Amino Acids, Peptides and Proteins | Organic Chemistry 3

Amino acids: carboxylic acids bearing an amine group

α-amino acids (or 2-amino acids): amine group on the α-carbon. These are the most common amino acids in nature and the α-carbon has the S configuration:

Properties of amino acids:

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
 

$\mathrm{pI} = \frac{\mathrm{pKa}{ }_{\mathrm{COOH}} + \mathrm{pKa}{ }_{\mathrm{NH}2}}{2}$

Hell-Volhard-Zelinsky Synthesis:

Mechanism:

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 are polypeptides (polymers of α-amino acids). 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 (left) to the carboxy end (right). They are organized in 4 different structures:

• primary structure ⇒ 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 is a technique for determining the primary structure of polypeptides
 

1. Purification of the polypeptide:
   
   gel-filtration chromatography, ion-exchange chromatography, electrophoresis ...
    
2. Determination of which the amino acids are present
   
   - complete hydrolysis
   
   - amino acid analysis (amino acid analyzer)
    
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:
   

The synthesis of polypeptides consists in a coupling between an amino-protected amino acid and a carboxy-protected amino acid:

Mechanism:

• Protection of the carboxy group: esterification
• Protection and deprotection of the amino group:

The synthesis of polypeptides 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:

1. Cycles of coupling and deprotection:
   
   Attachment of protected amino acid:
   
   
   
   Deprotection of amino terminus:
   
   
    
2. At the end of the synthesis, disconnection from polymer: