Histidine is an important catalytic residue found at the

Problem 30P Show how you would synthesize Leu-Gly-Ala-Val-Phe starting with Boc-Ala-Val-Phe— P .

Suggest how you would separate the free ?-amino acid from its acylated ? enantiomer in Figure 24-5.

Show how you would synthesize any of the standard amino acids from each starting material. You may use any necessary reagents. Equation Transcription: Text Transcription: (CH_3)_{2}CH-C-COOH CH_{3}-CH-CH_{2}-COOH CH_{2}CH_{3} (CH_{3})_{2}CH-CH_{2}-CHO CH_{2}Br

Suggest a method for the synthesis of the unnatural D enantiomer of alanine from the readily available L enantiomer of lactic acid. \(\mathrm{CH}_{3}-\mathrm{CHOH}-\mathrm{COOH}\) lactic acid Equation Transcription: Text Transcription: CH_3-CHOH-COOH

Problem 13P (a) Show how you would use a Strecker synthesis to make phenylalanine. (b) Propose a mechanism for each step in the synthesis in part (a).

Problem 14P Show how you would use a Strecker synthesis to make (a) leucine (b) valine (c) aspartic acid

Problem 36SP Show how you would convert alanine to the following derivatives. Show the structure of the product in each case. (a) alanine isopropyl ester (b) N-benzoylalanine (c) N-benzyloxycarbonyl alanine (d) tert-butyloxycarbonyl alanine

Problem 29P Propose a mechanism for the coupling of acetic acid and aniline using DCC as a coupling agent.

Problem 19P Use resonance forms to show delocalization of the negative charge in the Ruhemann’s purple anion.

Draw the complete structures of the following peptides: (a) Thr-Phe-Met (b) serylarginylglycylphenylalanine (c) IMQDK (d) ELVIS

Problem 21P Draw the structure of the phenylthiohydantoin derivatives of (a) alanine (b) tryptophan (c) lysine (d) proline

The following structure is drawn in an unconventional manner. (a) Label the N terminus and the C terminus. (b) Label the peptide bonds. (c) Identify and label each amino acid present. (d) Give the full name and the abbreviated name. Equation Transcription: Text Transcription: CH_{3} CH_{3}CH_{2}-CH-CH-NH-C-CH-CH_{2}CH_{2}-C-NH CONH_{2} NH-CO-CH_{2}NH_{2}NH_{2}

Problem 42SP Aspartame (Nutrasweet®) is a remarkably sweet-tasting dipeptide ester. Complete hydrolysis of aspartame gives phenyl alanine, aspartic acid, and methanol. Mild incubation with carboxypeptidase has no effect on aspartame. Treatment of aspartame with phenyl isothiocyanate, followed by mild hydrolysis, gives the phenylthiohydantoin of aspartic acid.Propose a structure for aspartame.

A molecular weight determination has shown that an unknown peptide is a pentapeptide, and an amino acid analysis shows that it contains the following residues: one Gly, two Ala, one Met, one Phe. Treatment of the original pentapeptide with carboxypeptidase gives alanine as the first free amino acid released. Sequential treatment of the pentapeptide with phenyl isothiocyanate followed by mild hydrolysis gives the following derivatives: Equation Transcription: Text Transcription: Ph-N NH CH_{2}Ph PH-N NH CH_{3} PH-N NH

Problem 10P Show how you would use bromination followed by amination to synthesize the following amino acids. (a) glycine (b) leucine (c) glutamic acid

Problem 11P Show how the Gabriel–malonic ester synthesis could be used to make (a) valine (b) phenylalanine (c) glutamic acid (d) leucine

Problem 12P The Gabriel–malonic ester synthesis uses an aminomalonic ester with the amino group protected as a phthalimide. A variation has the amino group protected as an acetamido group. Propose how you might use an acetamidomalonic ester synthesis to make phenylalanine.

Problem 31P Show how solid-phase peptide synthesis would be used to make Ile-Gly-Asn.

Problem 33SP Draw the complete structure of the following peptide. Ser-Gln-Met.NH2

Predict the products of the following reactions. Equation Transcription: Text Transcription: Ile OH OH Ph-CH_{2}-O-C-NH-CH-COOH CH_{3} H_{2}, Pd Lys+excess (CH_{3}CO)_{2}O{rightarrow} Ac_{2}O H_{2}O CHO CH_{3}CH_{2}-CH-CH_{3} NH_{3}, HCN H_{2}O H_{3}O^+ Br_{2}/PBr_{3}{rightarrow} (g)+excess NH_{3}{rightarrow}

Sometimes chemists need the unnatural D enantiomer of an amino acid, often as part of a drug or an insecticide. Most L-amino acids are isolated from proteins, but the D-amino acids are rarely found in natural proteins. D-amino acids can be synthesized from the corresponding L-amino acids. The following synthetic scheme is one of the possible methods. (a) Draw the structures of intermediates 1 and 2 in this scheme. (b) How do we know that the product is entirely the unnatural D configuration? Equation Transcription: Text Transcription: COOH H_{2}N NaNO_{2} HCl NaN_{3} H_{2} Pd COOH NH_{2}

Problem 16P Propose a mechanism for the acid-catalyzed hydrolysis of phenylalanine ethyl ester.

