26 • Additional Problems
26 • Additional Problems
Give the sequence of the following tetrapeptide (yellow = S):
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.
Is the following structure a D amino acid or an L amino acid? Identify it.
Give the sequence of the following tetrapeptide:
The final step is formation of the purple anion. Show the mechanism of the reaction.
The chloromethylated polystyrene resin originally used for Merrifield solid-phase peptide synthesis was prepared by treatment of polystyrene with chloromethyl methyl ether and a Lewis acid catalyst. Propose a mechanism for the reaction.
An Fmoc protecting group can be removed from an amino acid by treatment with the amine base piperidine. Propose a mechanism.
Proteins can be cleaved specifically at the amide bond on the carboxyl side of methionine residues by reaction with cyanogen bromide, BrC≡N.
The reaction occurs in several steps:
The first step is a nucleophilic substitution reaction of the sulfur on the methionine side chain with BrCN to give a cyanosulfonium ion, [R2SCN]+. Show the structure of the product, and propose a mechanism for the reaction.
The second step is an internal SN2 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.
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.
The final step is a hydrolysis of the lactone to give the product shown. Show the mechanism of the reaction.
A clever recent method of peptide synthesis involves formation of an amide bond by reaction of an α-keto acid with an N-alkylhydroxylamine:
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.
Amino Acid Structures and Chirality
Amino Acid Synthesis and Reactions
Peptides and Enzymes
Which amide bonds in the following polypeptide are cleaved by trypsin? By chymotrypsin?
Leuprolide is a synthetic nonapeptide used to treat both endometriosis in women and prostate cancer in men.
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.
Evidence for restricted rotation around amide bonds comes from NMR studies. At room temperature, the 1H NMR spectrum of N,N-dimethylformamide shows three peaks: 2.9 δ (singlet, 3 H), 3.0 δ (singlet, 3 H), and 8.0 δ (singlet, 1 H). As the temperature is raised, however, the two singlets at 2.9 δ and 3.0 δ slowly merge. At 180 °C, the 1H NMR spectrum shows only two peaks: 2.95 δ (singlet, 6 H) and 8.0 δ (singlet, 1 H). Explain this temperature-dependent behavior.
Propose a structure for an octapeptide that shows the composition Asp, Gly2, Leu, Phe, Pro2, 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
Look at the structure of human insulin, and indicate where in each chain the molecule is cleaved by trypsin and chymotrypsin.
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
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, Cys2, Gln, Gly, Ile, Leu, Pro, Tyr.
3. Partial hydrolysis of reduced oxytocin yields seven fragments: Asp-Cys, Ile-Glu, Cys-Tyr, Leu-Gly, Tyr-Ile-Glu, Glu-Asp-Cys, and Cys-Pro-Leu.
4. Gly is the C-terminal group.
5. Both Glu and Asp are present as their side-chain amides (Gln 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?
The first step in the biological degradation of histidine is formation of a 4-methylidene-5-imidazolone (MIO) by cyclization of a segment of the peptide chain in the histidine ammonia lyase enzyme. Propose a mechanism.
The first step in the biological degradation of lysine is reductive amination with α-ketoglutarate to give saccharopine. Nicotinamide adenine dinucleotide phosphate (NADPH), a relative of NADH, is the reducing agent. Show the mechanism.