Dissociation between Degree of Iodination and Iodoamino Acid Distribution in Thyroglobulin*

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Abstract
The iodamino acid distribution in thyroglobulin is largely determined by the degree of iodination of the protein. Apparently the degree of iodination is not the sole determinant of iodoamino acid distribution. This was shown in 2 different incubation systems employing purified thyroid peroxidase, which catalyzes both iodination and coupling in thyroglobulin. In one system, iodination and coupling were measured simultaneously. In the other, coupling alone was measured in the absence of iodination. Formation of both T3 [triiodothyronine] and T4 [thyroxine] was markedly stimulated in both systems by the addition of very low concentrations of free diiodotyrosine (DIT; 0.1-1.0 .mu.M), without a significant change in the degree of iodination. The increase in T3 and T4 was demonstrated both with 131I-labeling and with radioimmunoassay techniques. Formation of T3 was preferentially increased, especially at lower levels of iodination, resulting in an increase in the T3:T4 ratio. Experiments with [14C]DIT indicated that the added DIT was not itself converted to iodothyronines. Its mode of action, therefore, must be through stimulation of intramolecular coupling, involving iodotyrosyl residues within the thyroglobulin polypeptide chains. Although the physiological significance of the in vitro observations with DIT has not been established, the present findings demonstrate that factors other than the degree of iodination of thyroglobulin can markedly affect its hormonal content. Similar factors may exist in vivo which can modulate the thyroid hormone content of thyroglobulin at a given level of iodination.