Organic Chemistry

John McMurry

Chapter 26

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

Educators

Chapter Questions

Problem 1

How many of the $\alpha$ -amino acids shown in Table 26.1 contain aromatic rings? How many contain sulfur? How many contain alcohols? How many contain hydrocarbon side chains?

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 2

Eighteen of the nineteen $L$ amino acids have the 5 configuration at the $\alpha$ carbon. Cysteine is the only $\mathrm{L}$ amino acid that has an $R$ configuration. Explain.

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 3

The amino acid threonine, ( $25,3 R$ )-2-amino-3-hydroxybutanoic acid, has two chirality centers.
(a) Draw a Fischer projection of threonine.
(b) Draw a Fischer projection of a threonine diastereomer, and label its chirality centers as R or S.

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 4

Hemoglobin has $p I=6.8 .$ Does hemoglobin have a net negative charge or net positive charge at $p H=5.3 ?$ At $p H=7.3 ?$

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 5

Show how you could prepare the following $\alpha$ -amino acids from the appropriate carboxylic acids:
(a) Phenylalanine
(b) Valine

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 6

What alkyl halides would you use to prepare the following $\alpha$ -amino acids by the amidomalonate method?
(a) Leucine
(b) Histidine
(c) Tryptophan
(d) Methionine

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 7

Show how you could prepare the following amino acid enantioselectively:
CAN'T COPY THE FIGURE

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 8

There are six isomeric tripeptides that contain valine, tyrosine, and glycine. Name them using both three- and one-letter abbreviations.

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 9

Draw the structure of M-P-V-G, and indicate the amide bonds.

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 10

Show the structure of the product you would expect to obtain by $S_{N}$ ? reaction of a cysteine residue with iodoacetic acid.

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 11

Show the structures of the products obtained on reaction of valine with ninhydrin.

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 12

The octapeptide angiotensin II has the sequence Asp-Arg-Val-Tyr-lle-His-Pro-Phe. What fragments would result if angiotensin II were cleaved with trypsin? With chymotrypsin?

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 13

What is the N-terminal residue on a peptide that gives the following PTH derivative on Edman degradation?
CAN'T COPY THE FIGURE

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 14

Draw the structure of the PTH derivative that would be formed on Edman degradation of angiotensin II (Problem 26.12).

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 15

Give the amino acid sequence of hexapeptides that produce the following sets of fragments on partial acid hydrolysis:
(a) Arg. Gly, lle, Leu, Pro, Val gives Pro-Leu-Gly, Arg-Pro, Gly-lle-Val
(b) $\mathrm{N}, \mathrm{L}, \mathrm{M}, \mathrm{W}, \mathrm{V}_{2} \mathrm{g}$ ives $\mathrm{V}-\mathrm{L}, \mathrm{V}-\mathrm{M}-\mathrm{W}, \mathrm{W}-\mathrm{N}-\mathrm{V}$

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 16

Show the mechanism for formation of a Boc derivative by reaction of an amino acid with di-tert-butyl dicarbonate.

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 17

Write all five steps required for the synthesis of Leu-Ala from alanine and leucine.

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 18

To what classes do the following enzymes belong?
(a) Pyruvate decarboxylase
(b) Chymotrypsin
(c) Alcohol dehydrogenase

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 19

Identify the following amino acids:
a.CAN'T COPY THE FIGURE
b.CAN'T COPY THE FIGURE
c.CAN'T COPY THE FIGURE

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 20

Give the sequence of the following tetrapeptide (yellow $=\mathrm{S}$ ):
CAN'T COPY THE FIGURE

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 21

Isoleucine and threonine are the only two amino acids with two chirality centers. Assign $R$ or $S$ configuration to the methyl-bearing carbon atom of isoleucine.
CAN'T COPY THE FIGURE

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 22

Is the following structure a D amino acid or an L amino acid? Identify it.
CAN'T COPY THE FIGURE

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 23

Give the sequence of the following tetrapeptide:
CAN'T COPY THE FIGURE

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 24

Except for cysteine, only $S$ amino acids occur in proteins. Several $R$ amino acids are also found in nature, however. $(R)$ -Serine is found in earthworms, and
(R)-alanine is found in insect larvae. Draw Fischer projections of ( $R$ )-serine and
(R)-alanine. Are these D or L amino acids?

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 25

Cysteine is the only amino acid that has L stereochemistry but an $R$ configuration. Make up a structure for another $L$ amino acid of your own creation that also has an $R$ configuration.

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 26

Draw a Fischer projection of ( $S$ )-proline.

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 27

Show the structures of the following amino acids in their zwitterionic forms:
(a) Trp
(b) Ile
(c) Cys
(d) His

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 28

Proline has $\mathrm{p} K_{\mathrm{a} 1}=1.99$ and $\mathrm{p} K_{\mathrm{a} 2}=10.60 .$ Use the Henderson-Hasselbalch equation to calculate the ratio of protonated and neutral forms at $\mathrm{pH}=2.50$ Calculate the ratio of neutral and deprotonated forms at $\mathrm{pH}=9.70$.

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 29

Using both three- and one-letter codes for amino acids, write the structures of all possible peptides containing the following amino acids:
(a) Val, Ser, Leu
(b) Ser, Leu_Pro

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 30

Look at the side chains of the 20 amino acids in Table $26.1,$ and then think about what is not present. None of the 20 contain either an aldehyde or a ketone carbonyl group, for instance. Is this just one of nature's oversights, or is there a likely chemical reason? What complications might an aldehyde or ketone carbonyl group cause?

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 31

Show how you could use the acetamidomalonate method to prepare the following amino acids:
(a) Leucine
(b) Tryptophan

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 32

Show how you could prepare the following amino acids using a reductive amination:
(a) Methionine
(b) Isoleucine

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 33

Show how you could prepare the following amino acids enantioselectively:
(a) Pro
(b) Val

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 34

Serine can be synthesized by a simple variation of the amidomalonate method using formaldehyde rather than an alkyl halide. How might this be done?

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 35

5 Predict the product of the reaction of valine with the following reagents:
(a) $\mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{OH},$ acid
(b) Di-tert-butyl dicarbonate
(c) $\mathrm{KOH}, \mathrm{H}_{2} \mathrm{O}$
(d) $\mathrm{CH}_{3} \mathrm{COCl},$ pyridine; then $\mathrm{H}_{2} \mathrm{O}$

Pronoy Sinha

Numerade Educator

Problem 36

The reaction of ninhydrin with an $\alpha$ -amino acid occurs in several steps.
(a) The first step is formation of an imine by reaction of the amino acid with ninhydrin. Show its structure and the mechanism of its formation.
(b) The second step is a decarboxylation. Show the structure of the product and the mechanism of the decarboxylation reaction.
(c) The third step is hydrolysis of an imine to yield an amine and an aldehyde. Show the structures of both products and the mechanism of the hydrolysis reaction.
(d) The final step is formation of the purple anion. Show the mechanism of the reaction.
CAN'T COPY THE FIGURE

Nicholas Sacco

Numerade Educator

Problem 37

Draw resonance forms for the purple anion obtained by reaction of ninhydrin with an $\alpha$ -amino acid (Problem 26.36 ).

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 38

Write full structures for the following peptides:
(a) C-H-E-M
(b) P-E-P-T-I-D-E

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 39

Propose two structures for a tripeptide that gives Leu, Ala, and Phe on hydrolysis but does not react with phenyl isothiocyanate.

Ronald Prasad

Numerade Educator

Problem 40

Show the steps involved in a synthesis of Phe-Ala-Val using the Merrifield procedure.

Zubair Abdulla

Numerade Educator

Problem 41

Draw the structure of the PTH derivative product you would obtain by Edman degradation of the following peptides:
(a) I-L-P-F
(b) D-T-S-G-A

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 42

Which amide bonds in the following polypeptide are cleaved by trypsin? By chymotrypsin?
$$Phe-Leu-Met-Lys-Tyr-Asp-Gly-Gly-Arg-Val-Ile-Pro-Tyr$$

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 43

What kinds of reactions do the following classes of enzymes catalyze?
(a) Hydrolases
(b) Lyases
(c) Transferases

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 44

Which of the following amino acids are more likely to be found on the outside of a globular protein, and which on the inside? Explain.
(a) Valine
(b) Aspartic acid
(c) Phenylalanine
(d) Lysine

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 45

Leuprolide is a synthetic nonapeptide used to treat both endometriosis in women and prostate cancer in men.
(a) Both C-terminal and N-terminal amino acids in leuprolide have been structurally modified. Identify the modifications.
(b) One of the nine amino acids in leuprolide has D stereochemistry rather than the usual $L$. Which one?
(c) Write the structure of leuprolide using both one- and three-letter abbreviations.
(d) What charge would you expect leuprolide to have at neutral $\mathrm{pH} ?$
CAN'T COPY THE FIGURE

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 46

The $\alpha$ -helical parts of myoglobin and other proteins stop whenever a proline residue is encountered in the chain. Why is proline never present in a protein $\alpha$ -helix?

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 47

The chloromethylated polystyrene resin used for Merrifield solid-phase peptide synthesis is prepared by treatment of polystyrene with chloromethyl methyl ether and a Lewis acid catalyst. Propose a mechanism for the reaction.
CAN'T COPY THE FIGURE

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 48

An Fmoc protecting group can be removed from an amino acid by treatment with the amine base piperidine. Propose a mechanism.
CAN'T COPY THE FIGURE

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 49

Proteins can be cleaved specifically at the amide bond on the carboxyl side of methionine residues by reaction with cyanogen bromide, BrC=N.
CAN'T COPY THE FIGURE
The reaction occurs in several steps:
(a) The first step is a nucleophilic substitution reaction of the sulfur on the methionine side chain with BrCN to give a cyanosulfonium ion, $\left[\mathrm{R}_{2} \mathrm{SCN}\right]^{+} .$ Show the structure of the product, and propose a mechanism for the reaction.
(b) The second step is an internal $S_{N} 2$ reaction, with the carbonyl oxygen of the methionine residue displacing the positively charged sulfur leaving group and forming a five-membered ring product. Show the structure of the product and the mechanism of its formation.
(c) The third step is a hydrolysis reaction to split the peptide chain. The carboxyl group of the former methionine residue is now part of a lactone (cyclic ester) ring. Show the structure of the lactone product and the mechanism of its formation.
(d) The final step is a hydrolysis of the lactone to give the product shown. Show the mechanism of the reaction.

Lainey Roebuck

Numerade Educator

Problem 50

A clever new method of peptide synthesis involves formation of an amide bond by reaction of an $\alpha$ -keto acid with an $N$ -alkylhydroxylamine:
CAN'T COPY THE FIGURE
The reaction is thought to occur by nucleophilic addition of the N-alkylhydroxylamine to the keto acid as if forming an oxime (Section 19.8 ), followed by decarboxylation and elimination of water. Show the mechanism.

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 51

Arginine, the most basic of the 20 common amino acids, contains a guanidino functional group in its side chain. Explain, using resonance structures to show how the protonated guanidino group is stabilized.
CAN'T COPY THE FIGURE

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 52

Cytochrome $c$ is an enzyme found in the cells of all aerobic organisms. Elemental analysis of cytochrome $c$ shows that it contains $0.43 \%$ iron. What is the minimum molecular weight of this enzyme?

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 53

Evidence for restricted rotation around amide CO-N bonds comes from NMR studies. At room temperature, the $^{1} \mathrm{H}$ NMR spectrum of $N, N$ -dimethylformamide shows three peaks: 2.9 \& (singlet, 3 H), 3.0 \& (singlet, 3 H),
$8.0 \delta(\text { singlet, } 1 \mathrm{H}) .$ As the temperature is raised, however, the two singlets at
2.98 and 3.08 slowly merge. At $180^{\circ} \mathrm{C},$ the $^{1} \mathrm{H}$ NMR spectrum shows only two peaks: $2.95 . \delta$ (singlet, $6 \mathrm{H}$ ) and 8.08 (singlet, 1 H). Explain this temperature-dependent behavior.
CAN'T COPY THE FIGURE

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 54

Propose a structure for an octapeptide that shows the composition Asp, Gly, Leu, Phe, Pro_, Val on amino acid analysis. Edman analysis shows a glycine N-terminal group, and leucine is the C-terminal group. Acidic hydrolysis gives the following fragments:
$$Val-Pro-Leu, Gly, Gly-Asp-Phe-Pro, Phe-Pro-Val$$

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 55

Look up the structure of human insulin (page 1057 ), and indicate where in each chain the molecule is cleaved by trypsin and chymotrypsin.

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 56

What is the structure of a nonapeptide that gives the following fragments when cleaved?
Trypsin cleavage: Val-Val-Pro-Tyr-Leu-Arg, Ser-Ile-Arg
Chymotrypsin cleavage: Leu-Arg, Ser-Ile-Arg-Val-Val-Pro-Tyr

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 57

Oxytocin, a nonapeptide hormone secreted by the pituitary gland, functions by stimulating uterine contraction and lactation during childbirth. Its sequence was determined from the following evidence:
1. Oxytocin is a cyclic compound containing a disulfide bridge between two cysteine residues.
2. When the disulfide bridge is reduced, oxytocin has the constitution Asn, Cys $_{2},$ Gln, Gly, Ile, Leu, Pro, Tyr.
3. Partial hydrolysis of reduced oxytocin yields seven fragments: Asp-Cys, Ile-Glu, Cys-Tyr, Leu-Gly, Tyr-lle-Glu, Glu-Asp-Cys, Cys-Pro-Leu.
4. Gly is the C-terminal group.
5. Both Glu and Asp are present as their side-chain amides (Gin and Asn) rather than as free side-chain acids. What is the amino acid sequence of reduced oxytocin? What is the structure
of oxytocin itself?

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 58

Aspartame, a nonnutritive sweetener marketed under such trade names as Equal, NutraSweet, and Canderel, is the methyl ester of a simple dipeptide, Asp-Phe-OCH $_{3}$
(a) Draw the structure of aspartame.
(b) The isoelectric point of aspartame is $5.9 .$ Draw the principal structure present in aqueous solution at this pH.
(c) Draw the principal form of aspartame present at physiological $\mathrm{pH}=7.3$.

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 59

Refer to Figure 26.4 on page 1060 and propose a mechanism for the final step in the Edman degradation - the acid-catalyzed rearrangement of the ATZ derivative to the PTH derivative.

Alma Victoriano

Alma Victoriano

North Carolina State University

Problem 60

Amino acids are metabolized by a transamination reaction in which the
-NH $_{2}$ group of the amino acid changes places with the keto group of an $\alpha$ -keto acid. The products are a new amino acid and a new $\alpha$ -keto acid. Show the product from transamination of isoleucine.

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 61

The first step in the biological degradation of histidine is formation of a 4-methylideneimidazol-S-one (MIO) by cyclization of a segment of the peptide chain in the histidine ammonia lyase enzyme. Propose a mechanism.
CAN'T COPY THE FIGURE

Dalton Hilovsky

Dalton Hilovsky

Numerade Educator

Problem 62

The first step in the biological degradation of lysine is reductive amination with $\alpha$ -ketoglutarate to give saccharopine. Nicotinamide adenine dinucleotide phosphate (NADPH), a relative of NADH, is the reducing agent. Show the mechanism.
CAN'T COPY THE FIGURE

Lottie Adams

Numerade Educator