Amino Acids, Peptides and Proteins | Organic Chemistry 3

Amino acids, peptides and proteins are studied in this chapter: structure and properties of amino acids, synthesis of amino acids (Hell-Volhard-Zelinsky , Gabriel and Strecker synthesis), structure and properties of peptides and proteins, amino acids sequencing, synthesis of polypeptides, 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. 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
 

pI = pKa COOH + pKa NH22

Synthesis of Amino Acids

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

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

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:

Synthesis of Polypeptides

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:

Merrifield Solid-Phase Peptide Synthesis

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: