Amino Acids, Peptides and Proteins | Organic Chemistry 3

The Amino Acids, Peptides and Proteins are studied in this chapter : the structure and properties of amino acids, the synthesis of amino acids (Hell-Volhard-Zelinsky , Gabriel and Strecker synthesis), the structure and properties of peptides and proteins, the amino acids sequencing, the synthesis of polypeptides, the Merrifield solid-phase peptide synthesis.

Structure and Properties of Amino Acids

Amino acids = carboxylic acids bearing an amine group.
α-amino acids (or 2-amino acids) = amine group on the α-carbon.
They are the most common amino acids in nature and the α-carbon has the S configuration.


 

 

Amine (pKa ~ 9-10) and carboxylic acid (pKa ~ 2-3) groups ⇒ amino acids are both basic and acidic.
The structure of an amino acid depends on the pH:
 

 

Isoelectric pH (or isoelectric point pI) = pH with the maximum number of amino acids with net zero charge.
 

pI = pKa COOH + pKa NH22

Synthesis of Amino Acids

Hell-Volhard-Zelinsky Synthesis:
 


 

 

Gabriel Synthesis:
 


Mechanism:

 


Strecker synthesis:
 

 


All these methods produce amino acids in racemic form.
Optically pure amino acids can be obtained by:
- resolution of a racemic mixture (resolution of their diastereomeric salts)
- enantioselective formation of the C2 stereocenter

Peptides and Proteins

Peptides and Proteins are polypeptides = polymers of α-amino acids
The polypeptides are formed by repeated reaction between COOH and NH2 to form amide bonds called peptide bonds.

 

 

Polypeptides are characterized by their sequence of amino acid from the amino end (at the left) to the carboxy end (at the right).


Polypeptides are organized in 4 different structures:

- primary structure ⇒ the sequence of amino acids
- secondary structure (pleated sheet + α helix) ⇒ folding of the primary structure
- tertiary structure (pleated sheet + α helix) ⇒ further folding and coiling
- quaternary structure ⇒ aggregation of several polypeptides

Amino Acids Sequencing

Amino Acids Sequencing = Determination of primary structure

 

Step 1: purification of the polypeptide

gel-filtration chromatography, ion-exchange chromatography, electrophoresis ...


Step 2: determination of which the amino acids are present

- complete hydrolysis

- amino acid analysis (amino acid analyzer)


Step 3: sequencing from the amino end to the carboxy end

Repeated Edman degradation ⇒ access to the sequence of short polypeptides
For long polypeptides: cleavage with enzymes then Edman degradation

Edman Degradation:

Synthesis of Polypeptides

Polypeptides synthesis = coupling between an amino-protected amino acid and a carboxy-protected amino acid:

 

 

Protection of the carboxy group ⇒ esterification.

Protection and Deprotection of the amino group:
 

Merrifield Solid-Phase Peptide Synthesis

Polypeptide synthesis has been automated: solid-phase synthesis using a solid support of polystyrene
⇒ a carboxy-anchored peptide chain is built up from amino protected monomers.

Mechanism: cycles of coupling and deprotection.
At the end: disconnection from polymer.

 

Attachment of protected amino acid:
 

 

Deprotection of amino terminus:
 

 

Disconnection from polymer: