PHENOLIC OXIDATIVE COUPLING
345
Too little thyroxine may lead to cretinism in children, with poor growth and mental deficiency, or myxoedema
in adults, resulting in a slowing down of all body processes.
Thyroxine is actually a simple derivative of the aromatic amino acid tyrosine (see Section 13.1), but is believed
to be derived by degradation of a larger protein molecule containing tyrosine residues. One hypothesis for their
formation invokes suitably placed tyrosine residues in the protein thyroglobulin being iodinated to di-iodotyrosine.
These residues then react together by phenolic oxidative coupling.
Coupling allows formation of an ether linkage, but since the position para to the original phenol is already
substituted, it does not allow rearomatization through simple keto–enol tautomerization. Instead, rearomatization
is achieved by an E2 elimination reaction in the side-chain of one residue, resulting in cleavage of the ring from
the side-chain. This is feasible, since the phenolate anion is a good leaving group. Thyroxine is then released
from the protein by hydrolytic cleavage of peptide (amide) bonds (see Box 13.5).
345
Too little thyroxine may lead to cretinism in children, with poor growth and mental deficiency, or myxoedema
in adults, resulting in a slowing down of all body processes.
Thyroxine is actually a simple derivative of the aromatic amino acid tyrosine (see Section 13.1), but is believed
to be derived by degradation of a larger protein molecule containing tyrosine residues. One hypothesis for their
formation invokes suitably placed tyrosine residues in the protein thyroglobulin being iodinated to di-iodotyrosine.
These residues then react together by phenolic oxidative coupling.
Coupling allows formation of an ether linkage, but since the position para to the original phenol is already
substituted, it does not allow rearomatization through simple keto–enol tautomerization. Instead, rearomatization
is achieved by an E2 elimination reaction in the side-chain of one residue, resulting in cleavage of the ring from
the side-chain. This is feasible, since the phenolate anion is a good leaving group. Thyroxine is then released
from the protein by hydrolytic cleavage of peptide (amide) bonds (see Box 13.5).