
c. serine
d. aspartate

Megha Ramappan

Numerade Educator

Problem 11

a. Which amino acid has the lowest pI value?
b. Which amino acid has the highest pI value?
c. Which amino acid has the greatest amount of negative charge at $\mathrm{pH}=6.20 ?$
d. Which amino acid has a greater negative charge at $\mathrm{pH}=6.20,$ glycine or methionine?

Megha Ramappan

Numerade Educator

Problem 12

Explain why the pI values of tyrosine and cysteine cannot be determined by the method described on page 995.

Zubair Abdulla

Numerade Educator

Problem 13

a. What percentage of the $\alpha$ -amino group of lysine will be protonated at its pI?
$$<25 \%$$
$$50 \%$$
$$>75 \%$$
b. Answer the same question for the $\varepsilon$ -amino group of lysine.

Dennis Howard

Numerade Educator

Problem 14

Explain why the pI of lysine is the average of the $\mathrm{p} K_{\mathrm{u}}$ values of its two protonated amino groups.

Megha Ramappan

Numerade Educator

Problem 15

What aldehyde is formed when valine is treated with ninhydrin?

Megha Ramappan

Numerade Educator

Problem 16

A mixture of seven amino acids (glycine, glutamate, leucine, lysine, alanine, isoleucine, and aspartate) is separated by chromatography. Explain why only six spots show up when the chromatographic plate is coated with ninhydrin and heated.

Megha Ramappan

Numerade Educator

Problem 17

Why are buffer solutions of increasingly higher pH used to elute the column that generates the chromatogram shown in Figure $21.5 ?$ (Elute means wash out with a solvent.)

Zubair Abdulla

Numerade Educator

Problem 18

Explain the order of elution (with a buffer of $\mathrm{pH}$ 4) of the following pairs of amino acids through a column packed with Dowex 50 (Figure 21.3):a. aspartate before serine
b. serine before alanine
c. valine before leucine
d. tyrosine before phenylalanine

Zubair Abdulla

Numerade Educator

Problem 19

In what order would histidine, serine, aspartate, and valine be eluted with a buffer of $\mathrm{pH} 4$ from a column containing an anion-exchange resin (Dowex 1)?

Megha Ramappan

Numerade Educator

Problem 20

Why is excess ammonia used in the preceding reaction?

Megha Ramappan

Numerade Educator

Problem 21

Cells can also convert $\alpha$ -keto acids into amino acids, but because the reagents organic chemists use for this reaction are not available in cells, they carry out this reaction by a different mechanism (Section 24.14 ).
a. What amino acid is obtained from the reductive amination of each of the following metabolic intermediates in a cell by reductive amination?
b. What amino acids are obtained from the same metabolic intermediates when the amino acids are synthesized in the laboratory?

Megha Ramappan

Numerade Educator

Problem 22

What amino acid is formed using the $N$ -phthalimidomalonic ester synthesis when the following alkyl halides are used in the third step?

Megha Ramappan

Numerade Educator

Problem 23

What alkyl halide is used in the acetamidomalonic ester synthesis to prepare
a. lysine?
b. phenylalanine?

Megha Ramappan

Numerade Educator

Problem 24

What amino acid is formed when the aldehyde used in the Strecker synthesis is
a. acetaldehyde?
b. 2-methylbutanal?
c. 3-methylbutanal?

Megha Ramappan

Numerade Educator

Problem 25

Esterase is an enzyme that catalyzes the hydrolysis of esters. It hydrolyzes esters of $\mathbf{L}$ -amino acids more rapidly than esters of D-amino acids. How can this enzyme be used to separate a racemic mixture of amino acids?

Ronald Prasad

Numerade Educator

Problem 26

Draw the tetrapeptide Ala-Thr-Asp-Asn and indicate the peptide bonds.

Zubair Abdulla

Numerade Educator

Problem 27

Draw the resonance contributors of the peptide bond in the less stable configuration.

Zubair Abdulla

Numerade Educator

Problem 28

Which bonds in the backbone of a peptide can rotate freely?

Zubair Abdulla

Numerade Educator

Problem 29

An opioid pentapeptide has the following structure: Tyr-Cys-Gly-Phe-Cys
a. Draw the structure of the pentapeptide including all the side chains.
b. Write its structure following mild oxidation.

Zubair Abdulla

Numerade Educator

Problem 30

What is the configuration about each of the asymmetric centers in aspartame?

Zubair Abdulla

Numerade Educator

Problem 31

Glutathione is a tripeptide whose function is to destroy harmful oxidizing agents in the body. Oxidizing agents are thought to be responsible for some of the effects of aging and to play a causative role in cancer. Glutathione removes oxidizing agents by reducing them. In the process, glutathione is oxidized, resulting in the formation of a disulfide bond between two glutathione molecules. An enzyme subsequently reduces the disulfide bond, returning glutathione to its original condition so it can react with another oxidizing agent.
a. What amino acids make up glutathione?
b. What is unusual about glutathione's structure? (If you cannot answer this question, draw the structure you would expect for the tripeptide and compare your structure with the actual structure.)

Zubair Abdulla

Numerade Educator

Problem 32

What dipeptides would be formed by heating a mixture of valine and N-protected leucine?

Zubair Abdulla

Numerade Educator

Problem 33

Suppose you are trying to synthesize the dipcptide Val-Ser. Compare the product that would be obtained if thionyl chloride were used to activate the carboxyl group of N-protected valine with the product that would be obtained if it were activated with DCCD.

Zubair Abdulla

Numerade Educator

Problem 34

Show the steps in the synthesis of the tetrapeptide Leu-Phe-Ala-Val.

Zubair Abdulla

Numerade Educator

Problem 35

a. Calculate the overall yield of bradykinin when the yield for the addition of each amino acid to the chain is $70 \%.$
b. What would be the overall yield of a peptide containing 15 amino acids if the yield for the incorporation of each is $80 \% ?$

Zubair Abdulla

Numerade Educator

Problem 36

Show the steps in the synthesis of the tetrapeptide in Problem $34,$ using Merrifield's method.

Sanjeev Kumar

Numerade Educator

Problem 37

Write the mechanism for the reaction of a cysteine side chain with iodoacetic acid.

Zubair Abdulla

Numerade Educator

Problem 38

In determining the primary structure of insulin, what would lead you to conclude that insulin had more than one polypeptide chain?

Zubair Abdulla

Numerade Educator

Problem 39

A decapeptide undergoes partial hydrolysis to give peptides whose amino acid compositions are shown. Reaction of the intact decapeptide with Edman's reagent releases PTH-Gly. What is the sequence of the decapeptide?
1. Ala, Trp
2. Val, Pro, Asp
3. Pro, Val
4. Ala, Glu
5. Trp, Ala, Arg
6. Arg. Gly
7. Glu, Ala, Leu
8. Met, Pro, Leu, Glu

Zubair Abdulla

Numerade Educator

Problem 40

Explain why cyanogen bromide does not cleave on the C-side of cysteine.

Zubair Abdulla

Numerade Educator

Problem 41

Indicate the peptides produced from cleavage by the indicated reagent:
a. His-Lys-Leu-Val-Glu-Pro-Arg-Ala-Gly-Ala by trypsin
b. Leu-Gly-Ser-Met-Phe-Pro-Tyr-Gly-Val by chymotrypsin

Zubair Abdulla

Numerade Educator

Problem 42

Determine the amino acid sequence of a polypeptide from the following data:
Acid-catalyzed hydrolysis gives Ala, Arg, His, 2 Lys, Leu, 2 Met, Pro, 2 Ser, Thr, and Val. xypeptidase A releases Val.
Edman's reagent releases PTH-Leu. Treatment with cyanogen bromide gives three peptides with the following amino acid compositions:
1. His, Lys, Met, Pro, Ser
2. Thr, Val
3. Ala, Arg, Leu, Lys, Met, Ser
Trypsin-catalyzed hydrolysis gives three peptides and a single amino acid:
1. Arg, Leu, Ser
2. Met, Pro, Ser, Thr, Val
3. Lys
4. Ala, His, Lys, Met

Zubair Abdulla

Numerade Educator

Problem 43

Determine the primary structure of an octapeptide from the following data:
Acid-catalyzed hydrolysis gives 2 Arg, Leu, Lys, Met, Phe, Ser, and Tyr. Carboxypeptidase A releases Ser. Edman's reagent releases Leu.
Treatment with cyanogen bromide forms two peptides with the following amino acid compositions:
1. Arg. Phe, Ser $\quad$ 2. Arg. Leu, Lys. Met, Tyr
Trypsin-catalyzed hydrolysis forms the following two amino acids and two peptides:
1. Arg
2. Ser
3. Arg, Met, Phe
4. Leu, Lys, Tyr

Zubair Abdulla

Numerade Educator

Problem 44

Three peptides were obtained from a trypsin digestion of two different polypeptides. In each case, indicate the possible sequences from the given data and tell what further experiment should be carried out in order to determine the primary structure of the polypeptide.
a. polypeptide I: $1 .$ Val-Gly-Asp-Lys
b. polypeptide II: 1. Val-Leu-Gly-Glu
2. Leu-Glu-Pro-Ala-Arg
2. Ala-Glu-Pro-Arg
3. Ala-Leu-Gly-Asp
3. Ala-Met-Gly-Lys

Zubair Abdulla

Numerade Educator

Problem 45

a. How long is an $\alpha$ -helix that contains 74 amino acids?
b. How long is a fully extended peptide chain that contains the same number of amino acids? (The distance between consecutive amino acids in a fully extended chain is $3.5 \AA$; the repeat distance of an $\alpha \text { -helix is } 5.4 \AA .)$

Zubair Abdulla

Numerade Educator

Problem 46

How would a protein that resides in the nonpolar interior of a membrane fold compared with the water soluble protein just discussed?

Zubair Abdulla

Numerade Educator

Problem 47

a. Which would have the greatest percentage of polar amino acids, a spherical protein, a cigar-shaped protein, or a subunit of a hexamer?
b. Which would have the smallest percentage of polar amino acids?

Zubair Abdulla

Numerade Educator

Problem 48

When apples that have been cut are exposed to oxygen, an enzyme-catalyzed reaction causes them to turn brown. Explain why coating them with lemon juice $(\mathrm{pH} \cdot 3.5)$ as soon as they are cut prevents the color change.

Crystal Wang

Numerade Educator

Problem 49

Glycine has $\mathrm{p} K_{\mathrm{a}}$ values of 2.34 and $9.60 .$ At what $\mathrm{pH}$ does glycine exist in the indicated form?

Zubair Abdulla

Numerade Educator

Problem 50

Show the peptides that would result from cleavage by the indicated reagent:
a. Val-Arg-Gly-Met-Arg-Ala-Ser by carboxypeptidase A
b. Ser-Phe-Lys-Met-Pro-Ser-Ala-Asp by cyanogen bromide
c. Arg-Ser-Pro-Lys-Lys-Ser-Glu-Gly by trypsin

Zubair Abdulla

Numerade Educator

Problem 51

A titration curve is a plot of the pH of a solution as a function of added equivalents of hydroxide ion. As hydroxide ion is added to the aqueous solution,
the pH increases because hydroxide ion removes protons from the solution. The pH flattens out when hydroxide ion can remove a proton from an ionizable group of an amino acid rather than a proton from the solution.

Charles Thomas

Numerade Educator

Problem 52

Which has a higher percentage of negative charge at physiological pH (7.4), leucine with pI = 5.98 or asparagine with pI = 5.43?

Zubair Abdulla

Numerade Educator

Problem 53

Aspartame (its structure is on page 1007 ) has a pI of $5.9 .$ Draw its prevailing form at physiological pH (7.4) .

Zubair Abdulla

Numerade Educator

Problem 54

Draw the form of aspartate that predominates at the following pH values:
a. $\mathrm{pH}=1.0$
b. $\mathrm{pH}=2.6$
c. $p H=6.0$
d. $\mathrm{pH}=11.0$

Zubair Abdulla

Numerade Educator

Problem 55

Show how phenylalanine can be prepared by reductive amination of an $\alpha$ -ketocarboxylic acid.

Zubair Abdulla

Numerade Educator

Problem 56

A professor was preparing a manuscript for publication in which she reported that the pI of the tripeptide Lys-Lys-Lys was $10.6 .$ One of her students pointed out that there must be an error in her calculations because the $\mathrm{p} K_{\mathrm{a}}$ of the $\varepsilon$ -amino group of lysine is 10.8 and the pI of the tripeptide has to be greater than any of its individual $\mathrm{p} K_{\mathrm{a}}$ values. Was the student correct?

Zubair Abdulla

Numerade Educator

Problem 57

What aldehydes are formed when the following amino acids are treated with ninhydrin?
a. tyrosine
b. leucine
c. arginine

Ronald Prasad

Numerade Educator

Problem 58

A mixture of amino acids that do not separate sufficiently when a single technique is used can often be separated by two-dimensional chromatography. In this technique, the mixture of amino acids is applied to a piece of filter paper and separated by chromatographic techniques. The paper is then rotated $90^{\circ}$ and the amino acids are further separated by electrophoresis, producing a type ef chromatogram called a fingerprint. Identify the spots in the fingerprint obtained from a mixture of Ser, Glu, Leu, His, Met, and Thr.

Zubair Abdulla

Numerade Educator

Problem 59

Determine the amino acid sequence of a polypeptide from the following data:
Complete hydrolysis of the peptide yields Arg. 2 Gly, Ile, 3 Leu, 2 Lys, 2 Met, 2 Phe, Pro, Ser, 2 Tyr, and Val.
Treatment with cyanogen bromide yields the following three peptides:
1. Gly-Leu-Tyr-Phe-Lys-Ser-Met
2. Gly-Leu-Tyr-Lys-Val-Ile-Arg-Met
3. Leu-Pro-Phe
Treatment with trypsin yields the following four peptides:
1. Gly-Leu-Tyr-Phe-Lys
2. Ser-Met-Gly-Leu-Tyr-Lys
3. Val-Ile-Arg
4. Met-Leu-Pro-Phe

Zubair Abdulla

Numerade Educator

Problem 60

Explain why amino acids, unlike most amines and carboxylic acids, are insoluble in diethyl ether.

Nima Gharibi

Numerade Educator

Problem 61

Explain the difference in the $p K_{a}$ values of the carboxyl groups of alanine, serine, and cysteine.

Zubair Abdulla

Numerade Educator

Problem 62

Which is the more effective buffer at physiological pH, a solution of 0.1 M glycylglycylglycylglycine or a solution of 0.2 M glycine?

Zubair Abdulla

Numerade Educator

Problem 63

Identify the location and type of charge on the hexapeptide Lys-Ser-Asp-Cys-His-Tyr at each of the following pH values:
a. $\mathrm{pH}=1$
b. $\mathrm{pH}=5$
c. $p H=7$
d. $\mathrm{pH}=12$

Zubair Abdulla

Numerade Educator

Problem 64

Draw the product obtained when a lysine side chain in a polypeptide reacts with maleic anhydride.

Zubair Abdulla

Numerade Educator

Problem 65

After the polypeptide shown below was treated with maleic anhydride, it was hydrolyzed by trypsin. (After a polypeptide is treated with maleic anhy-dride, trypsin will cleave the polypeptide only on the C-side of arginine.)
Gly-Ala-Asp-Ala-Leu-Pro-Gly-Ile-Leu-Val-Arg-Asp-Val-Gly-Lys-Val-Glu-Val-Phe-Glu-Ala-GlyArg-Ala-Glu-Phe-Lys-Glu-Pro-Arg-Leu-Val-Met-Lys-Val-Gilu-Gly-Arg-Pro-Val-Gly-Ala-Gly-Leu-Trp
a. After a polypeptide is treated with maleic anhydride, why does trypsin no longer cleave it on the C-side of lysine?
b. How many fragments are obtained from the polypeptide?
c. In what order will the fragments be eluted from an anion-exchange column using a buffer of $\mathrm{pH}=5 ?$

Zubair Abdulla

Numerade Educator

Problem 66

Treatment of a polypeptide with 2-mercaptoethanol yields two polypeptides with the following primary structures:
Val-Met-Tyr-Ala-Cys-Ser-Phe-Ala-Glu-Ser Ser-Cys-Phe-Lys-Cys-Trp-Lys-Tyr-Cys-Phe-Arg-Cys-Ser
Treatment of the original intact polypeptide with chymotrypsin yields the following peptides:
1. Ala, Glu, Ser
2. 2 Phe, 2 Cys, Ser
3. Tyr, Val, Met
4. Arg. Ser, Cys
5. Ser, Phe, 2 Cys, Lys, Ala, Trp
6 Tyr, Lys
Determine the positions of the disulfide bridges in the original polypeptide.

Susan Hallstrom

Susan Hallstrom

Numerade Educator

Problem 67

Show how aspartame can be synthesized using DCCD.

Zubair Abdulla

Numerade Educator

Problem 68

$\alpha$ -Amino acids can be prepared by treating an aldehyde with ammonia/trace acid, followed by hydrogen cyanide, followed by acid-catalyzed hydrolysis.
a. Draw the structures of the two intermediates formed in this reaction.
b. What amino acid is formed when the aldehyde that is used is 3 -methylbutanal?
c. What aldehyde is needed to prepare isoleucine?

Zubair Abdulla

Numerade Educator

Problem 69

Reaction of a polypeptide with carboxypeptidase A releases Met. The polypeptide undergoes partial hydrolysis to give the following peptides.
What is the sequence of the polypeptide?
1. Ser, Lys, Trp
2. Gly, His, Ala
3. Glu, Val, Ser
4. Leu, Glu, Ser
5. Met, Ala, Gly
6. Ser, Lys, Val
7. Glu, His
8. Leu, Lys, Trp
9. Lys, Ser
10. Glu, His, Val
11. Trp, Leu, Glu
12. Ala, Met

Zubair Abdulla

Numerade Educator

Problem 70

a. How many different octapeptides can be made from the 20 naturally occurring amino acids?
b. How many different proteins containing 100 amino acids can be made from the 20 naturally occurring amino acids?

Zubair Abdulla

Numerade Educator

Problem 71

Glycine has $\mathrm{p} K_{\mathrm{a}}$ values of 2.3 and $9.6 .$ Do you expect the $\mathrm{p} K_{\mathrm{a}}$ values of glycylglycine to be higher or lower than these values?

Zubair Abdulla

Numerade Educator

Problem 72

A mixture of 15 amino acids gave the fingerprint shown here (see Problem 58 ).
Identify the spots. (Hint $I:$ Pro reacts with ninhydrin to produce a yellow color; Phe and Tyr produce a green color. Hint 2: Count the number of spots before you start.)

Shahina -

Numerade Educator

Problem 73

Write the mechanism for the reaction of an amino acid with di-tert-butyl dicarbonate.

Zubair Abdulla

Numerade Educator

Problem 74

Dithiothreitol reacts with disulfide bridges in the same way that 2 -mercaptoethanol does. With dithiothreitol, however, the equilibrium lies much more to the right. Explain.

Zubair Abdulla

Numerade Educator

Problem 75

Show how valine can be prepared by
a. a Hell-Volhard-Zelinski reaction.
b. a Strecker synthesis.
c. a reductive amination.
d. a $N$ -phthalimidomalonic ester synthesis.
e. an acetamidomalonic ester synthesis.

Ronald Prasad

Numerade Educator

Problem 76

The primary structure of $\beta$ -endorphin, a peptide containing 31 amino acids synthesized by the body to control pain, is shown here:
Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-GIn-Thr-Pro-Leu-Val-ThrLeu-Phe-Lys-Asn-Ala-Ile-Ile-Lys-Asn-Ala-Tyr-Lys-Lys-Gly-Glu
a. What fragments are obtained as a result of treatment with each of the following?
1. trypsin
2. cyanogen bromide
3. chymotrypsin

Emily Himsel

Numerade Educator

Problem 77

chemist wanted to test his hypothesis that the disulfide bridges that form in many proteins do so after the minimum energy conformation of the protein has been achieved. He treated a sample of an enzyme that contained four disulfide bridges with 2-mercaptoethanol and then added urea to denature the enzyme. He slowly removed these reagents so that the enzyme could re-fold and re-form the disulfide bridge The enzyme he recovered had $80 \%$ of its original activity. What would be the percent activity in the recovered enzyme if disulfide bridge formation were entirely random rather than determined by the tertiary structure? Does this experiment support his hypothesis?

Zubair Abdulla

Numerade Educator

Problem 78

Propose a mechanism for the rearrangement of the thiazoline obtained from the reaction of Edman's reagent with a peptide to a PTH-amino acid (page 1014 ). (Hint: Thioesters are very reactive toward nucleophiles.)

Zubair Abdulla

Numerade Educator

Problem 79

A normal polypeptide and a mutant of the polypeptide were hydrolyzed by an endopeptidase under the same conditions. The normal and mutant polypeptide differ by one amino acid. The fingerprints of the peptides obtained from the two polypeptides are shown below. What kind of amino acid substitution occurred as a result of the mutation? (That is, is the substituted amino acid more or less polar than the original amino acid? Is its pI lower or higher?) (Hint: Photocopy the fingerprints, cut them out, and overlay them.)

Zubair Abdulla

Numerade Educator

Problem 80

Determine the amino acid sequence of a polypeptide from the following data:
Complete hydrolysis of the peptide yields Ala, Arg. Gly. 2 Lys, Met, Phe, Pro, 2 Ser, Tyr, and Val.
Treatment with Edman's reagent releases PTH-Val. Carboxypeptidase A releases Ala.
Treatment with cyanogen bromide yields the following two peptides:
1. Ala, 2 Lys, Phe, Pro, Ser, Tyr
2. Arg, Gly, Met, Ser, Val
Treatment with trypsin yields the following three peptides:
1. Gly, Lys, Met, Tyr
2. Ala, Lys, Phe, Pro, Ser
3. Arg, Ser, Val
Treatment with chymotrypsin yields the following three peptides:
1. 2 Lys, Phe, Pro
2. Arg, Gly, Met, Ser, Tyr, Val
3. Ala, Ser

Zubair Abdulla

Numerade Educator