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Chapter 5: Problem 10

Describe the synthesis of the dipeptide Lys-Ala by Merrifield's solidphase chemical method of peptide synthesis. What pitfalls might be encountered if you attempted to add a leucine residue to Lys-Ala to make a tripeptide?

Short Answer

Expert verified
The Merrifield method for synthesizing Lys-Ala involves attaching Ala to a solid phase resin, removing N-terminal protection, coupling Lys with its alpha-amino group protected, and finally cleaving from the resin and removing side-chain protecting groups. Adding leucine could encounter pitfalls such as incomplete coupling or side reactions, hence necessitating steps such as double coupling and capping.

Step by step solution

01

Attachment of C-terminal Amino Acid

Attach the C-terminal amino acid, in this case, alanine to a resin bead using a linker. The reaction creates a polystyrene support with a linker molecule and the protected C-terminal amino acid alanine.
02

Deprotection or Deblocking

Remove the alpha-amino group protection to expose the reactive amino group. This is done by washing the resin in a solution containing a compound such as trifluoroacetic acid (TFA), which cleaves the protective group.
03

Coupling of next Amino Acid

Couple the next amino acid (Lysine, with its alpha-amino group protected) to alanine by washing the resin with a solution of the protected amino acid in activation reagent (e.g., benzotriazol-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate, or BOP). This results in the formation of a peptide bond.
04

Repeat Steps 2 and 3 for Necessary Length

Repeat the deprotection and coupling steps (Steps 2 and 3) until the desired peptide chain length is obtained (in this case, the chain has now a Lys-Ala dipeptide).
05

Cleavage from Resin and Final Deprotection

Once the desired peptide sequence is obtained, the peptide needs to be cleaved from the resin and the side chain protection groups need to be removed. This is typically done using a cleavage cocktail (e.g., trifluoroacetic acid (TFA) with water and triisopropylsilane). This gives the final dipeptide.
06

Additional Step: Attachment of Leucine Residue

To create a tripeptide by adding leucine, repeat the deprotection and coupling process. However, there might be a pitfall. One common issue can be incomplete coupling leading to deletion sequences. Also, side reactions such as aspartimide formation, diketopiperazine formation, etc. can occur. To avoid these problems, double coupling, capping steps and use of appropriate protection strategies will be needed.

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Most popular questions from this chapter

The human insulin receptor substrate- 1 (IRS-1) is designated protein \(\mathrm{P} 35568\) in the protein knowledge base on the ExPASy Web site (http://us.expasy.org/). Go to the PeptideMass tool on this Web site and use it to see the results of trypsin digestion of IRS-1. How many amino acids does IRS-1 have? What is the average molecular mass of IRS-1? What is the amino acid sequence of the tryptic peptide of IRS-1 that has a mass of \(1741.9629 ?\)

Amino acid analysis of an octapeptide revealed the following composition: \(\begin{array}{llllll}\text { 2 Arg } & \text { 1 Gly } & \text { 1 Met } & \text { 1 Trp } & \text { 1 Tyr } & \text { 1 Phe } & \text { 1 Lys }\end{array}\) The following facts were observed: a. Edman degradation gave b. CNBr treatment yielded a pentapeptide and a tripeptide containing phenylalanine. c. Chymotrypsin treatment yielded a tetrapeptide containing a C-terminal indole amino acid and two dipeptides. d. Trypsin treatment yielded a tetrapeptide, a dipeptide, and free Lys and Phe. e. Clostripain yielded a pentapeptide, a dipeptide, and free Phe. What is the amino acid sequence of this octapeptide?

Proteases such as trypsin and chymotrypsin cleave proteins at different sites, but both use the same reaction mechanism. Based on your knowledge of organic chemistry, suggest a "universal" protease reaction mechanism for hydrolysis of the peptide bond.

Amino acid analysis of a decapeptide revealed the presence of the following products: \(\begin{array}{lllll}\mathrm{NH}_{4}^{+} & \text {Asp } & \text { Glu } & \text { Tyr } & \text { Arg } \\ \text { Met } & \text { Pro } & \text { Lys } & \text { Ser } & \text { Phe }\end{array}\) The following facts were observed: a. Neither carboxypeptidase \(A\) or \(B\) treatment of the decapeptide had any effect. b. Trypsin treatment yielded two tetrapeptides and free Lys. c. Clostripain treatment yielded a tetrapeptide and a hexapeptide. d. Cyanogen bromide treatment yielded an octapeptide and a dipeptide of sequence NP (using the one-letter codes). e. Chymotrypsin treatment yielded two tripeptides and a tetrapeptide. The N-terminal chymotryptic peptide had a net charge of -1 at neutral \(\mathrm{pH}\) and a net charge of -3 at pH 12 f. One cycle of Edman degradation gave the PTH derivative What is the amino acid sequence of this decapeptide?

Amino acid analysis of an oligopeptide 7 residues long gave \(\begin{array}{lllll}\text { Asp } & \text { Leu } & \text { Lys } & \text { Met } & \text { Phe } & \text { Tyr }\end{array}\) The following facts were observed: a. Trypsin treatment had no apparent effect. b. The phenylthiohydantoin released by Edman degradation was c. Brief chymotrypsin treatment yielded several products, including a dipeptide and a tetrapeptide. The amino acid composition of the tetrapeptide was Leu, Lys, and Met. d. Cyanogen bromide treatment yielded a dipeptide, a tetrapeptide, and free Lys. What is the amino acid sequence of this heptapeptide?
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