Problem 17P Give equations for the formation and hydrogenolysis of glutamine benzyl ester.

Problem 18P Give equations for the formation and hydrogenolysis of N-benzyloxycarbonyl methionine.

Problem 38SP Show how you would use the Gabriel–malonic ester synthesis to make histidine. What stereochemistry would you expect in your synthetic product?

Problem 39SP Show how you would use the Strecker synthesis to make tryptophan. What stereochemistry would you expect in your synthetic product?

Problem 40SP Show how you would use the Strecker synthesis to make tryptophan. What stereochemistry would you expect in your synthetic product?

Problem 7P Draw the electrophoretic separation of Ala, Lys, and Asp at pH 9.7.

Problem 8P Draw the electrophoretic separation of Trp, Cys, and His at pH 6.0.

Problem 9P Show how the following amino acids might be formed in the laboratory by reductive amination of the appropriate ?- ketoacid. (a) alanine (b) leucine (c) serine (d) glutamine

Problem 28P Show how the solution-phase synthesis would be used to synthesize Ile-Gly-Asn.

Problem 50SP Glutathione (GSH) is a tripeptide that serves as a mild reducing agent to detoxify peroxides and maintain the cysteine residues of hemoglobin and other red blood cell proteins in the reduced state. Complete hydrolysis of glutathione gives Gly, Glu, and Cys. Treatment of glutathione with carboxypeptidase gives glycine as the first free amino acid released. Treatment of glutathione with 2,4-dinitrofluorobenzene (Sanger reagent, Problem 24-23, page 1180), followed by complete hydrolysis, gives the 2,4-dinitrophenyl derivative of glutamic acid. Treatment of glutathione with phenyl isothiocyanate does not give a recognizable phenylthiohydantoin, however. (a) Propose a structure for glutathione consistent with this information. Why would glutathione fail to give a normal product from Edman degradation, even though it gives a normal product from the Sanger reagent followed by hydrolysis? (b) Oxidation of glutathione forms glutathione disulfide (GSSG). Propose a structure for glutathione disulfide, and write a balanced equation for the reaction of glutathione with hydrogen peroxide.

Problem 51SP Complete hydrolysis of an unknown basic decapeptide gives Gly, Ala, Leu, Ile, Phe, Tyr, Glu, Arg, Lys, and Ser. Terminal residue analysis shows that the N terminus is Ala and the C terminus is Ile. Incubation of the decapeptide with chymotrypsin gives two tripeptides, A and B, and a tetrapeptide, C. Amino acid analysis shows that peptide A contains Gly, Glu, Tyr, and NH3; peptide B contains Ala, Phe, and Lys; and peptide C contains Leu, Ile, Ser, and Arg. Terminal residue analysis gives the following results. N terminus C terminus A Gln Tyr B Ala Phe C Arg Ile Incubation of the decapeptide with trypsin gives a dipeptide D, a pentapeptide E, and a tripeptide F. Terminal residue analysis of F shows that the N terminus is Ser, and the C terminus is Ile. Propose a structure for the decapeptide and for fragments A through F.

There are many methods for activating a carboxylic acid in preparation for coupling with an amine. The following method converts the acid to an N-hydroxysuccinimide (NHS) ester. (a) Explain why an NHS ester is much more reactive than a simple alkyl ester. (b) Propose a mechanism for the reaction shown. (c) Propose a mechanism for the reaction of the NHS ester with an amine, \(\mathrm{R}-\mathrm{NH}_{2}\). Equation Transcription: Text Transcription: (NHS) OH F_{3}C O-N Et_{3}N O-N F_{3}C OH NHS NHS R-NH_{2}

Problem 1P Draw three-dimensional representations of the following amino acids. (a) L-phenylalanine (b) L-histidine (c) D-serine (d) L-tryptophan

Most naturally occurring amino acids have chirality centers (the asymmetric carbon atoms) that are named (S) by the Cahn–Ingold–Prelog convention (Section 5-3). The common naturally occurring form of cysteine has a chirality center that is named (R), however. (a) What is the relationship between (R)-cysteine and (S)-alanine? Do they have the opposite three-dimensional configuration (as the names might suggest) or the same configuration? (b) (S)-alanine is an L-amino acid (Figure 24-2). Is (R)-cysteine a D-amino acid or an L-amino acid?

Problem 3P The herbicide glyphosate (Roundup®) kills plants by inhibiting an enzyme needed for synthesis of phenylalanine. Deprived of phenylalanine, the plant cannot make the proteins it needs, and it gradually weakens and dies. Although a small amount of glyphosate is deadly to a plant, its human toxicity is quite low. Suggest why this powerful herbicide has little effect on humans.

Show the third and fourth steps in the sequencing of oxytocin. Use Figure 24-14 as a guide.

Problem 24P Show where trypsin and chymotrypsin would cleave the following peptide. Tyr-Ile-Gln-Arg-Leu-Gly-Phe-Lys-Asn-Trp-Phe-Gly-Ala-Lys-Gly-Gln-Gln . NH2

Problem 23P The Sanger method for N-terminus determination is a less common alternative to the Edman degradation. In the Sanger method, the peptide is treated with the Sanger reagent, 2,4-dinitrofluorobenzene, and then hydrolyzed by reaction with 6 M aqueous HCl. The N-terminal amino acid is recovered as its 2,4-dinitrophenyl derivative and identified.

Problem 44SP Show the steps and intermediates in the synthesis of Leu-Ala-Phe (a) by the solution-phase process. (b) by the solid-phase process.

Problem 45SP Using classical solution-phase techniques, show how you would synthesize Ala-Val and then combine it with Ile-Leu-Phe to give Ile-Leu-Phe-Ala-Val.

Peptides often have functional groups other than free amino groups at the N terminus and other than carboxyl groups at the C terminus. (a) A tetrapeptide is hydrolyzed by heating with 6 M HCl, and the hydrolysate is found to contain Ala, Phe, Val, and Glu. When the hydrolysate is neutralized, the odor of ammonia is detected. Explain where this ammonia might have been incorporated in the original peptide. (b) The tripeptide thyrotropic hormone releasing factor (TRF) has the full name pyroglutamylhistidylprolinamide. The structure appears here. Explain the functional groups at the N terminus and at the C terminus. (c) On acidic hydrolysis, an unknown pentapeptide gives glycine, alanine, valine, leucine, and isoleucine. No odor of ammonia is detected when the hydrolysate is neutralized. Reaction with phenyl isothiocyanate followed by mild hydrolysis gives no phenylthiohydantoin derivative. Incubation with carboxypeptidase has no effect. Explain these findings. Equation Transcription: Text Transcription: 6 M HCl (TRF) H_2 H_2 H_{2}C CH-C-N-C-C-N CH_2 CH_2 HC CH_2 H_{2}N

Problem 4P Draw the structure of the predominant form of (a) isoleucine at pH 11 (b) proline at pH 2 (c) arginine at pH 7 (d) glutamic acid at pH 7 (e) a mixture of alanine, lysine, and aspartic acid at (i) pH 6; (ii) pH 11; (iii) pH 2

Problem 5P Draw the resonance forms of a protonated guanidino group, and explain why arginine has such a strongly basic isoelectric point.

Problem 6P Although tryptophan contains a heterocyclic amine, it is considered a neutral amino acid. Explain why the indole nitrogen of tryptophan is more weakly basic than one of the imidazole nitrogens of histidine.

Problem 25P After treatment with peroxyformic acid, the peptide hormone vasopressin is partially hydrolyzed. The following fragments are recovered. Propose a structure for vasopressin. Phe-Gln-Asn Pro-Arg-Gly . NH2 Cys-Tyr-Phe Asn-Cys-Pro-Arg Tyr-Phe-Gln-Asn

Problem 27P Show how you would synthesize Ala-Val-Phe-Gly-Leu starting with Z-Ala-Val-Phe.

Problem 26P Give complete mechanisms for the formation of Z-Ala, its activation by ethyl chloroformate, and the coupling with valine.

Lipoic acid is often found near the active sites of enzymes, usually bound to the peptide by a long, flexible amide linkage with a lysine residue. (a) Is lipoic acid a mild oxidizing agent or a mild reducing agent? Draw it in both its oxidized and reduced forms. (b) Show how lipoic acid might react with two Cys residues to form a disulfide bridge. (c) Give a balanced equation for the hypothetical oxidation or reduction, as you predicted in part (a), of an aldehyde by lipoic acid. Equation Transcription: Text Transcription: COOH S-S S-S NH CH C=O R-C-H S-S COOH H_{2}O

Problem 48SP Histidine is an important catalytic residue found at the active sites of many enzymes. In many cases, histidine appears to remove protons or to transfer protons from one location to another. (a) Show which nitrogen atom of the histidine heterocycle is basic and which is not. (b) Use resonance forms to show why the protonated form of histidine is a particularly stable cation. (c) Show the structure that results when histidine accepts a proton on the basic nitrogen of the heterocycle and then is deprotonated on the other heterocyclic nitrogen. Explain how histidine might function as a pipeline to transfer protons between sites within an enzyme and its substrate.

Problem 49SP Metabolism of arginine produces urea and the rare amino acid ornithine. Ornithine has an isoelectric point close to 10. Propose a structure for ornithine.